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Mariusz Z. Ratajczak - One of the best experts on this subject based on the ideXlab platform.

  • A Novel Evidence That Mannan Binding Lectin (MBL) Pathway of Complement Cascade Activation is Involved in Homing and Engraftment of Hematopoietic Stem Progenitor Cells (HSPCs)
    Stem Cell Reviews and Reports, 2020
    Co-Authors: Mateusz Adamiak, Monika Cymer, Krzysztof Anusz, Michał Tracz, Mariusz Z. Ratajczak
    Abstract:

    Delayed homing and engraftment of hematopoietic stem progenitor cells (HSPCs) or even failure to engraft at all is significant clinical problem after hematopoietic transplant. Therefore, in order to develop more efficient homing and engraftment facilitating strategies it is important to learn more about this process. Our team has postulated that myeloablative conditioning for transplantation induces in bone marrow (BM) microenvironment a state of sterile inflammation in which elements of innate immunity activated by radio- or chemotherapy conditioning for transplant play an important role. In frame with this claim we reported that a significant role in this process plays activation of Complement Cascade (ComC). Accordingly, mice that that lack a fifth component (C5) of ComC turned out to engraft poorly with normal syngeneic BM cells as compared to normal control animals. In extension of our previous studies we provide for first time evidence that mannan binding lectin (MBL) pathway is involved in activation of ComC in myeloablated transplant recipient BM and thus plays an important role in homing and engraftment of HSPCs. To support this MBL-KO mice show significant defect in hematopoietic reconstitution after hematopoietic transplantation. This correlates with a decrease in expression of stromal derived factor-1 (SDF-1) and impaired activation of Nlrp3 inflammasome in irradiated BM of these mice.

  • ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking
    Stem Cell Reviews and Reports, 2019
    Co-Authors: Mariusz Z. Ratajczak, Jolanta Kucharska-mazur, Magda Kucia, Janina Ratajczak, Kamila Bujko, Aaron Mack, Alison Domingues, Daniel Pedziwiatr, Henning Ulrich, Jerzy Samochowiec
    Abstract:

    Recent evidence indicates that the occurrence of psychiatric disorders in patients is linked to a local “sterile” inflammation of brain or due to a systemic inflammation process that affects the central nervous system. This is supported by the observation that in peripheral blood of psychotic patients are detectable several mediators and markers of inflammation as well as clinical data on correlations between systemic chronic inflammatory processes and psychiatric disorders. This may explain why some reported anti-inflammatory treatment strategies have beneficial effects on ameliorating psychotic events. In this review we will present a concept that aberrant purinergic signaling and increases in extracellular level of adenosine triphosphate (ATP) in the brain parenchyma may lead to activation of Nlrp3 inflammasome in microglia cells and as a consequence microglia released danger associated molecular pattern (DAMP) proteins activate Complement Cascade (ComC) in mannan binding lectin (MBL) – dependent manner. Activation of ATP-Nlrp3 inflammasome-ComC axis may also orchestrate trafficking of stem cells released from bone marrow into peripheral blood observed in psychotic patients. Based on this, the ATP-Nlrp3 inflammasome-ComC axis may become a target for new therapeutic approaches, which justifies the development and clinical application of efficient anti-inflammatory treatment strategies targeting this axis in psychiatry.

  • NLRP3 inflammasome couples purinergic signaling with activation of the Complement Cascade for the optimal release of cells from bone marrow
    Leukemia, 2019
    Co-Authors: Mariusz Z. Ratajczak, Kamila Bujko, Katarzyna Brzezniakiewicz-janus, Mateusz Adamiak, Arjun Thapa, Anna M Lenkiewicz
    Abstract:

    The mechanisms that regulate egress of hematopoietic stem/progenitor cells (HSPCs) into peripheral blood (PB) in response to stress, inflammation, tissue/organ injury, or administration of mobilization-inducing drugs are still not well understood, and because of the importance of stem cell trafficking in maintaining organism homeostasis, several Complementary pathways are believed to be involved. Our group proposes that mobilization of HSPCs is mainly a result of sterile inflammation in the bone marrow (BM) microenvironment in response to pro-mobilizing stimuli and that during the initiation phase of the mobilization process BM-residing cells belonging to the innate immunity system, including granulocytes and monocytes, release danger-associated molecular pattern molecules (DAMPs, also known as alarmins), reactive oxygen species (ROS), as well as proteolytic and lipolytic enzymes. These factors together orchestrate the release of HSPCs into PB. One of the most important DAMPs released in the initiation phase of mobilization is extracellular adenosine triphosphate, a potent activator of the inflammasome. As a result of its activation, IL-1β and IL-18 as well as other pro-mobilizing mediators, including DAMPs such as high molecular group box 1 (Hmgb1) and S100 calcium-binding protein A9 (S100a9), are released. These DAMPs are important activators of the Complement Cascade (ComC) in the mannan-binding lectin (MBL)-dependent pathway. Specifically, Hmgb1 and S100a9 bind to MBL, which leads to activation of MBL-associated proteases, which activate the ComC and in parallel also trigger activation of the coagulation Cascade (CoaC). In this review, we will highlight the novel role of the innate immunity cell-expressed NLRP3 inflammasome, which, during the initiation phase of HSPC mobilization, couples purinergic signaling with the MBL-dependent pathway of the ComC and, in parallel, the CoaC for optimal release of HSPCs. These data are important to optimize the pharmacological mobilization of HSPCs.

  • Assessment of Complement Cascade Components in Patients With Bipolar Disorder.
    Frontiers in psychiatry, 2018
    Co-Authors: Artur Reginia, Jolanta Kucharska-mazur, Marcin Jabłoński, Marta Budkowska, Barbara Dołȩgowska, Leszek Sagan, Błażej Misiak, Mariusz Z. Ratajczak, Janusz K. Rybakowski, Jerzy Samochowiec
    Abstract:

    Introduction: The immune system is undoubtedly involved in the pathogenesis of various psychiatric disorders, such as schizophrenia, bipolar disorder, or depression. Although its role is not fully understood, it appears that this area of research can help to understand the etiology of mental illness. One of the components of the human immune system is the Complement system, which forms a part of the innate immune response. Physiologically, except for its essential protective role, it is a vital element in the regeneration processes, including neurogenesis. To date, few studies have tried to clarify the role of the Complement Cascade in mental disorders. Materials and Methods: We evaluated concentrations of C3a, C5a, and C5b-9 Complement Cascade components in the peripheral blood of 30 patients suffering from bipolar disorder (BD) for at least 10 years, in euthymia, who were not treated with lithium salts. In addition, we divided our study sample into BD type I (BD-I, 22 persons), and BD type II (BD-II, 8 patients). The control group consisted of 30 healthy volunteers matched for age, sex, BMI, and smoking habits. Results: Compared to healthy controls, BD patients had elevated concentrations of all the investigated components. Furthermore, in patients with BD-II, we observed higher concentrations of C5b-9 as compared to patients with BD-I. However, there was a significant effect of BD diagnosis only on the levels of C3a and C5a but not on the level of C5b-9 after adjustment for potential confounding factors. Conclusions: Increased concentrations of components C3a and C5a of the Complement system in the investigated group as compared to healthy controls suggest involvement of the Complement Cascade in the pathogenesis of BD, and provides further evidence of immune system dysregulation in BD patients.

  • A Circadian Rhythm in both Complement Cascade (ComC) Activation and Sphingosine-1-Phosphate (S1P) Levels in Human Peripheral Blood Supports a Role for the ComC–S1P Axis in Circadian Changes in the Number of Stem Cells Circulating in Peripheral Blood
    Stem Cell Reviews and Reports, 2018
    Co-Authors: Marta Budkowska, Mariusz Z. Ratajczak, Ewa Ostrycharz, Adrianna Wojtowicz, Zuzanna Marcinowska, Jarosław Woźniak, Barbara Dołęgowska
    Abstract:

    The number of hematopoietic stem/progenitor cells (HSPCs) circulating in peripheral blood (PB) is regulated by a circadian rhythm, and more HSPCs circulate in PB in the morning hours than at night. Different mechanisms have been proposed that might regulate this process, including changes in tonus of β-adrenergic innervation of bone marrow (BM) tissue. Our group reported that in mice circadian changes in the number of HSPCs circulating in PB correlates with diurnal activation of the Complement Cascade (ComC) and that the mice deficient in C5 component of ComC (C5-KO mice) do not show circadian changes in the number of circulating HSPCs in PB. We also reported the existence of a gradient between PB and BM of a bioactive phosphosphingolipid, sphingosine-1-phosphate (S1P), which is a major PB chemottractant for BM-residing HSPCs. Based on these observations, we investigated activation of the ComC and the level of S1P in the PB of 66 healthy volunteers. We found that both ComC activation and the S1P level undergo changes in a circadian cycle. While the ComC becomes highly activated during deep sleep at 2 am, S1P becomes activated later, and its highest level is observed at 8 am, which precedes circadian egress of HSPCs from BM into PB. In sum, circadian activation of the ComC–S1P axis releases HSPCs from BM into PB.

Janina Ratajczak - One of the best experts on this subject based on the ideXlab platform.

  • ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking
    Stem Cell Reviews and Reports, 2019
    Co-Authors: Mariusz Z. Ratajczak, Jolanta Kucharska-mazur, Magda Kucia, Janina Ratajczak, Kamila Bujko, Aaron Mack, Alison Domingues, Daniel Pedziwiatr, Henning Ulrich, Jerzy Samochowiec
    Abstract:

    Recent evidence indicates that the occurrence of psychiatric disorders in patients is linked to a local “sterile” inflammation of brain or due to a systemic inflammation process that affects the central nervous system. This is supported by the observation that in peripheral blood of psychotic patients are detectable several mediators and markers of inflammation as well as clinical data on correlations between systemic chronic inflammatory processes and psychiatric disorders. This may explain why some reported anti-inflammatory treatment strategies have beneficial effects on ameliorating psychotic events. In this review we will present a concept that aberrant purinergic signaling and increases in extracellular level of adenosine triphosphate (ATP) in the brain parenchyma may lead to activation of Nlrp3 inflammasome in microglia cells and as a consequence microglia released danger associated molecular pattern (DAMP) proteins activate Complement Cascade (ComC) in mannan binding lectin (MBL) – dependent manner. Activation of ATP-Nlrp3 inflammasome-ComC axis may also orchestrate trafficking of stem cells released from bone marrow into peripheral blood observed in psychotic patients. Based on this, the ATP-Nlrp3 inflammasome-ComC axis may become a target for new therapeutic approaches, which justifies the development and clinical application of efficient anti-inflammatory treatment strategies targeting this axis in psychiatry.

  • The Emerging Link Between the Complement Cascade and Purinergic Signaling in Stress Hematopoiesis
    Frontiers Media S.A., 2018
    Co-Authors: Mariusz Z. Ratajczak, Magda Kucia, Janina Ratajczak, Mateusz Adamiak, William Tse, Wieslaw Wiktor-jedrzejczak
    Abstract:

    Innate immunity plays an important role in orchestrating the immune response, and the Complement Cascade (ComC) is a major component of this ancient defense system, which is activated by the classical-, alternative-, or mannan-binding lectin (MBL) pathways. However, the MBL-dependent ComC-activation pathway has been somewhat underappreciated for many years; recent evidence indicates that it plays a crucial role in regulating the trafficking of hematopoietic stem/progenitor cells (HSPCs) by promoting their egress from bone marrow (BM) into peripheral blood (PB). This process is initiated by the release of danger-associated molecular patterns (DAMPs) from BM cells, including the most abundant member of this family, adenosine triphosphate (ATP). This nucleotide is well known as a ubiquitous intracellular molecular energy source, but when secreted becomes an important extracellular nucleotide signaling molecule and mediator of purinergic signaling. What is important for the topic of this review, ATP released from BM cells is recognized as a DAMP by MBL, and the MBL-dependent pathway of ComC activation induces a state of “sterile inflammation” in the BM microenvironment. This activation of the ComC by MBL leads to the release of several potent mediators, including the anaphylatoxins C5a and desArgC5a, which are crucial for egress of HSPCs into the circulation. In parallel, as a ligand for purinergic receptors, ATP affects mobilization of HSPCs by activating other pro-mobilizing pathways. This emerging link between the release of ATP, which on the one hand is an activator of the MBL pathway of the ComC and on the other hand is a purinergic signaling molecule, will be discussed in this review. This mechanism plays an important role in triggering defense mechanisms in response to tissue/organ injury but may also have a negative impact by triggering autoimmune disorders, aging of HSPCs, induction of myelodysplasia, and graft-versus-host disease after transplantation of histoincompatible hematopoietic cells

  • a novel and pivotal role of the mannose binding lectin mbl pathway of Complement Cascade comc activation in triggering mobilization of hematopoietic stem progenitor cells hspcs
    Blood, 2015
    Co-Authors: Mateusz Adamiak, Janina Ratajczak, Ahmed Abdellatif, Mariusz Z. Ratajczak
    Abstract:

    Background . The Complement Cascade (ComC) is part of the innate immunity system, which is not adaptable and does not change over the course of an individual's lifetime; however, it can be recruited and brought into action by the adaptive immune system. The ComC has several pleiotropic effects, and, as we have previously demonstrated, it is required for mobilization of HSPCs during infection or tissue/organ injuries and responding to pharmacological mobilizing agents ( Blood 2004, 103, 2071-2078 ) . The ComC is activated by three pathways: the classical, alternative, and mannose-binding lectin (MBL) pathways. While a requirement for ComC activation and, in particular, the pivotal role of the distal part of Complement activation and generation of C5 cleavage fragments was previously demonstrated by us ( Leukemia 2009, 23, 2052-2062 ), mice with mutations to components of the classical and alternative pathways in which the distal pathway of C5 activation remained intact did not show impairment of HSPC mobilization ( Leukemia 2010, 24, 1667-1675 ). However, no studies so far have been performed to address the role of the MBL pathway of ComC activation in triggering the mobilization of HSPCs. The MBL pathway is homologous to the classical pathway, but contains opsonin, MBL, and ficolins instead of C1q. MBL functions by pattern recognition, as opsonin binds to mannose residues on the surface of pathogens and certain cells, and activates the MBL-associated serine proteases, MASP-1, and MASP-2, which can then split C4 (into C4a and C4b) and C2 (into C2a and C2b) to form the classical C3-convertase, as in the classical pathway. Interestingly, it is known that ~10% of the population has defective activation of the MBL pathway. Hypothesis. We hypothesized for first time that the MBL ComC-activation pathway is involved in triggering ComC-mediated mobilization of HSPCs and that MBL deficiency results in poor mobilization. Materials and Methods . In our experiments, 2-month-old, MBL-deficient mice (MBL-/-) and normal wild type (WT) littermates were mobilized for 6 days with G-CSF or AMD3100. Following mobilization, we measured in peripheral blood (PB) i) the total number of white blood cells (WBC), ii) the number of circulating clonogenic colony-forming unit granulocyte/macrophage (CFU-GM) progenitors, and iii) the number of Sca-1+ c-kit+ lineage- (SKL) cells. In parallel, we evaluated activation of the MBL pathway in WT animals after administration of G-CSF and AMD3100. Results . We found that pattern recognition by the MBL ComC activation pathway is involved in pharmacological G-CSF- and AMD3100-induced mobilization of HSPCs, and activation of the MBL pathway was confirmed by ELISA in WT animals. As predicted, MBL KO mice were found to be poor mobilizers. Conclusions . We identified a previously unrecognized role of the MBL pathway in triggering ComC activation in the process of HSPC mobilization. This finding explains the pivotal role of the MBL pathway in triggering activation of the proximal part of the ComC and explains why, even with a deficiency in activation of classical and alternative pathway components, mobilization of HSPCs proceeds normally as long as the MBL pathway is intact. On the other hand, if the MBL pathway of the ComC is defective, neither classical nor alternative pathways can trigger optimal mobilization of HSPCs. Taking into consideration that ~10% of normal people are poor activators of the MBL pathway, we are currently investigating whether MBL deficiency correlates with poor mobilization in these patients. Disclosures No relevant conflicts of interest to declare.

  • Mice Deficient in the Fifth Complement Cascade Protein (C5) Do Not Display Circadian Changes in the Number of Circulating Hematopoietic Stem/Progenitor Cells (HSPCs) in Peripheral Blood (PB)—evidence for the Pivotal Role of the Distal Part of the Complement Cascade in Inducing the Circadian Release of HSPCs into PB
    Blood, 2014
    Co-Authors: Sylwia Borkowska, Janina Ratajczak, Malwina Suszynska, Mariusz Z. Ratajczak
    Abstract:

    Introduction . Activation of three ancient serum proteolytic Cascades, the Complement Cascade (ComC), the coagulation Cascade (CoaC), and the fibrynolytic Cascade (FibC), is essential for release of hematopoietic stem progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) during stress- or pharmacology-induced mobilization ( Leukemia 2014, doi:10.1038/leu.2014.115 ). On the other hand, it has been convincingly demonstrated that there is a circadian oscillation in the number of circulating HSPCs in PB, with the peak occurring in the early morning hours and the nadir at night ( Nature 2008, 452, 442-447 ). The timing of this peak has been attributed to the enhanced tonus of the vegetative nervous system in the early morning hours. In support of such a role for the vegetative nervous system, it has been shown that UDP-galactose:ceramide galactosyltransferase-deficient mice, which exhibit aberrant nerve conduction and do not release norepinephrine (NE) into the BM microenvironment, do not mobilize HSPCs. However, by contrast, modification of the sympathetic output, as seen in normal human HSPC volunteer donors receiving NE reuptake inhibitors (NRI) for depression or β2-blockers for hypertension, induces mobilization in a similar manner as normal controls ( Leukemia 2013, 27, 24–31 ). Mobilization in these patients was neither enhanced by NRI administration nor suppressed by β2-blockers, as one would expect based on the murine data reported in the literature. Aim of the study . Since it is known that the ComC, CoaC, and FibC show circadian activation at late/night early morning hours due to deep sleep hypoxia, we became interested in the role of these proteolytic Cascades in the circadian release of HSPCs from the BM into PB. Materials and Methods . To address this important question, we studied the circadian oscillation in the number of circulating HSPCs in C5-deficient (C5 –/– ) mice, which do not activate the distal part of the ComC, unlike their wild type (WT) littermates. Mice were accustomed to alternating periods of 12 hours light and 12 hours darkness. Light was turned on at 6 AM (T0), and the number of circulating white blood cells (WBC), Sca-1 + kit + Lin – HSCs, Sca-1 + Lin – CD45 + HSCs, clonogenic CFU-GM progenitors, and the number of non-hematopoietic Sca-1 + Lin – CD45 – (VSELs) were measured at 7 AM (T1), 11 AM (T5), 7 PM (T13), and 3 AM (T21). At the same time points, we evaluated activation of the ComC (by C5a ELISA), the CoaC (by thrombin/antithrombin ELISA), and the FibC (by plasmin/antiplasmin complex ELISA). Results . We observed circadian changes in the number of circulating WBCs, HSCs, and non-HSCs at T5 in WT but not in C5 –/– animals. This increase in the number of circulating cells in WT animals was preceeded by an increase in C5a concentration in PB at T1 as well as activation of the CoaC and FibC at T21. As expected, C5 –/– mice did not have measurable levels of C5a; however, they displayed an increase in activation of the CoaC and FibC at T21 that was similar to WT. Conclusions . Our study confirms circadian activation of the ComC, CoaC, and FibC in WT animals at late night/early morning hours preceding the release of HSPCs from BM into PB. The fact that we did not observe circadian changes in the number of circulating cells in PB in C5a –/– mice confirms the pivotal role of the ComC in executing circadian release of HSPCs from BM into PB. Moreover, the fact that C5a –/– mice show normal activation of the CoaC and FibC indicates that, of the ancient proteolytic Cascades tested, the ComC is the major player regulating circadian egress of HSPCs. Disclosures No relevant conflicts of interest to declare.

  • studies in c4b deficient mice provide further evidence that Complement Cascade orchestrates the mobilization of hematopoietic stem progenitor cells
    Blood, 2012
    Co-Authors: Anna Janowskawieczorek, Janina Ratajczak, Leah A Marquezcurtis, Danila Leontyev, Donald R Branch, Mariusz Z. Ratajczak
    Abstract:

    Abstract 2316 Introduction: Complement Cascade (CC) and innate immunity have emerged as important modulators of hematopoietic stem/progenitor cell (HSPC) trafficking. We reported that the CC becomes activated in bone marrow (BM) during HSPC mobilization induced by G-CSF or AMD3100 and proposed that the generation of C5a and C5b-C9 (membrane attack complex; MAC) is required for optimal mobilization (Stem Cells 2007; 25:3093; Leukemia 2010; 24:976). While C5a induces a proteolytic microenvironment in BM that attenuates SDF-1-CXCR4 retention signals for HSPC and promotes egress of leucocytes, C5b-C9 (MAC) induces the release of a crucial chemoattractant, sphingosine-1 phosphate (S1P), from red blood cells and augments mobilization of HSPC from BM. On the other hand, C3 cleavage fragments attenuate mobilization by enhancing responsiveness of HSPC to SDF-1 retention signals thus promoting HSPC retention in BM. Thus our findings suggest that mobilization is differently regulated by the proximal and distal parts of CC (upstream and downstream of C3, respectively). We also demonstrated that C3-deficient mice (lacking C3 cleavage fragments) are easy mobilizers whereas C5-deficient mice (lacking C5 cleavage fragments and not generating MAC) mobilize HSPC very poorly (Leukemia 2009; 23:2052). C4 is part of the classical pathway of CC whose activation/cleavage is initiated by C1 and C2, releasing smaller (C4a and C2b) and larger (C4b and C2a) fragments. C2a binds with C4b to form an enzymatic complex termed C3 convertase that cleaves C3 into C3a anaphylatoxin and C3b. Aim of Study: In the present study we investigated the role of C4 in HSPC mobilization and hypothesized that C4-deficient mice are easy mobilizers, supporting the notion that the proximal part of CC is crucial for retention of HSPC in the BM microenvironment. Experimental Approach: We employed 6–8 week old C4b-deficient mice (strain B6.129S-C4b tm1Crr /J from Jackson Laboratory, Bar Harbour, ME) and wild type (WT) littermates. Mice were injected subcutaneously with 250 μg/kg of human recombinant G-CSF (Amgen, Thousand Oaks, CA) or saline (control) daily for 3 days. At 6 h after the last G-CSF injection, the mice were sacrificed and blood was collected from the vena cavae. Mobilization was evaluated by determining the number of leukocytes (WBC) and colony-forming unit granulocyte-macrophages (CFU-GM) circulating in the peripheral blood (PB). We also measured the level of mouse terminal Complement complex C5b-C9 (MAC) in plasma using ELISA (Kamiya) in G-CSF-mobilized and non-mobilized C4b-deficient and WT mice. Results: We found that C4b-deficient mice treated with saline have slightly higher WBC counts than WT mice and that G-CSF induced a greater increase in WBC counts in these mice than in WT mice. Based on CFU-GM counts after G-CSF mobilization, C4b-deficient mice mobilized significantly more HSPCs into PB than WT mice ( p < 0.0065). These observations were consistent in all four experiments performed involving 18–20 mice per experiment. The G-CSF mobilization responses correlated with a greater increase in activation of the distal part of CC in C4b-deficient mice compared to WT mice, as evidenced by C5b-C9 levels evaluated by ELISA. Conclusions: Our data indicate that C4-deficient mice are easy mobilizers, thus supporting a role for the proximal part of CC in retention of HSPC in BM. Furthermore, mobilization of HSPC in C4b-deficient mice correlated with activation of the distal part of CC and generation of C5b-C9 (MAC) suggesting that activation of the distal part of CC is crucial for egress of HSPCs into PB. Moreover, activation of the distal part of CC in C4-deficient mice that have defective activation of the proximal part of CC indicates that C5 may be cleaved in a C3-independent manner by other proteolytic enzymes present in blood plasma. Finally, our data further support that mobilization is part of a more general immune response in which all Complement components, including C4, play a significant role. Disclosures: No relevant conflicts of interest to declare.

Gareth R Howell - One of the best experts on this subject based on the ideXlab platform.

  • deficiency of Complement component c1q prevents cerebrovascular damage and white matter loss in a mouse model of chronic obesity
    bioRxiv, 2020
    Co-Authors: Leah C. Graham, Gareth R Howell, Ileana Soto, Heidi E Kocalis
    Abstract:

    ABSTRACT Age-related cognitive decline and many dementias involve complex interactions of both genetic and environmental risk factors. Recent evidence has demonstrated a strong association of obesity with the development of dementia. Furthermore, white matter damage is found in obese subjects and mouse models of obesity. Here, we found that components of the Complement Cascade, including C1QA and C3 are increased in the brain of western diet (WD)-fed obese mice, particularly in white matter regions. To functionally test the role of the Complement Cascade in obesity induced brain pathology, female and male mice deficient in Complement component 1qa (C1QA), an essential molecule in the activation of the classical pathway of the Complement Cascade, were fed a WD and compared to WD-fed WT mice, and to C1qa knockout (KO) and WT mice fed a control diet (CD). C1qa KO mice fed a WD became obese but did not show pericyte loss or a decrease in laminin density in the cortex and hippocampus that was observed in obese WT controls. Furthermore, obesity-induced microglia phagocytosis and breakdown of myelin in the corpus callosum were also prevented by deficiency of C1QA. Collectively, these data show that C1QA is necessary for damage to the cerebrovasculature and white matter damage in diet-induced obesity. SIGNIFICANCE STATEMENT Economic growth, an increasingly sedentary lifestyle and a nutritional transition to processed foods and high calorie diets have led to a significant increase in obesity prevalence. Several chronic diseases have been associated with obesity, including dementia. Obesity-induced, peripheral inflammation has been proposed as a possible trigger of pathological changes in the brain that lead to cognitive dysfunction and predisposition to dementia. Here we show that genetic deletion of the Complement component C1QA prevents cerebrovascular damage, neuroinflammation and white matter degradation in a mouse model of western diet-induced obesity, demonstrating that inflammatory responses play a significant role in obesity-induced brain pathology. The Complement pathway is an attractive therapeutic target to prevent cognitive decline and reduction of dementia risk caused by obesity.

  • inhibition of the classical pathway of the Complement Cascade prevents early dendritic and synaptic degeneration in glaucoma
    Molecular Neurodegeneration, 2016
    Co-Authors: Peter A Williams, James R Tribble, Keating W Pepper, Stephen Daniel Cross, Paul B Morgan, James Edwards Morgan, Simon W M John, Gareth R Howell
    Abstract:

    Background Glaucoma is a complex, multifactorial disease characterised by the loss of retinal ganglion cells and their axons leading to a decrease in visual function. The earliest events that damage retinal ganglion cells in glaucoma are currently unknown. Retinal ganglion cell death appears to be compartmentalised, with soma, dendrite and axon changes potentially occurring through different mechanisms. There is mounting evidence from other neurodegenerative diseases suggesting that neuronal dendrites undergo a prolonged period of atrophy, including the pruning of synapses, prior to cell loss. In addition, recent evidence has shown the role of the Complement Cascade in synaptic pruning in glaucoma and other diseases.

  • the classical Complement Cascade mediates cns synapse elimination
    Cell, 2007
    Co-Authors: Beth Stevens, Kristina D Micheva, Karen S Christopherson, Nicola J Allen, Luis E Vazquez, Gareth R Howell, Navid Nouri, Adrienne K Mehalow, Andrew D Huberman, Benjamin K Stafford
    Abstract:

    During development, the formation of mature neural circuits requires the selective elimination of inappropriate synaptic connections. Here we show that C1q, the initiating protein in the classical Complement Cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina. Mice deficient in Complement protein C1q or the downstream Complement protein C3 exhibit large sustained defects in CNS synapse elimination, as shown by the failure of anatomical refinement of retinogeniculate connections and the retention of excess retinal innervation by lateral geniculate neurons. Neuronal C1q is normally downregulated in the adult CNS; however, in a mouse model of glaucoma, C1q becomes upregulated and synaptically relocalized in the adult retina early in the disease. These findings support a model in which unwanted synapses are tagged by Complement for elimination and suggest that Complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.

Magda Kucia - One of the best experts on this subject based on the ideXlab platform.

  • ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking
    Stem Cell Reviews and Reports, 2019
    Co-Authors: Mariusz Z. Ratajczak, Jolanta Kucharska-mazur, Magda Kucia, Janina Ratajczak, Kamila Bujko, Aaron Mack, Alison Domingues, Daniel Pedziwiatr, Henning Ulrich, Jerzy Samochowiec
    Abstract:

    Recent evidence indicates that the occurrence of psychiatric disorders in patients is linked to a local “sterile” inflammation of brain or due to a systemic inflammation process that affects the central nervous system. This is supported by the observation that in peripheral blood of psychotic patients are detectable several mediators and markers of inflammation as well as clinical data on correlations between systemic chronic inflammatory processes and psychiatric disorders. This may explain why some reported anti-inflammatory treatment strategies have beneficial effects on ameliorating psychotic events. In this review we will present a concept that aberrant purinergic signaling and increases in extracellular level of adenosine triphosphate (ATP) in the brain parenchyma may lead to activation of Nlrp3 inflammasome in microglia cells and as a consequence microglia released danger associated molecular pattern (DAMP) proteins activate Complement Cascade (ComC) in mannan binding lectin (MBL) – dependent manner. Activation of ATP-Nlrp3 inflammasome-ComC axis may also orchestrate trafficking of stem cells released from bone marrow into peripheral blood observed in psychotic patients. Based on this, the ATP-Nlrp3 inflammasome-ComC axis may become a target for new therapeutic approaches, which justifies the development and clinical application of efficient anti-inflammatory treatment strategies targeting this axis in psychiatry.

  • The Emerging Link Between the Complement Cascade and Purinergic Signaling in Stress Hematopoiesis
    Frontiers Media S.A., 2018
    Co-Authors: Mariusz Z. Ratajczak, Magda Kucia, Janina Ratajczak, Mateusz Adamiak, William Tse, Wieslaw Wiktor-jedrzejczak
    Abstract:

    Innate immunity plays an important role in orchestrating the immune response, and the Complement Cascade (ComC) is a major component of this ancient defense system, which is activated by the classical-, alternative-, or mannan-binding lectin (MBL) pathways. However, the MBL-dependent ComC-activation pathway has been somewhat underappreciated for many years; recent evidence indicates that it plays a crucial role in regulating the trafficking of hematopoietic stem/progenitor cells (HSPCs) by promoting their egress from bone marrow (BM) into peripheral blood (PB). This process is initiated by the release of danger-associated molecular patterns (DAMPs) from BM cells, including the most abundant member of this family, adenosine triphosphate (ATP). This nucleotide is well known as a ubiquitous intracellular molecular energy source, but when secreted becomes an important extracellular nucleotide signaling molecule and mediator of purinergic signaling. What is important for the topic of this review, ATP released from BM cells is recognized as a DAMP by MBL, and the MBL-dependent pathway of ComC activation induces a state of “sterile inflammation” in the BM microenvironment. This activation of the ComC by MBL leads to the release of several potent mediators, including the anaphylatoxins C5a and desArgC5a, which are crucial for egress of HSPCs into the circulation. In parallel, as a ligand for purinergic receptors, ATP affects mobilization of HSPCs by activating other pro-mobilizing pathways. This emerging link between the release of ATP, which on the one hand is an activator of the MBL pathway of the ComC and on the other hand is a purinergic signaling molecule, will be discussed in this review. This mechanism plays an important role in triggering defense mechanisms in response to tissue/organ injury but may also have a negative impact by triggering autoimmune disorders, aging of HSPCs, induction of myelodysplasia, and graft-versus-host disease after transplantation of histoincompatible hematopoietic cells

  • Conditioning for hematopoietic transplantation activates the Complement Cascade and induces a proteolytic environment in bone marrow: a novel role for bioactive lipids and soluble C5b-C9 as homing factors
    Leukemia, 2011
    Co-Authors: Chihwa Kim, Marcin Wysoczynski, Magda Kucia, Janina Ratajczak, Ahmed Abdel-latif, Manjula Sunkara, Andrew J. Morris, Mariusz Z. Ratajczak
    Abstract:

    We have observed that conditioning for hematopoietic transplantation by lethal irradiation induces a proteolytic microenvironment in the bone marrow (BM) that activates the Complement Cascade (CC). As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC). At the same time, proteolytic enzymes induced in irradiated BM impair the chemotactic activity of α-chemokine stromal-derived factor-1 (SDF-1). As SDF-1 is considered a crucial BM chemoattractant for transplanted hematopoietic stem/progenitor cells (HSPCs), we sought to determine whether other factors that are resistant to proteolytic enzymes have a role in this process, focusing on proteolysis-resistant bioactive lipids. We found that the concentrations of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) increase in the BM after conditioning for transplantation and that both S1P and, as we show here for the first time, C1P are potent chemoattractants for HSPCs. Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs. In support of a role for MAC in homing and engraftment, we found that soluble MAC enhances in a CR3 (CD11b/CD18)-dependent manner the adhesion of HSPCs to BM stromal cells and increases the secretion of SDF-1 by BM stroma. We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

  • novel insight into stem cell mobilization plasma sphingosine 1 phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization du
    Leukemia, 2010
    Co-Authors: Mariusz Z. Ratajczak, Marcin Wysoczynski, Magda Kucia, Anna Janowskawieczorek, Wojciech Marlicz, Mary J Laughlin, Janina Ratajczak
    Abstract:

    Complement Cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemottractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the BM. We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal derived factor-1 (SDF-1)-independent manner because i) plasma SDF-1 level does not correlate with mobilization efficiency, ii) the chemotactic plasma gradient is not affected in the presence of AMD3100, and iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested involvement of bioactive lipids and we focused on sphingosine-1 phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P i) creates in plasma a continuously present gradient for BM-residing HSPCs, ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1, and iii) its plasma level increases during mobilization due to CC activation and the interaction of membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC via MAC induces release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

  • novel insight into stem cell mobilization plasma sphingosine 1 phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization du
    Leukemia, 2010
    Co-Authors: Mariusz Z. Ratajczak, Marcin Wysoczynski, Wu Wan, Magda Kucia, Hakmo Lee, Anna Janowskawieczorek, Wojciech Marlicz, Mary J Laughlin, Janina Ratajczak
    Abstract:

    The Complement Cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemoattractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the bone marrow (BM). We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal-derived factor-1 (SDF-1)-independent manner because (i) plasma SDF-1 level does not correlate with mobilization efficiency; (ii) the chemotactic plasma gradient is not affected in the presence of AMD3100 and (iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested the involvement of bioactive lipids and we focused on sphingosine-1-phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P (i) creates in plasma a continuously present gradient for BM-residing HSPCs; (ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1 and (iii) its plasma level increases during mobilization due to CC activation and interaction of the membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC through MAC induces the release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

Marcin Wysoczynski - One of the best experts on this subject based on the ideXlab platform.

  • Conditioning for hematopoietic transplantation activates the Complement Cascade and induces a proteolytic environment in bone marrow: a novel role for bioactive lipids and soluble C5b-C9 as homing factors
    Leukemia, 2011
    Co-Authors: Chihwa Kim, Marcin Wysoczynski, Magda Kucia, Janina Ratajczak, Ahmed Abdel-latif, Manjula Sunkara, Andrew J. Morris, Mariusz Z. Ratajczak
    Abstract:

    We have observed that conditioning for hematopoietic transplantation by lethal irradiation induces a proteolytic microenvironment in the bone marrow (BM) that activates the Complement Cascade (CC). As a result, BM is enriched for proteolytic enzymes and the soluble form of the terminal product of CC activation, the membrane attack complex C5b-C9 (MAC). At the same time, proteolytic enzymes induced in irradiated BM impair the chemotactic activity of α-chemokine stromal-derived factor-1 (SDF-1). As SDF-1 is considered a crucial BM chemoattractant for transplanted hematopoietic stem/progenitor cells (HSPCs), we sought to determine whether other factors that are resistant to proteolytic enzymes have a role in this process, focusing on proteolysis-resistant bioactive lipids. We found that the concentrations of sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) increase in the BM after conditioning for transplantation and that both S1P and, as we show here for the first time, C1P are potent chemoattractants for HSPCs. Next, we observed that C5-deficient mice that do not generate MAC show impaired engraftment of HSPCs. In support of a role for MAC in homing and engraftment, we found that soluble MAC enhances in a CR3 (CD11b/CD18)-dependent manner the adhesion of HSPCs to BM stromal cells and increases the secretion of SDF-1 by BM stroma. We conclude that an increase in BM levels of proteolytic enzyme-resistant S1P and C1P and activation of CC, which leads to the generation of MAC, has an important and previously underappreciated role in the homing of transplanted HSPCs.

  • novel insight into stem cell mobilization plasma sphingosine 1 phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization du
    Leukemia, 2010
    Co-Authors: Mariusz Z. Ratajczak, Marcin Wysoczynski, Magda Kucia, Anna Janowskawieczorek, Wojciech Marlicz, Mary J Laughlin, Janina Ratajczak
    Abstract:

    Complement Cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemottractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the BM. We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal derived factor-1 (SDF-1)-independent manner because i) plasma SDF-1 level does not correlate with mobilization efficiency, ii) the chemotactic plasma gradient is not affected in the presence of AMD3100, and iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested involvement of bioactive lipids and we focused on sphingosine-1 phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P i) creates in plasma a continuously present gradient for BM-residing HSPCs, ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1, and iii) its plasma level increases during mobilization due to CC activation and the interaction of membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC via MAC induces release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

  • novel insight into stem cell mobilization plasma sphingosine 1 phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization du
    Leukemia, 2010
    Co-Authors: Mariusz Z. Ratajczak, Marcin Wysoczynski, Wu Wan, Magda Kucia, Hakmo Lee, Anna Janowskawieczorek, Wojciech Marlicz, Mary J Laughlin, Janina Ratajczak
    Abstract:

    The Complement Cascade (CC) becomes activated and its cleavage fragments play a crucial role in the mobilization of hematopoietic stem/progenitor cells (HSPCs). Here, we sought to determine which major chemoattractant present in peripheral blood (PB) is responsible for the egress of HSPCs from the bone marrow (BM). We noticed that normal and mobilized plasma strongly chemoattracts HSPCs in a stromal-derived factor-1 (SDF-1)-independent manner because (i) plasma SDF-1 level does not correlate with mobilization efficiency; (ii) the chemotactic plasma gradient is not affected in the presence of AMD3100 and (iii) it is resistant to denaturation by heat. Surprisingly, the observed loss of plasma chemotactic activity after charcoal stripping suggested the involvement of bioactive lipids and we focused on sphingosine-1-phosphate (S1P), a known chemoattracant of HSPCs. We found that S1P (i) creates in plasma a continuously present gradient for BM-residing HSPCs; (ii) is at physiologically relevant concentrations a chemoattractant several magnitudes stronger than SDF-1 and (iii) its plasma level increases during mobilization due to CC activation and interaction of the membrane attack complex (MAC) with erythrocytes that are a major reservoir of S1P. We conclude and propose a new paradigm that S1P is a crucial chemoattractant for BM-residing HSPCs and that CC through MAC induces the release of S1P from erythrocytes for optimal egress/mobilization of HSPCs.

  • mobilization studies in Complement deficient mice reveal that optimal amd3100 mobilization of hematopoietic stem cells depends on Complement Cascade activation by amd3100 stimulated granulocytes
    Leukemia, 2010
    Co-Authors: Hakmo Lee, Marcin Wysoczynski, Magda Kucia, Janina Ratajczak, Dong-myung Shin, Rui Liu, Marina Botto, Mariusz Z. Ratajczak
    Abstract:

    We reported that Complement Cascade (CC) becomes activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPCs) induced by granulocyte colony-stimulating factor (G-CSF) and C5 cleavage has an important function in optimal egress of HSPCs. In this work, we explored whether CC is involved in mobilization of HSPCs induced by the CXCR4 antagonist, AMD3100. To address this question, we performed mobilization studies in mice that display a defect in the activation of the proximal steps of CC (Rag(-/-), severe combined immune deficient (SCID), C2.Cfb(-/-)) as well as in mice that do not activate the distal steps of CC (C5(-/-)). We noticed that proximal CC activation-deficient mice (above C5 level), in contrast to distal step CC activation-deficient C5(-/-) ones, mobilize normally in response to AMD3100 administration. We hypothesized that this discrepancy in mobilization could be explained by AMD3100-activating C5 in Rag(-/-), SCID, and C2.Cfb(-/-) animals in a non-canonical mechanism involving activated granulocytes. To support this, granulocytes (i) first egress from BM and (ii) secrete several proteases that cleave/activate C5 in response to AMD3100. We conclude that AMD3100-directed mobilization of HSPCs, similarly to G-CSF-induced mobilization, depends on activation of CC; however, in contrast to G-CSF, AMD3100 activates the distal steps of CC directly at the C5 level. Overall, these data support that C5 cleavage fragments and distal steps of CC activation are required for optimal mobilization of HSPCs.

  • novel mechanistic insight into mobilization of hematopoietic stem progenitor cells hspcs Complement Cascade and membrane attack complex activated in bone marrow sinusoids during mobilization release from erythrocytes sphingosine 1 phosphate an underappreciated chemoattractant executing egress of hspcs
    Blood, 2009
    Co-Authors: Hakmo Lee, Marcin Wysoczynski, Magda Kucia, Janina Ratajczak, Rui Liu, Anna Janowskawieczorek, Mariusz Z. Ratajczak
    Abstract:

    Abstract 31 We reported that Complement Cascade (CC) is activated in bone marrow (BM) during mobilization of hematopoietic stem/progenitor cells (HSPCs) and that CC clevage fragments direct egress of HSPCs from BM into peripheral blood (PB) ( Blood 2003;101,3784; Blood 2004;103,2071; Blood 2005;105,40 ). We also reported that C5 cleavage fragments play a crucial role in the mobilization process by: i) inducing proteolytic activity in the BM environment; ii) directing BM egress of granulocytes that “pave a road” for HSPCs; and iii) inducing secretion of cationic peptides from activated granulocytes that prime HSPC egress ( Leukemia 2009; in press ). In this study, we sought to determine which major chemottractant is present in PB that is responsible for egress of HSPCs and whether activation of CC plays some role in its level/expression. We noticed that plasma derived from normal and mobilized PB strongly chemoattracts murine and human HSPCs. This chemotactic effect was not dependent on plasma SDF-1 levels because: i) it occurs unaffectedly in the presence of CXCR4 antagonist AMD3100; ii) it was still robust to heat-inactivated sera; and iii) ELISA studies revealed negligible concentrations of SDF-1, which did not correlate with good or poor mobilizer status. However, to our surprise, we noticed that plasma isolated from G-CSF-mobilized mice and patients contains traces of free hemoglobin, which suggests some level of hemolysis occurs in mobilized PB. As such, we performed chemotactic assays in the presence of different concentrations of lysed erythrocytes and noticed that such diluted lysates are potent chemoattractants for HSPCs. The chemotactic activities of these lysates were resistant to heat inactivation similarly as patient sera. Based on this, we focused on S1P, a thermo-resistant lipid that, as reported, chemoattracts HSPCs and whose major reservoirs are erythrocytes ( FASEB J 2007:21;1202 ). In fact we found by ELISA that S1P level increases during mobilization in PB and that SP1 is the most potent chemoattractant for BM-residing HSPCs, much stronger than SDF-1 - if both compounds are compared in physiologically relevant concentrations. Furthermore, activation of S1P receptors on BM-derived HSPCs augmented responsiveness to SDF-1 gradient up to 50%. However, these chemotactic effects of S1P were not visible for previously mobilized PB or umbilical cord blood HSPCs, which we explain by a fact that these mobilized cells are already desensitized to S1P gradient. Therefore, we propose the following scenario. First, a mobilizing agent (e.g., G-CSF) induces activation of CC in BM that subsequently contributes to the release of protelolytic enzymes from granulocytes that perturb SDF-1-CXCR4/VLA-4-VCAM1 interactions and stimulate egress of activated granulocytes from BM that “pave a road” for egress of HSPCs. Simultaneously, the final product of CC activation (C5b-C9), the membrane attack complex (MAC), induces in BM sinusoids the release of S1P from erythrocytes. S1P accumulating in BM sinusoids and cationic peptides released from activated granulocytes, but not changes in plasma SDF-1 levels, are crucial executors of HSPCs egress from BM into PB. Thus, our results provide novel evidence that CC activation/membrane attack complex (MAC)-induced elevated plasma S1P level is essential for egress/mobilization of HSPCs. Disclosures: No relevant conflicts of interest to declare.