The Experts below are selected from a list of 32727 Experts worldwide ranked by ideXlab platform

Alberto Mantovani - One of the best experts on this subject based on the ideXlab platform.

  • the long pentraxin ptx3 as a prototypic humoral Pattern Recognition Receptor interplay with cellular innate immunity
    Immunological Reviews, 2009
    Co-Authors: Barbara Bottazzi, Cecilia Garlanda, Alessia Cotena, Federica Moalli, Sebastien Jaillon, Livija Deban, Alberto Mantovani
    Abstract:

    Summary:  The innate immune system consists of a cellular arm and a humoral arm. Components of humoral immunity include diverse molecular families, which represent functional ancestors of antibodies. They play a key role as effectors and modulators of innate resistance in animals and humans, interacting with cellular innate immunity. The prototypic long pentraxin, pentraxin 3 (PTX3), represents a case in point of this interplay. Gene targeting of this evolutionarily conserved long pentraxin has unequivocally defined its role at the crossroads of innate immunity, inflammation, matrix deposition, and female fertility. Phagocytes represent a key source of this fluid-phase Pattern Recognition Receptor, which, in turn, facilitates microbial Recognition by phagocytes acting as an opsonin. Moreover, PTX3 has modulatory functions on innate immunity and inflammation. Here, we review the studies on PTX3 which emphasize the complexity and complementarity of the crosstalk between the cellular and humoral arms of innate immunity.

  • identification of an antiangiogenic fgf2 binding site in the n terminus of the soluble Pattern Recognition Receptor ptx3
    Journal of Biological Chemistry, 2006
    Co-Authors: Maura Camozzi, Alberto Mantovani, Barbara Bottazzi, Marco Rusnati, Antonella Bugatti, Antonio Bastone, Antonio Inforzato, Silvia Vincenti, Luisa Bracci, Domenico Mastroianni
    Abstract:

    Long-pentraxin 3 (PTX3) is a soluble Pattern Recognition Receptor with non-redundant functions in inflammation and innate immunity. PTX3 comprises a pentraxin-like C-terminal domain involved in complement activation via C1q interaction and an N-terminal extension with unknown functions. PTX3 binds fibroblast growth factor-2 (FGF2), inhibiting its pro-angiogenic and pro-restenotic activity. Here, retroviral transduced endothelial cells (ECs) overexpressing the N-terminal fragment PTX3-(1–178) showed reduced mitogenic activity in response to FGF2. Accordingly, purified recombinant PTX3-(1–178) binds FGF2, prevents PTX3/FGF2 interaction, and inhibits FGF2 mitogenic activity in ECs. Also, the monoclonal antibody mAb-MNB4, which recognizes the PTX3-(87–99) epitope, prevents FGF2/PTX3 interaction and abolishes the FGF2 antagonist activity of PTX3. Consistently, the synthetic peptides PTX3-(82–110) and PTX3-(97–110) bind FGF2 and inhibit the interaction of FGF2 with PTX3 immobilized to a BIAcore sensor chip, FGF2-dependent EC proliferation, and angiogenesis in vivo. Thus, the data identify a FGF2-binding domain in the N-terminal extension of PTX3 spanning the PTX3-(97–110) region, pointing to a novel function for the N-terminal extension of PTX3 and underlining the complexity of the PTX3 molecule for modular humoral Pattern Recognition.

  • production of the soluble Pattern Recognition Receptor ptx3 by myeloid but not plasmacytoid dendritic cells
    European Journal of Immunology, 2003
    Co-Authors: Andrea Doni, Alberto Mantovani, Cecilia Garlanda, Paola Allavena, Marcello Chieppa, Giuseppe Peri, Fabio Pasqualini, Luca Vago, Luigina Romani
    Abstract:

    PTX3 is a prototypic of long pentraxin consisting of an N-terminal portion coupled to a C-terminal pentraxin domain, the latter related to short pentraxins (C-reactive protein and serum amyloid P component). PTX3 is a soluble Pattern Recognition Receptor, which plays a non-redundant role in resistance against selected pathogens and in female fertility. The present study was designed to analyze the production of PTX3 by human dendritic cells (DC) and to define the role of different innate immunity Receptors in its induction. Human monocyte-derived DC produced copious amounts of PTX3in response to microbial ligands engaging different members of the Toll-like Receptor (TLR) family (TLR1 through TLR6), whereas engagement of the mannose Receptor had no substantial effect. DC werebetter producers of PTX3 than monocytes and macrophages. Freshly isolated peripheral blood myeloid DC produced PTX3 in response to diverse microbial stimuli. In contrast, plasmacytoid DC exposed to influenza virus or to CpG oligodeoxynucleotides engaging TLR9, did not produce PTX3. PTX3-expressing DC were present in inflammatory lymph nodes from HIV-infected patients. These results suggest that DC of myelomonocytic origin are a major source of PTX3, a molecule which facilitates pathogen Recognition and subsequent activation of innate and adaptive immunity.

  • pentraxin 3 a non redundant soluble Pattern Recognition Receptor involved in innate immunity
    Vaccine, 2003
    Co-Authors: Alberto Mantovani, Cecilia Garlanda, Barbara Bottazzi
    Abstract:

    Pentraxin 3 (PTX3) is the first long pentraxin identified. Long pentraxins consist of a C-terminal pentraxin domain, which has sequence similarity to C-reactive protein (CRP) and serum amyloid P (SAP) component (the classic short pentraxins), and of an unrelated N-terminal portion. PTX3 is made by diverse cell types, most prominently endothelial cells, macrophages and dendritic cells, in response to primary inflammatory signals (e.g. interleukin-1 (IL-1), tumour necrosis factor (TNF), lipopolysaccharide (LPS)). It binds diverse ligands, including microbial moieties, C1q and apoptotic cells. Evidence suggests that PTX3 plays a role in the regulation of innate resistance to pathogens, inflammatory reactions, possibly clearance of self-components and female fertility.

Linsheng Song - One of the best experts on this subject based on the ideXlab platform.

  • a hypervariable immunoglobulin superfamily member from crassostrea gigas functions as Pattern Recognition Receptor with opsonic activity
    Developmental and Comparative Immunology, 2018
    Co-Authors: Dongyang Liu, Lingling Wang, Conghui Liu, Xiaorui Song, Changhao Gong, Jiejie Sun, Linsheng Song
    Abstract:

    lmmunoglobulin superfamily (IgSF), an extensive collection of proteins possessing at least one immunoglobulin-like (Ig-like) domain, performs a wide range of functions in Recognition, binding or adhesion process of cells. In the present study, a cysteine-rich motif associated immunoglobulin domain containing protein (designated CgCAICP-1) was identified in Pacific oyster Crassostrea gigas. The deduced protein sequence of CgCAICP-1 contained 534 amino acidresidues, with three Ig domains which were designated as IG1, IG2 and IG3, and a cysteine-rich motif between the first and second Ig domain. The mRNA transcripts of CgCAICP-1 were highly expressed in hemocytes and up-regulated significantly (p < 0.05) after the stimulation of Iipopolysaccharides (LPS), but not peptidoglycan (PGN). The recombinant CgCAICP-1 protein (rCgCAICP-1) exhibited binding activity to various pathogen-associated molecular Patterns (PAMPs) including LPS, PGN, mannose (Man) and D-galactose (D-Gal), and microorganisms including Vibrio splendidus, Escherichia coli, Staphylococcus aureus, Micrococcus luteus and Pichia pastoris. The phagocytic rates of oyster hemocytes towards Gram-negative bacteria V. splendidus and Gram-positive bacteria M. luteus were significantly enhanced (p < 0.05) after pre-incubation of microbes with rCgCAICP-1. Furthermore, the transcripts of CgCAICP-1 exhibited high level of polymorphism among individuals. The ratio of nonsynonymous and synonymous distances (dN/dS) for AA'BCC'D strands of IG1 (the possible binding sites 1, pbs1) across all allelic variants was 2.09 (p < 0.05), while the ratio for the non-pbs regions was less than 1.0. The 1248 bp fragment amplified from the 5' end of CgCAICP-1 open reading frame (ORF) from 24 transcript variants could be divided artificially into seven regions of 50 elements, and all of the allelic variants might be derived from these elements by point mutation and recombination processes. These results collectively suggested that CgCAICP-1 might function as an important Pattern Recognition Receptor (PRR) to recognize various PAMPs and facilitated the phagocytosis of oyster hemocytes towards both Gram-positive and Gram-negative bacteria. Diverse isoforms of CgCAICP-1 were generated through point mutation and recombination processes and maintained by balancing selection, which would provide a broader spectrum of interaction surface and be associated with immune resistance of oysters to infectious pathogens. (C) 2018 Elsevier Ltd. All rights reserved.

  • an lrr only protein representing a new type of Pattern Recognition Receptor in chlamys farreri
    Developmental and Comparative Immunology, 2016
    Co-Authors: Mengqiang Wang, Lingling Wang, Ying Guo, Linsheng Song
    Abstract:

    Accumulating evidence has demonstrated that leucine-rich repeat (LRR)-only proteins could mediate protein-ligand and protein protein interactions and were involved in the immune response. In the present study, an LRR-only protein (designed as CfLRRop-1) was cloned from Zhikong scallop Chlamys farreri. The complete cDNA sequence of CfLRRop-1 contained an open reading frame (ORF) of 1377 bp, which encoded a protein of 458 amino acids. An LRRNT motif, an LRR_7 motif and seven LRR motifs were found in the deduced amino acid sequence of CfLRRop-1. And these seven LRR motifs contained a conserved signature sequence LxxLxxNxL. The mRNA transcripts of CfLRRop-1 were constitutively expressed in all the tested tissues, including haemocytes, muscle, mantle, gill, hepatopancreas and gonad, with the highest expression level in hepatopancreas. After the stimulation of lipopolysaccharide (LPS), peptidoglycan (PGN), glucan (GLU) and polyinosinic-polycytidylic acid (poly I:C), the mRNA transcripts of CARRop-1 in haemocytes all increased firstly within the first 6 h and secondly during 12-24 h post stimulation. The mRNA expression level of CfLRRop-1 was continuously up-regulated, after the expression of CfTLR (previously identified Toll-like Receptor in C. farreri) was suppressed via RNA interference (RNAi). The recombinant CfLRRop-1 protein could directly bind LPS, PGN, GLU and poly I:C, and induce the release of TNF-alpha in mixed primary cultured scallop haemocytes. These results collectively indicated that CfLRRop-1 would function as a powerful Pattern Recognition Receptor (PRR) and play a pivotal role in the immune response of scallops. (C) 2015 Elsevier Ltd. All rights reserved.

  • a c1q domain containing protein from crassostrea gigas serves as Pattern Recognition Receptor and opsonin with high binding affinity to lps
    Fish & Shellfish Immunology, 2015
    Co-Authors: Shuai Jiang, Lingling Wang, Huan Zhang, Daoxiang Zhang, Jinsheng Sun, Linsheng Song
    Abstract:

    C1q proteins serve as Pattern Recognition Receptors and involve in the pathogen Recognition and complement pathway activation. In the present study, a novel C1q domain containing protein from Crassostrea gigas (designated CgC1qDC-1) was isolated by liposaccharide-Sepharose 6B affinity chromatography. The coding sequence of CgC1 qDC-1 gene was determined by performing a homologous search of eight tryptic peptides identified by IVIALDI-TOF/TOF-MS against the genome of C. gigas. The coding sequence of CgC1qDC-1 was of 387 bp encoding a polypeptide of 128 amino acids containing a typical globular C1q domain. The globular C1q domain possessed eight beta strands with a jelly-roll topology structure, which was similar to the structure of human gC1q domain. The mRNA transcripts of CgC1 qDC-1 were dominantly expressed in mantle and hemocytes, while low expressed in hepatopancreas, gonad, gill and muscle. The expression level of CgC1qDC-1 increased drastically at 6 h after Vibrio splendidus stimulation, and then gradually fell to the normal level at about 24 h. ELISA assay quantified that CgC1qDC-1 bound to LPS with high binding affinity (Kd = 0.09 x 10(-6) M). Moreover, CgC1qDC-1 significantly enhanced the phagocytosis of oyster hemocytes towards Gram-negative bacteria Escherichia con and V. splendidus. These results collectively indicated that CgC1qDC-1 could serve as Pattern Recognition Receptor and opsonin in the innate immune response against invading Gram-negative bacteria. (C) 2015 Elsevier Ltd. All rights reserved.

  • a novel c1qdc protein acting as Pattern Recognition Receptor in scallop argopecten irradians
    Fish & Shellfish Immunology, 2012
    Co-Authors: Leilei Wang, Lingling Wang, Pengfei Kong, Jialong Yang, Huan Zhang, Mengqiang Wang, Zhi Zhou, Limei Qiu, Linsheng Song
    Abstract:

    The C1q domain containing (C1qDC) proteins refer to a family of proteins containing the versatile charge Pattern Recognition globular C1q domain in the C-terminus, which could bind various ligands including PAMPs and trigger a serial of immune response. In this study, a novel C1qDC protein was identified from Argopecten irradians (designated as AiC1qDC-2). Its full-length cDNA was of 1062 bp with an open reading frame of 720 bp encoding a polypeptide of 240 amino acids containing a typical gC1 q domain. This gC1q domain possessed the typical 10-stranded beta-sandwich fold with a jelly-roll topology common to all C1q family members, and shared high homology with most of the other identified gC1q domains. The mRNA transcripts of AiC1qDC-2 were mainly detected in hepatopancreas, and also marginally detectable in mantle, gonad, adductor, gill and hemocytes. Its relative expression level in hemocytes was significantly up-regulated after challenges of fungi Pichia pastoris GS115 (P < 0.05), Gram-positive bacteria Micrococcus luteus (P < 0.05) and Gram-negative bacteria Vibrio anguillarum (P < 0.05). The recombinant protein of AiC1qDC-2 (rAiC1qDC-2) could bind various PAMPs, including LPS, PGN, polyI:C, mannan, beta-1,3-glucan as well as Yeast-glucan, and displayed agglutinating activity to fungi P. pastoris GS115, Gram-positive bacteria Bacillus subtilis and Gram-negative bacteria Escherichia coli TOP10F as well as V. anguillarum. All these results indicated that AiC1qDC-2 could function as a Pattern Recognition Receptor to recognize various PAMPs on different pathogens in the innate immune responses of scallop, and provided new clues to understand the role of invertebrate C1qDC proteins in the ancient complement system. (c) 2012 Elsevier Ltd. All rights reserved.

  • cflec 5 a Pattern Recognition Receptor in scallop chlamys farreri agglutinating yeast pichia pastoris
    Fish & Shellfish Immunology, 2010
    Co-Authors: Huan Zhang, Lingling Wang, Pengfei Kong, Jialong Yang, Zhi Zhou, Limei Qiu, Ying Zhang, Linsheng Song
    Abstract:

    C-type lectins are a superfamily of carbohydrate-Recognition proteins which play crucial roles as Pattern Recognition Receptors (PRRs) in the innate immunity. In this study, the full-length cDNA of a C-type lectin was cloned from scallop Chlamys farreri (designated as Cflec-5) by expression sequence tag (EST) analysis and rapid amplification of cDNA ends (RACE) approach. The full-length cDNA of Cflec-5 was of 1412 bp. The open reading frame encoded a polypeptide of 153 amino acids, including a signal sequence and a conserved carbohydrate-Recognition domain with the EPN motif determining the mannose-binding specificity. The deduced amino acid sequence of Cflec-5 showed high similarity to members of C-type lectin superfamily. The quantitative real-time PCR was performed to investigate the tissue distribution of Cflec-5 mRNA and its temporal expression profiles in hemocytes post pathogen-associated molecular Patterns (PAMPs) stimulation. In healthy scallops, the Cflec-5 mRNA was mainly detected in gill and mantle, and marginally in other tissues. The mRNA expression of Cflec-5 could be significantly induced by lipopolysaccharide (LPS) and glucan stimulation and reached the maximum level at 6 h and 12 h, respectively. But its expression level did not change significantly during peptidoglycan (PGN) stimulation. The function of Cflec-5 was investigated by recombination and expression of the cDNA fragment encoding its mature peptide in Escherichia coli Rosetta Gami (DE3). The recombinant Cflec-5 agglutinated Pichia pastoris in a calcium-independent way. The agglutinating activity could be inhibited by d-mannose, LPS and glucan, but not by d-galactose or PGN. These results collectively suggested that Cflec-5 was involved in the innate immune response of scallops and might contribute to nonself-Recognition through its interaction with various PAMPs.

Clara Abraham - One of the best experts on this subject based on the ideXlab platform.

  • disease risk associated genetic variants in stat1 and stat4 function in a complementary manner to increase Pattern Recognition Receptor induced outcomes in human macrophages
    Journal of Immunology, 2020
    Co-Authors: Matija Hedl, Rui Sun, Clara Abraham
    Abstract:

    STAT proteins can regulate both pro- and anti-inflammatory cytokine signaling. Therefore, identifying consequences of modulating expression of a given STAT is ultimately critical for determining its potential as a therapeutic target and for defining the mechanisms through which immune-mediated disease variants in STAT genes contribute to disease pathogenesis. Genetic variants in the STAT1/STAT4 region are associated with multiple immune-mediated diseases, including inflammatory bowel disease (IBD). These diseases are characterized by dysregulated cytokine secretion in response to Pattern-Recognition Receptor (PRR) stimulation. We found that the common IBD-associated rs1517352 C risk allele increased both STAT1 and STAT4 expression in human monocyte-derived macrophages (MDMs). We therefore hypothesized that the STAT1/STAT4 variant might regulate PRR-initiated responses in a complementary and cooperative manner because of the important role of autocrine/paracrine cytokines in modulating PRR-initiated signaling. STAT1 and STAT4 were required for PRR- and live bacterial-induced secretion of multiple cytokines. These outcomes were particularly dependent on PRR-initiated autocrine/paracrine IL-12-induced STAT4 activation to generate IFN-γ, with autocrine IFN-γ then signaling through STAT1. STAT1 and STAT4 also promoted bacterial-induced cytokines in intestinal myeloid cells and PRR-enhanced antimicrobial pathways in MDMs. Importantly, MDMs from rs1517352 C IBD risk allele carriers demonstrated increased TLR4-, IFN-γ- and IL-12-induced STAT1 and STAT4 phosphorylation and cytokine secretion and increased TLR4-enhanced antimicrobial pathways. Taken together, STAT1 and STAT4 expression is coregulated by a shared genetic region, and STAT1 /STAT4-immune disease-associated variants modulate IFN-γ- and IL-12-associated outcomes, and in turn, PRR-induced outcomes, highlighting that these genes cooperate to regulate pathways relevant to disease pathogenesis.

  • a tpl2 map3k8 disease risk polymorphism increases tpl2 expression thereby leading to increased Pattern Recognition Receptor initiated caspase 1 and caspase 8 activation signalling and cytokine secretion
    Gut, 2016
    Co-Authors: Matija Hedl, Clara Abraham
    Abstract:

    Objective IBD is characterised by dysregulated intestinal immune homeostasis and cytokine secretion. In the intestine, properly regulating Pattern Recognition Receptor (PRR)-mediated signalling and cytokines is crucial given the ongoing host–microbial interactions. TPL2 (MAP3K8, COT) contributes to PRR-initiated pathways, yet the mechanisms for TPL2 signalling contributions in primary human myeloid cells are incompletely understood and its role in intestinal myeloid cells is poorly defined. Furthermore, functional consequences for the IBD-risk locus rs1042058 in TPL2 are unknown. Methods We analysed protein, cytokine and RNA expression, and signalling in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR and flow cytometry. Results PRR-induced cytokine secretion was increased in MDMs from rs1042058 TPL2 GG risk individuals. TPL2 activation by the Crohn9s disease-associated PRR nucleotide-oligomerisation domain (NOD)2 required PKC, and IKKβ, IKKα and IKKγ signalling. TPL2, in turn, significantly enhanced NOD2-induced ERK, JNK and NFκB signalling. We found that another major mechanism for the TPL2 contribution to NOD2 signalling was through ERK-dependent and JNK-dependent caspase-1 and caspase-8 activation, which in turn, led to early autocrine interleukin (IL)-1β and IL-18 secretion and amplification of long-term cytokines. Importantly, Salmonella typhimurium -induced cytokines from human intestinal myeloid-derived cells required TPL2 as well as autocrine IL-1β and IL-18. Finally, rs1042058 GG risk carrier MDMs from healthy individuals and patients with Crohn9s disease had increased TPL2 expression and NOD2-initiated TPL2 phosphorylation, ERK, JNK and NFκB activation, and early autocrine IL-1β and IL-18 secretion. Conclusions Taken together, the rs1042058 GG IBD-risk polymorphism in TPL2 results in a gain-of-function by increasing TPL2 expression and signalling, thereby amplifying PRR-initiated outcomes.

  • a tnfsf15 disease risk polymorphism increases Pattern Recognition Receptor induced signaling through caspase 8 induced il 1
    Proceedings of the National Academy of Sciences of the United States of America, 2014
    Co-Authors: Matija Hedl, Clara Abraham
    Abstract:

    Inflammatory diseases are characterized by dysregulated cytokine production. Altered functions for most risk loci, including the inflammatory bowel disease and leprosy-associated tumor necrosis factor ligand superfamily member 15 (TNFSF15) region, are unclear. Regulation of Pattern-Recognition-Receptor (PRR)-induced signaling and cytokines is crucial for immune homeostasis; TNFSF15:death Receptor 3 (DR3) contributions to PRR responses have not been described. We found that human macrophages expressed DR3 and that TNFSF15:DR3 interactions were critical for amplifying PRR-initiated MAPK/NF-κB/PI3K signaling and cytokine secretion in macrophages. Mechanisms mediating TNFSF15:DR3 contributions to PRR outcomes included TACE-induced TNFSF15 cleavage to soluble TNFSF15; soluble TNFSF15 then led to TRADD/FADD/MALT-1- and caspase-8-mediated autocrine IL-1 secretion. Notably, TNFSF15 treatment also induced cytokine secretion through a caspase-8-dependent pathway in intestinal myeloid cells. Importantly, rs6478108 A disease risk-carrier macrophages demonstrated increased TNFSF15 expression and PRR-induced signaling and cytokines. Taken together, TNFSF15:DR3 interactions amplify PRR-induced signaling and cytokines, and the rs6478108 TNFSF15 disease-risk polymorphism results in a gain of function.

  • Pattern Recognition Receptor signaling in human dendritic cells is enhanced by icos ligand and modulated by the crohn s disease icoslg risk allele
    Immunity, 2014
    Co-Authors: Matija Hedl, Amit Lahiri, Kaida Ning, Judy H Cho, Clara Abraham
    Abstract:

    Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune homeostasis and cytokine secretion. Multiple loci are associated with IBD, but a functional explanation is missing for most. Here we found that Pattern-Recognition Receptor (PRR)-induced cytokine secretion was diminished in human monocyte-derived dendritic cells (MDDC) from rs7282490 ICOSLG GG risk carriers. Homotypic interactions between the costimulatory molecule ICOS and the ICOS ligand on MDDCs amplified nucleotide-binding oligomerization domain 2 (NOD2)-initiated cytokine secretion. This amplification required arginine residues in the ICOSL cytoplasmic tail that recruited the adaptor protein RACK1 and the kinases PKC and JNK leading to PKC, MAPK, and NF-κB activation. MDDC from rs7282490 GG risk-carriers had reduced ICOSL expression and PRR-initiated signaling and this loss-of-function ICOSLG risk allele associated with an ileal Crohn's disease phenotype, similar to polymorphisms in NOD2. Taken together, ICOSL amplifies PRR-initiated outcomes, which might contribute to immune homeostasis.

  • irf5 risk polymorphisms contribute to interindividual variance in Pattern Recognition Receptor mediated cytokine secretion in human monocyte derived cells
    Journal of Immunology, 2012
    Co-Authors: Matija Hedl, Clara Abraham
    Abstract:

    Monocyte-derived cells display highly variable cytokine secretion upon Pattern Recognition Receptor (PRR) stimulation across individuals; such variability likely affects interindividual inflammatory/autoimmune disease susceptibility. To define mechanisms for this heterogeneity, we examined PRR-induced monocyte-derived cell cytokine secretion from a large cohort of healthy individuals. Although cytokine secretion ranged widely among individuals, the magnitude of cytokine induction after individual nucleotide-binding oligomerization domain 2 (Nod2) and TLR2 stimulation (a cohort of 86 individuals) or stimulation of multiple TLRs (a cohort of 77 individuals), either alone or in combination with Nod2, was consistent intraindividually across these stimuli. Nod2 and TLRs signal through IFN regulatory factor 5 (IRF5), and common IRF5 polymorphisms confer risk for autoimmunity. We find that cells from rs2004640 IRF5 risk-associated allele carriers secrete increased cytokines upon individual or synergistic PRR stimulation in a gene dose- and ligand dose-dependent manner in both monocyte-derived dendritic cells and monocyte-derived macrophages. IRF5 expression knockdown in IRF5 risk allele carrier cells significantly decreases PRR-induced cytokines. Moreover, we find that IRF5 knockdown profoundly decreases Nod2-mediated MAPK and NF-κB pathway activation, whereas the PI3K and mammalian target of rapamycin pathways are not impaired. Finally, the IRF5 rs2004640 polymorphism is a major determinant of the variance (r(2) = 0.53) in Nod2-induced cytokine secretion by monocyte-derived cells from different individuals. We therefore show a profound contribution of a single gene to the variance in interindividual PRR-induced cytokines. The hyperresponsiveness of IRF5 disease-associated polymorphisms to a wide spectrum of microbial triggers has broad implications on global immunological responses, host defenses against pathogens, and inflammatory/autoimmune disease susceptibility.

Silke Robatzek - One of the best experts on this subject based on the ideXlab platform.

  • Attenuation of Pattern Recognition Receptor signaling is mediated by a MAP kinase kinase kinase
    EMBO reports, 2016
    Co-Authors: Sharon C. Mithoe, Christina Ludwig, Michiel Jc Pel, Alberto Casartelli, Malick Mbengue, Mara Cucinotta, Jan Sklenar, Silke Robatzek, Paul Derbyshire, Corné M. J. Pieterse
    Abstract:

    Pattern Recognition Receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN-SENSITIVE 2 (FLS2) induces the activation of mitogen-activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin-triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7-mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex.

  • a moving view subcellular trafficking processes in Pattern Recognition Receptor triggered plant immunity
    Annual Review of Phytopathology, 2015
    Co-Authors: Sara Ben Khaled, J Postma, Silke Robatzek
    Abstract:

    A significant challenge for plants is to induce localized defense responses at sites of pathogen attack. Therefore, host subcellular trafficking processes enable accumulation and exchange of defense compounds, which contributes to the plant on-site defenses in response to pathogen perception. This review summarizes our current understanding of the transport processes that facilitate immunity, the significance of which is highlighted by pathogens reprogramming membrane trafficking through host cell translocated effectors. Prominent immune-related cargos of plant trafficking pathways are the Pattern Recognition Receptors (PRRs), which must be present at the plasma membrane to sense microbes in the apoplast. We focus on the dynamic localization of the FLS2 Receptor and discuss the pathways that regulate Receptor transport within the cell and their link to FLS2-mediated immunity. One emerging theme is that ligand-induced late endocytic trafficking is conserved across different PRR protein families as well as across different plant species.

  • plant Pattern Recognition Receptor fls2 is directed for degradation by the bacterial ubiquitin ligase avrptob
    Current Biology, 2008
    Co-Authors: Vera Gohre, Thomas Spallek, Thomas Boller, Heidrun Haweker, Sophia Mersmann, Tobias Mentzel, Marta De Torres, John W Mansfield, Silke Robatzek
    Abstract:

    Background: An important layer of active defense in plant immunity is the detection of pathogen-associated molecular Patterns (PAMPs) mediated by cell-surface Receptors. For the establishment of disease, pathogens depend on the ability to overcome PAMP perception and disable plant signaling pathways activated in response to PAMPs. Pattern Recognition Receptors (PRRs) are therefore prime targets for pathogen effectors. FLS2, its coReceptor BAK1, and EFR encode Receptor-like kinases that play a role in immunity against bacterial pathogens. Results: Here, we report that virulence of Pseudomonas syringae pv tomato DC3000 (PtoDC3000) in Arabidopsis is enhanced through the action of its effector AvrPtoB, which promotes degradation of FLS2. We show that AvrPtoB, through its N terminus, associates with FLS2 and BAK1, of which interaction with FLS2 is enhanced by flg22 activation. In vitro, AvrPtoB is active as an E3 ligase to catalyze polyubiquitination of the kinase domain of FLS2, a process confirmed in planta. Full enhancement of PtoDC3000 virulence appears to require the E3 ligase activity of AvrPtoB. Conclusions: AvrPtoB, initially identified through its activation of hypersensitive resistance in tomato cultivars expressing the Pto kinase, is composed of at least two functional domains: the N terminus is responsible for interaction with Pto, and the C terminus carries an E3 ligase activity. Based on our findings, we propose that both domains of AvrPtoB act together to support the virulence of PtoDC3000 in Arabidopsis through their ability to eliminate FLS2 from the cell periphery, and probably also other PAMP sensors that are constitutively expressed or induced after pathogen challenge.

  • ligand induced endocytosis of the Pattern Recognition Receptor fls2 in arabidopsis
    Genes & Development, 2006
    Co-Authors: Silke Robatzek, Delphine Chinchilla, Thomas Boller
    Abstract:

    Pattern-Recognition Receptors (PRRs) trigger innate immune responses in animals and plants. One such PRR is the flagellin Receptor FLS2 in Arabidopsis. Here, we demonstrate that a functional fusion of FLS2 to the green fluorescent protein (GFP) resides in cell membranes of most tissues. Stimulation with the flagellin epitope flg22 induces its transfer into intracellular mobile vesicles, followed by degradation. FLS2 internalization depends on cytoskeleton and proteasome functions, and Receptor activation. A variant FLS2 mutated in Thr 867, a potential phosphorylation site, binds flg22 normally, but is impaired in flg22 responses and FLS2 endocytosis. We propose that plant cells regulate pathogen-associated molecular Pattern (PAMP)-mediated PRR activities by subcellular compartmentalization.

Lingling Wang - One of the best experts on this subject based on the ideXlab platform.

  • a hypervariable immunoglobulin superfamily member from crassostrea gigas functions as Pattern Recognition Receptor with opsonic activity
    Developmental and Comparative Immunology, 2018
    Co-Authors: Dongyang Liu, Lingling Wang, Conghui Liu, Xiaorui Song, Changhao Gong, Jiejie Sun, Linsheng Song
    Abstract:

    lmmunoglobulin superfamily (IgSF), an extensive collection of proteins possessing at least one immunoglobulin-like (Ig-like) domain, performs a wide range of functions in Recognition, binding or adhesion process of cells. In the present study, a cysteine-rich motif associated immunoglobulin domain containing protein (designated CgCAICP-1) was identified in Pacific oyster Crassostrea gigas. The deduced protein sequence of CgCAICP-1 contained 534 amino acidresidues, with three Ig domains which were designated as IG1, IG2 and IG3, and a cysteine-rich motif between the first and second Ig domain. The mRNA transcripts of CgCAICP-1 were highly expressed in hemocytes and up-regulated significantly (p < 0.05) after the stimulation of Iipopolysaccharides (LPS), but not peptidoglycan (PGN). The recombinant CgCAICP-1 protein (rCgCAICP-1) exhibited binding activity to various pathogen-associated molecular Patterns (PAMPs) including LPS, PGN, mannose (Man) and D-galactose (D-Gal), and microorganisms including Vibrio splendidus, Escherichia coli, Staphylococcus aureus, Micrococcus luteus and Pichia pastoris. The phagocytic rates of oyster hemocytes towards Gram-negative bacteria V. splendidus and Gram-positive bacteria M. luteus were significantly enhanced (p < 0.05) after pre-incubation of microbes with rCgCAICP-1. Furthermore, the transcripts of CgCAICP-1 exhibited high level of polymorphism among individuals. The ratio of nonsynonymous and synonymous distances (dN/dS) for AA'BCC'D strands of IG1 (the possible binding sites 1, pbs1) across all allelic variants was 2.09 (p < 0.05), while the ratio for the non-pbs regions was less than 1.0. The 1248 bp fragment amplified from the 5' end of CgCAICP-1 open reading frame (ORF) from 24 transcript variants could be divided artificially into seven regions of 50 elements, and all of the allelic variants might be derived from these elements by point mutation and recombination processes. These results collectively suggested that CgCAICP-1 might function as an important Pattern Recognition Receptor (PRR) to recognize various PAMPs and facilitated the phagocytosis of oyster hemocytes towards both Gram-positive and Gram-negative bacteria. Diverse isoforms of CgCAICP-1 were generated through point mutation and recombination processes and maintained by balancing selection, which would provide a broader spectrum of interaction surface and be associated with immune resistance of oysters to infectious pathogens. (C) 2018 Elsevier Ltd. All rights reserved.

  • a dm9 containing protein from oyster crassostrea gigas cgdm9cp 2 serves as a multipotent Pattern Recognition Receptor
    Developmental and Comparative Immunology, 2018
    Co-Authors: Yu Liu, Zhihao Jia, Changhao Gong, Peng Zhang, Weilin Wang, Miren Dong, Min Wang, Zhaoqun Liu, Anguo Zhang, Lingling Wang
    Abstract:

    DM9 is a novel protein domain with unknown function originally discovered in Drosophila melanogaster. Recently, a protein harboring DM9 repeats was identified as mannose-specific lectin (CgCGL1, renamed as CgDM9CP-1) from the Pacific oyster Crassostrea gigas. In the present study, another DM9 containing protein was identified from oyster C. gigas (designated as CgDM9CP-2). The open reading frame of CgDM9CP-2 gene was of 432 bp, encoding a polypeptide of 143 amino acids with two tandem DM9 repeats. The deduced amino acid sequence of CgDM9CP-2 shared 60.8% identity with that of CgDM9CP-1. In the unrooted phylogenetic tree, CgDM9CP-2 was closely clustered with CgDM9CP-1, and then assigned into the branch of invertebrate DM9CPs. The mRNA transcripts of CgDM9CP-2 were expressed in all the tested tissues, including mantle, gonad, gills, adductor muscle, hemocytes, and hepatopancreas, with the highest expression level in gills. CgDM9CP-2 protein was mainly distributed on the cytomembrane of oyster hemocytes. After mannose stimulation, the mRNA expression of CgDM9CP-2 in gills was up regulated to the peak level (5.90-fold of that in SSW group, p < 0.05) at 24 h, and kept at a significantly higher level compared with that in control group at 6-48 h. It significantly increased at 6 h (2.33-fold, p <0.05), and 12 h (3.08-fold, p <0.05) post Vibrio splendidus stimulation, and then gradually decreased from 48 to 72 h (p < 0.05) with significant difference comparing with that in control group. The recombinant CgDM9CP-2 protein (rCgDM9CP-2) displayed higher binding affinity to D-(+)-mannose while lower binding affinity to lipopolysaccharide and peptidoglycan. rCgDM9CP-2 also exhibited binding activity towards fungi (Pichia pastoris and Yarrowia lipolytica), gram-positive bacteria (Staphylococcus aureus and Micrococcus luteus), and gram-negative bacteria (Escherichia colt, Vibrio anguillarum, Aeromonas hydrophila and V. splendidus). It could agglutinate fungi P. pastoris and Y. lipolytica, and inhibit the growth of P. pastoris, S. aureus, V anguillarum, and V. splendidus. These results collectively indicated that CgDM9CP-2 not only served as a Pattern Recognition Receptor with a broad range of Recognition spectrum, but also involved in inhibiting the growth of invading microbe in the innate immune response of oyster, which would provide further evidence for the function of DM9 domain in the innate immune system. (C) 2018 Elsevier Ltd. All rights reserved.

  • dm9 domain containing protein functions as a Pattern Recognition Receptor with broad microbial Recognition spectrum
    Frontiers in Immunology, 2017
    Co-Authors: Shuai Jiang, Lingling Wang, Mengmeng Huang, Zhihao Jia, T Weinert, Eberhard Warkentin, Conghui Liu, Xiaorui Song, Haixia Zhang, Jennifer Witt
    Abstract:

    DM9 domain was first identified in Drosophila melanogaster, and it was subsequently found to integrate with or without other protein domains across a wide range of invertebrates and vertebrates. In the present study, a member of DM9 domain containing protein (DM9CP) family from marine invertebrate Crassostrea gigas (designated CgDM9CP-1), which was only composed of two DM9 domains, was taken as a protein model to study the biological functions of DM9 domain and its molecular determinants. CgDM9CP-1 was found to exhibit high binding specificity and avidity toward d-mannose residue. It served as a Pattern Recognition Receptor (PRR) with a broad range of Recognition spectrum to various pathogen-associated molecular Patterns, including lipopolysaccharide, peptidylglycan, mannan, and β-1, 3-glucan in a d-mannose-dependent manner, as well as bacteria and fungi. In order to reveal the molecular mechanism underlying its Pattern Recognition activity, the crystal structures of wild-type and loss-of-function mutants were solved, and Asp22 and Lys43 were found to be the critical residues for ligand Recognition. Moreover, CgDM9CP-1 protein was found to mainly distribute on the surface of C. gigas hemocytes, and it could be translocated into cytoplasm and colocalized with the engulfed microbes during hemocyte phagocytosis. The present result clearly indicated that CgDM9CP-1 was a PRR, and it provided an important clue for the better understanding of DM9CP function.

  • an lrr only protein representing a new type of Pattern Recognition Receptor in chlamys farreri
    Developmental and Comparative Immunology, 2016
    Co-Authors: Mengqiang Wang, Lingling Wang, Ying Guo, Linsheng Song
    Abstract:

    Accumulating evidence has demonstrated that leucine-rich repeat (LRR)-only proteins could mediate protein-ligand and protein protein interactions and were involved in the immune response. In the present study, an LRR-only protein (designed as CfLRRop-1) was cloned from Zhikong scallop Chlamys farreri. The complete cDNA sequence of CfLRRop-1 contained an open reading frame (ORF) of 1377 bp, which encoded a protein of 458 amino acids. An LRRNT motif, an LRR_7 motif and seven LRR motifs were found in the deduced amino acid sequence of CfLRRop-1. And these seven LRR motifs contained a conserved signature sequence LxxLxxNxL. The mRNA transcripts of CfLRRop-1 were constitutively expressed in all the tested tissues, including haemocytes, muscle, mantle, gill, hepatopancreas and gonad, with the highest expression level in hepatopancreas. After the stimulation of lipopolysaccharide (LPS), peptidoglycan (PGN), glucan (GLU) and polyinosinic-polycytidylic acid (poly I:C), the mRNA transcripts of CARRop-1 in haemocytes all increased firstly within the first 6 h and secondly during 12-24 h post stimulation. The mRNA expression level of CfLRRop-1 was continuously up-regulated, after the expression of CfTLR (previously identified Toll-like Receptor in C. farreri) was suppressed via RNA interference (RNAi). The recombinant CfLRRop-1 protein could directly bind LPS, PGN, GLU and poly I:C, and induce the release of TNF-alpha in mixed primary cultured scallop haemocytes. These results collectively indicated that CfLRRop-1 would function as a powerful Pattern Recognition Receptor (PRR) and play a pivotal role in the immune response of scallops. (C) 2015 Elsevier Ltd. All rights reserved.

  • a c1q domain containing protein from crassostrea gigas serves as Pattern Recognition Receptor and opsonin with high binding affinity to lps
    Fish & Shellfish Immunology, 2015
    Co-Authors: Shuai Jiang, Lingling Wang, Huan Zhang, Daoxiang Zhang, Jinsheng Sun, Linsheng Song
    Abstract:

    C1q proteins serve as Pattern Recognition Receptors and involve in the pathogen Recognition and complement pathway activation. In the present study, a novel C1q domain containing protein from Crassostrea gigas (designated CgC1qDC-1) was isolated by liposaccharide-Sepharose 6B affinity chromatography. The coding sequence of CgC1 qDC-1 gene was determined by performing a homologous search of eight tryptic peptides identified by IVIALDI-TOF/TOF-MS against the genome of C. gigas. The coding sequence of CgC1qDC-1 was of 387 bp encoding a polypeptide of 128 amino acids containing a typical globular C1q domain. The globular C1q domain possessed eight beta strands with a jelly-roll topology structure, which was similar to the structure of human gC1q domain. The mRNA transcripts of CgC1 qDC-1 were dominantly expressed in mantle and hemocytes, while low expressed in hepatopancreas, gonad, gill and muscle. The expression level of CgC1qDC-1 increased drastically at 6 h after Vibrio splendidus stimulation, and then gradually fell to the normal level at about 24 h. ELISA assay quantified that CgC1qDC-1 bound to LPS with high binding affinity (Kd = 0.09 x 10(-6) M). Moreover, CgC1qDC-1 significantly enhanced the phagocytosis of oyster hemocytes towards Gram-negative bacteria Escherichia con and V. splendidus. These results collectively indicated that CgC1qDC-1 could serve as Pattern Recognition Receptor and opsonin in the innate immune response against invading Gram-negative bacteria. (C) 2015 Elsevier Ltd. All rights reserved.