The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Shizuo Akira - One of the best experts on this subject based on the ideXlab platform.
-
MYD88 signaling inhibits protective immunity to the gastrointestinal helminth parasite heligmosomoides polygyrus
Journal of Immunology, 2014Co-Authors: Lisa A Reynolds, Shizuo Akira, James P Hewitson, Yvonne Harcus, Katherine A Smith, Lauren M Webb, Ewan A Ross, Sheila Brown, Satoshi Uematsu, David GrayAbstract:Helminth parasites remain one of the most common causes of infections worldwide, yet little is still known about the immune signaling pathways that control their expulsion. C57BL/6 mice are chronically susceptible to infection with the gastrointestinal helminth parasite Heligmosomoides polygyrus. In this article, we report that C57BL/6 mice lacking the adapter protein MYD88, which mediates signaling by TLRs and IL-1 family members, showed enhanced immunity to H. polygyrus infection. Alongside increased parasite expulsion, MYD88-deficient mice showed heightened IL-4 and IL-17A production from mesenteric lymph node CD4+ cells. In addition, MYD88−/− mice developed substantial numbers of intestinal granulomas around the site of infection, which were not seen in MYD88-sufficient C57BL/6 mice, nor when signaling through the adapter protein TRIF (TIR domain–containing adapter–inducing IFN-β adapter protein) was also ablated. Mice deficient solely in TLR2, TLR4, TLR5, or TLR9 did not show enhanced parasite expulsion, suggesting that these TLRs signal redundantly to maintain H. polygyrus susceptibility in wild-type mice. To further investigate signaling pathways that are MYD88 dependent, we infected IL-1R1−/− mice with H. polygyrus. This genotype displayed heightened granuloma numbers compared with wild-type mice, but without increased parasite expulsion. Thus, the IL-1R–MYD88 pathway is implicated in inhibiting granuloma formation; however, protective immunity in MYD88-deficient mice appears to be granuloma independent. Like IL-1R1−/− and MYD88−/− mice, animals lacking signaling through the type 1 IFN receptor (i.e., IFNAR1−/−) also developed intestinal granulomas. Hence, IL-1R1, MYD88, and type 1 IFN receptor signaling may provide pathways to impede granuloma formation in vivo, but additional MYD88-mediated signals are associated with inhibition of protective immunity in susceptible C57BL/6 mice.
-
MYD88 dependent signaling protects against anthrax lethal toxin induced impairment of intestinal barrier function
Infection and Immunity, 2011Co-Authors: Shu Okugawa, Shizuo Akira, Mahtab Moayeri, Michael Eckhaus, Devorah Crown, Sharmina Millerrandolph, Shihui Liu, Stephen H LepplaAbstract:MYD88-deficient mice were previously shown to have increased susceptibility to Bacillus anthracis infection relative to wild-type animals. To determine the mechanism by which MYD88 protects against B. anthracis infection, knockout mice were challenged with nonencapsulated, toxigenic B. anthracis or with anthrax toxins. MYD88-deficient mice had increased susceptibility to B. anthracis and anthrax lethal toxin but not to edema toxin. Lethal toxin alone induced marked multifocal intestinal ulcers in the knockout animals, compromising the intestinal epithelial barrier. The resulting enteric bacterial leakage in the knockout animals led to peritonitis and septicemia. Focal ulcers and erosion were also found in MYD88-heterozygous control mice but with far lower incidence and severity. B. anthracis infection also induced a similar enteric bacterial septicemia in MYD88-deficient mice but not in heterozygous controls. We show that lethal toxin and B. anthracis challenge induce bacteremia as a result of intestinal damage in MYD88-deficient mice. These results suggest that loss of the intestinal epithelial barrier and enteric bacterial septicemia may contribute to sensitizing MYD88-deficient mice to B. anthracis and that MYD88 plays a protective role against lethal toxin-induced impairment of intestinal barrier.
-
downstream signals for MYD88 mediated phagocytosis of borrelia burgdorferi can be initiated by trif and are dependent on pi3k
Journal of Immunology, 2009Co-Authors: Ok S Shin, Shizuo Akira, Lloyd S Miller, Robert L Modlin, Satoshi UematsuAbstract:We previously have shown that MYD88 is important for uptake of Borrelia burgdorferi by bone marrow derived macrophages (BMDMs). The mechanism by which MYD88 is involved in uptake of B. burgdorferi is currently is not well characterized. Here, we report that MYD88-mediated defect in the phagocytosis of B. burgdorferi can be complemented by TLR3/Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF) activation in BMDMs from MYD88 −/− mice. This effect of TLR3/TRIF activation was not due to its induction of type I IFNs, suggesting instead a convergence of signaling pathways downstream of MYD88 and TRIF. To characterize signaling pathways involved in MYD88-mediated phagocytosis of B. burgdorferi , BMDMs were treated with specific inhibitors of MAPK, protein kinase C, JAK/STAT, or PI3K. Only inhibition of PI3K resulted in a significant decrease of B. burgdorferi uptake. Consistent with this, B. burgdorferi activation of MYD88 or TLR3/TRIF signaling resulted in increased activity of PI3K. Additionally, association of B. burgdorferi with actin-related protein (Arp2/3) complexes, which facilitate actin rearrangements during phagocytosis, was similarly reduced in MYD88 −/− BMDMs and in BMDMs treated with a PI3K inhibitor. Taken together, these findings define an essential pathway whereby downstream signals from MYD88 or TRIF converge on PI3K, which triggers actin polymerization to initiate the phagocytosis of B. burgdorferi .
-
containment of aerogenic mycobacterium tuberculosis infection in mice does not require MYD88 adaptor function for tlr2 4 and 9
European Journal of Immunology, 2008Co-Authors: Christoph Holscher, Norbert Reiling, Ulrich E Schaible, Alexandra Holscher, Clara Bathmann, Daniel S Korbel, Insa Lenz, Tanja Sonntag, Svenja Kroger, Shizuo AkiraAbstract:The role of Toll-like receptors (TLR) and MYD88 for immune responses to Mycobacterium tuberculosis (Mtb) infection remains controversial. To address the impact of TLR-mediated pathogen recognition and MYD88-dependent signaling events on anti-mycobacterial host responses, we analyzed the outcome of Mtb infection in TLR2/4/9 triple- and MYD88-deficient mice. After aerosol infection, both TLR2/4/9-deficient and wild-type mice expressed pro-inflammatory cytokines promoting antigen-specific T cells and the production of IFN-gamma to similar extents. Moreover, TLR2/4/9-deficient mice expressed IFN-gamma-dependent inducible nitric oxide synthase and LRG-47 in infected lungs. MYD88-deficient mice expressed pro-inflammatory cytokines and were shown to expand IFN-gamma-producing antigen-specific T cells, albeit in a delayed fashion. Only mice that were deficient for MYD88 rapidly succumbed to unrestrained mycobacterial growth, whereas TLR2/4/9-deficient mice controlled Mtb replication. IFN-gamma-dependent restriction of mycobacterial growth was severely impaired only in Mtb-infected MYD88, but not in TLR2/4/9-deficient bone marrow-derived macrophages. Our results demonstrate that after Mtb infection neither TLR2, -4, and -9, nor MYD88 are required for the induction of adaptive T cell responses. Rather, MYD88, but not TLR2, TLR4 and TLR9, is critical for triggering macrophage effector mechanisms central to anti-mycobacterial defense.
-
myeloid differentiation factor 88 plays a crucial role in the pathogenesis of coxsackievirus b3 induced myocarditis and influences type i interferon production
Circulation, 2005Co-Authors: Koichi Fuse, Shizuo Akira, Grace Chan, Youan Liu, Patrick Gudgeon, Mansoor Husain, Manyin Chen, Wenchen Yeh, Peter LiuAbstract:Background—Myeloid differentiation factor (MyD)-88 is a key adaptor protein that plays a major role in the innate immune pathway. How MYD88 may regulate host response in inflammatory heart disease is unknown. Methods and Results—We found that the cardiac protein level of MYD88 was significantly increased in the hearts of wild-type mice after exposure to Coxsackievirus B3 (CVB3). MYD88 / mice showed a dramatic higher survival rate (86%) in contrast to the low survival (35%) in the MYD88 / mice after CVB3 infection (P0.0001). Pathological examination showed a significant decrease of cardiac and pancreatic inflammation in the MYD88 / mice. Viral concentrations in the hearts were significantly decreased in the MYD88 / mice. Cardiac mRNA levels for interleukin (IL)-1, tumor necrosis factor (TNF)-, interferon (IFN)-, and IL-18 were significantly decreased in the MYD88 / mice. Similarly, serum levels of T-helper 1 cytokines were significantly decreased in the MYD88 / mice. In contrast, cardiac protein levels of the activated interferon regulatory factor (IRF)-3 and IFN- were significantly increased in the MYD88 / mice but not other usual upstream signals to IRF-3. The cardiac expression of coxsackie-adenoviral receptor and p56 lck were also significantly decreased. Conclusions—MYD88 appears to be a key contributor to cardiac inflammation, mediating cytokine production and T-helper-1/2 cytokine balance, increasing coxsackie-adenoviral receptor and p56 lck expression and viral titers after CVB3 exposure. Absence of MYD88 confers host protection possibly through novel direct activation of IRF-3 and IFN-. (Circulation. 2005;112:2276-2285.)
Kiyoshi Takeda - One of the best experts on this subject based on the ideXlab platform.
-
toll like receptor 2 pathway drives streptococcal cell wall induced joint inflammation critical role of myeloid differentiation factor 88
Journal of Immunology, 2003Co-Authors: Leo A B Joosten, Kiyoshi Takeda, Shizuo Akira, Marije I Koenders, Ruben L Smeets, Marleen Heuvelmansjacobs, Monique M Helsen, Erik Lubberts, Fons A J Van De Loo, Wim B Van Den BergAbstract:The IL-1R/Toll-like receptor (TLR) superfamily of receptors has a key role in innate immunity and inflammation. In this study, we report that streptococcal cell wall (SCW)-induced joint inflammation is predominantly dependent on TLR-2 signaling, since TLR-2-deficient mice were unable to develop either joint swelling or inhibition of cartilage matrix synthesis. Myeloid differentiation factor 88 (MYD88) is a Toll/IL-1R domain containing adaptor molecule known to have a central role in both IL-1R/IL-18R and TLR signaling. Mice deficient for MYD88 did not develop SCW-induced arthritis; both joint swelling and disturbance of cartilage chondrocyte anabolic function was completely abolished. Local levels of proinflammatory cytokines and chemokines in synovial tissue washouts were strongly reduced in MYD88-deficient mice. Histology confirmed the pivotal role of MYD88 in acute joint inflammation. TLR-2-deficient mice still allow influx of inflammatory cells into the joint cavity, although the number of cells was markedly reduced. No influx of inflammatory cells was seen in joints of MYD88-deficient mice. In addition, cartilage matrix proteoglycan loss was completely absent in MYD88 knockout mice. These findings clearly demonstrated that MYD88 is a key component in SCW-induced joint inflammation. Since agonists of the Toll-like pathway are abundantly involved in both septic and rheumatoid arthritis, targeting of MYD88 may be a novel therapy in inflammatory joint diseases.
-
mycobacterial infection in MYD88 deficient mice
Microbiology and Immunology, 2003Co-Authors: Isamu Sugawara, Kiyoshi Takeda, Hiroyuki Yamada, Satoru Mizuno, Shizuo AkiraAbstract:MYD88 is an adaptor protein that plays a major role in TLR/IL-1 receptor family signaling. To understand the role of MYD88 in the development of murine tuberculosis in vivo, MYD88 knockout (KO) mice aerially were infected with Mycobacterium tuberculosis. Infected MYD88 mice were not highly susceptible to M. tuberculosis infection, but they developed granulomatous pulmonary lesions with neutrophil infiltration which were larger than those in wild-type (WT) mice (P<0.01). The pulmonary tissue levels of mRNA for iNOS and IL-18 were slightly lower, but levels of mRNA for IL-1β, IL-2, IL-4, IL-6, IL-10, IFN-γ, and TGF-β were higher in MYD88 KO mice. IFN-γ, TNF-α, IL-1β, and IL-12 also were high in the sera of MYD88 KO mice. There were no statistically significant differences in the expression of TNF-α, IL-12, and ICAM-1 mRNA between MYD88 KO and WT mice. Thus, MYD88 deficiency did not influence the development of murine tuberculosis. NF-κB activity was similar in the alveolar macrophages from the lung tissues of MYD88 KO and WT mice. Also, there may be a TLR2-specific, MYD88-independent IL-1 receptor/TLR-mediated pathway to activate NF-κB in the host defense against mycobacterial infection.
-
cutting edge a novel toll il 1 receptor domain containing adapter that preferentially activates the ifn beta promoter in the toll like receptor signaling
Journal of Immunology, 2002Co-Authors: Masahiro Yamamoto, Kiyotoshi Mori, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Kiyoshi TakedaAbstract:MYD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MYD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MYD88 adapter-like, a second adapter harboring the TIR domain, is essential for MYD88-dependent TLR2 and TLR4 signaling pathways, but not for MYD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-β (TRIF). As is the case in MYD88 and TIRAP, overexpression of TRIF activated the NF-κB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-κB activation. Furthermore, TRIF, but neither MYD88 nor TIRAP, activated the IFN-β promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-κB-dependent and IFN-β promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MYD88-independent pathway.
-
cutting edge a novel toll il 1 receptor domain containing adapter that preferentially activates the ifn beta promoter in the toll like receptor signaling
Journal of Immunology, 2002Co-Authors: Masahiro Yamamoto, Kiyotoshi Mori, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Kiyoshi Takeda, Shizuo AkiraAbstract:MYD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MYD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MYD88 adapter-like, a second adapter harboring the TIR domain, is essential for MYD88-dependent TLR2 and TLR4 signaling pathways, but not for MYD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-beta (TRIF). As is the case in MYD88 and TIRAP, overexpression of TRIF activated the NF-kappaB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. Furthermore, TRIF, but neither MYD88 nor TIRAP, activated the IFN-beta promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MYD88-independent pathway.
-
a variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MYD88 dependent and independent pathways
International Immunology, 2002Co-Authors: Shintaro Sato, Osamu Takeuchi, Kiyoshi Takeda, Takashi Fujita, Hideyuki Tomizawa, Shizuo AkiraAbstract:Exposure of macrophages to lipopolysaccharide (LPS) induces a hypo-responsive state to a second challenge with LPS that is termed LPS tolerance. LPS tolerance is also induced by pre-exposure to lipopeptides and lipoteichoic acid, which trigger Toll-like receptor (TLR) 2-mediated signaling. LPS signaling involves at least two pathways: a MYD88-dependent cascade that is essential for production of inflammatory cytokines and a MYD88-independent cascade that mediates the expression of IFN-inducible genes. We analyzed the induction of LPS tolerance by several microbial components in mouse peritoneal macrophages. Pre-exposure to LPS led to impaired activation of both the pathways. In contrast, mycoplasmal lipopeptides did not affect the MYD88-independent pathway, but impaired the MYD88-dependent signaling by inhibiting LPS-mediated activation of IL-1 receptor-associated kinase (IRAK) 1. The induction of LPS tolerance by recently identified TLR ligands was analyzed. Pretreatment with double-stranded RNA, which triggers the activation of TLR3, led to defective activation of the MYD88-independent, but not the MYD88-dependent, pathway. Imidazoquinoline compounds, which are recognized by TLR7, had no effect on the MYD88-independent pathway, but inhibited LPS-induced activation of MYD88-dependent signaling through down-regulation of IRAK1 expression. Thus, each microbial component induced LPS tolerance in macrophages.
Masahiro Yamamoto - One of the best experts on this subject based on the ideXlab platform.
-
MYD88 but not trif is essential for osteoclastogenesis induced by lipopolysaccharide diacyl lipopeptide and il 1α
Journal of Experimental Medicine, 2004Co-Authors: Nobuaki Sato, Ken-ichiro Shibata, Naoyuki Takahashi, Koji Suda, Midori Nakamura, Mariko Yamaki, Tadashi Ninomiya, Yasuhiro Kobayashi, Haruhiko Takada, Masahiro YamamotoAbstract:Myeloid differentiation factor 88 (MYD88) plays essential roles in the signaling of the Toll/interleukin (IL)-1 receptor family. Toll–IL-1 receptor domain-containing adaptor inducing interferon-β (TRIF)-mediated signals are involved in lipopolysaccharide (LPS)-induced MYD88-independent pathways. Using MYD88-deficient (MYD88−/−) mice and TRIF-deficient (TRIF−/−) mice, we examined roles of MYD88 and TRIF in osteoclast differentiation and function. LPS, diacyl lipopeptide, and IL-1α stimulated osteoclastogenesis in cocultures of osteoblasts and hemopoietic cells obtained from TRIF−/− mice, but not MYD88−/− mice. These factors stimulated receptor activator of nuclear factor-κB ligand mRNA expression in TRIF−/− osteoblasts, but not MYD88−/− osteoblasts. LPS stimulated IL-6 production in TRIF−/− osteoblasts, but not TRIF−/− macrophages. LPS and IL-1α enhanced the survival of TRIF−/− osteoclasts, but not MYD88−/− osteoclasts. Diacyl lipopeptide did not support the survival of osteoclasts because of the lack of Toll-like receptor (TLR)6 in osteoclasts. Macrophages expressed both TRIF and TRIF-related adaptor molecule (TRAM) mRNA, whereas osteoblasts and osteoclasts expressed only TRIF mRNA. Bone histomorphometry showed that MYD88−/− mice exhibited osteopenia with reduced bone resorption and formation. These results suggest that the MYD88-mediated signal is essential for the osteoclastogenesis and function induced by IL-1 and TLR ligands, and that MYD88 is physiologically involved in bone turnover.
-
cutting edge a novel toll il 1 receptor domain containing adapter that preferentially activates the ifn beta promoter in the toll like receptor signaling
Journal of Immunology, 2002Co-Authors: Masahiro Yamamoto, Kiyotoshi Mori, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Kiyoshi TakedaAbstract:MYD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MYD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MYD88 adapter-like, a second adapter harboring the TIR domain, is essential for MYD88-dependent TLR2 and TLR4 signaling pathways, but not for MYD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-β (TRIF). As is the case in MYD88 and TIRAP, overexpression of TRIF activated the NF-κB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-κB activation. Furthermore, TRIF, but neither MYD88 nor TIRAP, activated the IFN-β promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-κB-dependent and IFN-β promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MYD88-independent pathway.
-
cutting edge a novel toll il 1 receptor domain containing adapter that preferentially activates the ifn beta promoter in the toll like receptor signaling
Journal of Immunology, 2002Co-Authors: Masahiro Yamamoto, Kiyotoshi Mori, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Kiyoshi Takeda, Shizuo AkiraAbstract:MYD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MYD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MYD88 adapter-like, a second adapter harboring the TIR domain, is essential for MYD88-dependent TLR2 and TLR4 signaling pathways, but not for MYD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-beta (TRIF). As is the case in MYD88 and TIRAP, overexpression of TRIF activated the NF-kappaB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. Furthermore, TRIF, but neither MYD88 nor TIRAP, activated the IFN-beta promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MYD88-independent pathway.
Zachary R Hunter - One of the best experts on this subject based on the ideXlab platform.
-
genomic landscape of waldenstrom macroglobulinemia and its impact on treatment strategies
Journal of Clinical Oncology, 2020Co-Authors: Steven P Treon, Xia Liu, Zachary R Hunter, Maria Demos, Manit Munshi, Maria Luisa Guerrera, Gloria Chan, Cristina Jimenez, Joshua Gustine, Nicholas TsakmaklisAbstract:Next-generation sequencing has revealed recurring somatic mutations in Waldenstrom macroglobulinemia (WM), including MYD88 (95%-97%), CXCR4 (30%-40%), ARID1A (17%), and CD79B (8%-15%). Deletions involving chromosome 6q are common in patients with mutated MYD88 and include genes that modulate NFKB, BCL2, Bruton tyrosine kinase (BTK), and apoptosis. Patients with wild-type MYD88 WM show an increased risk of transformation and death and exhibit many mutations found in diffuse large B-cell lymphoma. The discovery of MYD88 and CXCR4 mutations in WM has facilitated rational drug development, including the development of BTK and CXCR4 inhibitors. Responses to many agents commonly used to treat WM, including the BTK inhibitor ibrutinib, are affected by MYD88 and/or CXCR4 mutation status. The mutation status of both MYD88 and CXCR4 can be used for a precision-guided treatment approach to WM.
-
syk is activated by mutated MYD88 and drives pro survival signaling in MYD88 driven b cell lymphomas
Blood Cancer Journal, 2020Co-Authors: Manit Munshi, Xia Liu, Jiaji G Chen, Nicholas Tsakmaklis, Maria Demos, Amanda Kofides, Maria Luisa Guerrera, Gloria Chan, Cristina Jimenez, Zachary R HunterAbstract:Activating MYD88 mutations promote pro-survival signaling through BTK and HCK, both targets of ibrutinib. Despite high response rates, complete responses to ibrutinib are lacking, and other MYD88 triggered pro-survival pathways may contribute to primary drug resistance. B-cell receptor (BCR) signaling has been observed in lymphomas driven by mutated MYD88, even without activating the BCR pathway mutations. We identified activated SYK (p-SYK), a component of BCR in complex with MYD88 in MYD88-mutated WM and ABC DLBCL lymphoma cells. Confocal microscopy confirmed co-localization of MYD88 with SYK in MYD88-mutated cells. Knockdown of MYD88 or use of a MYD88 signaling inhibitor abrogated SYK activation, while expression of mutated but not wild-type MYD88 amplified p-SYK in MYD88-mutated and wild-type lymphoma cells. Knockdown of SYK or use of inhibitors targeting SYK blocked p-STAT3 and p-AKT signaling in MYD88-mutated cells. Cell viability analysis showed that combining ibrutinib and SYK inhibitors triggered synthetic killing of MYD88-mutated lymphoma cells. Our findings extend the spectrum of mutated MYD88 pro-survival signaling to include SYK directed BCR cross talk in MYD88-mutated lymphomas. Targeting SYK in combination with ibrutinib produces synthetic lethality, providing a framework for the clinical investigation of ibrutinib with SYK inhibitors in MYD88-mutated lymphomas.
-
expression of the prosurvival kinase hck requires pax5 and mutated MYD88 signaling in MYD88 driven b cell lymphomas
Blood Advances, 2020Co-Authors: Xia Liu, Zachary R Hunter, Jiaji G Chen, Nicholas Tsakmaklis, Maria Demos, Manit Munshi, Amanda Kofides, Maria Luisa Guerrera, Gloria Chan, Cristina JimenezAbstract:Hematopoietic cell kinase (HCK) is an SRC family member that is aberrantly upregulated in B-cell neoplasms dependent on MYD88-activating mutations and supports their growth and survival. We showed herein that activation of Toll-like receptor (TLR) signaling in MYD88 wild-type B cells also triggered HCK expression, denoting on path regulatory function for HCK by MYD88. To clarify the signaling cascades responsible for aberrant HCK expression in MYD88-mutated B-cell lymphomas, we performed promoter-binding transcription factor (TF) profiling, PROMO weighted TF consensus binding motif analysis, and chromatin immunoprecipitation studies. We identified PAX5, and the mutated MYD88 downstream signaling mediators STAT3, NF-κB, and AP-1, as important drivers of HCK transcription. Knockdown of PAX5, a crucial regulatory factor required for B-cell commitment and identity, abrogated HCK transcription in MYD88-mutated lymphoma cells. Among AP-1 complex components, JunB showed greatest relevance to TLR/MYD88 signaling and HCK transcription regulation. In MYD88-mutated Waldenstrom macroglobulinemia and activated B-cell-diffuse large B-cell lymphoma cells, knockdown of MYD88 reduced phosphorylation of JunB but not c-Jun, and knockdown of JunB reduced HCK protein levels. Deletion of STAT3, NF-κB, and AP-1 binding sites reduced corresponding TFs binding and HCK promoter activity. Moreover, inhibitors to STAT3, NF-κB, and AP-1 reduced HCK promoter activity and messenger RNA levels, particularly in combination, in MYD88-mutated lymphoma cells. The findings provide new insights into the transcriptional regulation of HCK prosurvival signaling by mutated MYD88, and the importance of JunB as a downstream mediator of the MYD88-directed signaling apparatus.
-
genomics signaling and treatment of waldenstrom macroglobulinemia
Journal of Clinical Oncology, 2017Co-Authors: Zachary R Hunter, Guang Yang, Xia Liu, Jorge J Castillo, Steven P TreonAbstract:Next-generation sequencing has revealed recurring somatic mutations in Waldenstrom macroglobulinemia (WM). Commonly recurring mutations include MYD88 (95% to 97%), CXCR4 (30% to 40%), ARID1A (17%), and CD79B (8% to 15%). Diagnostic discrimination of WM from overlapping B-cell malignancies is aided by MYD88 mutation status. Transcription is affected by MYD88 and CXCR4 mutations and includes overexpression of genes involved in VDJ recombination, CXCR4 pathway signaling, and BCL2 family members. Among patients with MYD88 mutations, those with CXCR4 mutations show transcriptional silencing of tumor suppressors associated with acquisition of mutated MYD88. Deletions involving chromosome 6q are common and include genes that modulate nuclear factor-κB, BCL2, BTK, apoptosis, differentiation, and ARID1B. Non-chromosome 6q genes are also frequently deleted and include LYN, a regulator of B-cell receptor signaling. MYD88 and CXCR4 mutations affect WM disease presentation and treatment outcome. Patients with wild-type MYD88 show lower bone marrow disease burden and serum immunoglobulin M levels but show an increased risk of death. Patients with CXCR4 mutations have higher bone marrow disease burden, and those with nonsense CXCR4 mutations have higher serum immunoglobulin M levels and incidence of symptomatic hyperviscosity. Mutated MYD88 triggers BTK, IRAK1/IRAK4, and HCK growth and survival signaling, whereas CXCR4 mutations promote AKT and extracellular regulated kinase-1/2 signaling and drug resistance in the presence of its ligand CXCL12. Ibrutinib is active in patients with WM and is affected by MYD88 and CXCR4 mutation status. Patients with mutated MYD88 and wild-type CXCR4 mutation status exhibit best responses to ibrutinib. Lower response rates and delayed responses to ibrutinib are associated with mutated CXCR4 in patients with WM. MYD88 and CXCR4 mutation status may be helpful in treatment selection for symptomatic patients. Novel therapeutic approaches under investigation include therapeutics targeting MYD88, CXCR4, and BCL2 signaling.
-
somatic mutations in MYD88 and cxcr4 are determinants of clinical presentation and overall survival in waldenstrom macroglobulinemia
Blood, 2014Co-Authors: Steven P Treon, Guang Yang, Xia Liu, Yang Cao, Zachary R HunterAbstract:Whole genome sequencing has revealed activating somatic mutations in MYD88 (L265P) and CXCR4 in Waldenstrom macroglobulinemia (WM). CXCR4 somatic mutations in WM are the first ever reported in human cancer and are similar to nonsense (NS) and frameshift (FS) germline mutations found in warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome. We genotyped lymphoplasmacytic cells from 175 WM patients and observed significantly higher bone marrow (BM) disease involvement, serum immunoglobulin-M levels, and symptomatic disease requiring therapy, including hyperviscosity syndrome in those patients with MYD88(L265P)CXCR4(WHIM/NS) mutations (P < .03). Patients with MYD88(L265P)CXCR4(WHIM/FS) or MYD88(L265P)CXCR4(WILDTYPE (WT)) had intermediate BM and serum immunoglobulin-M levels; those with MYD88(WT)CXCR4(WT) showed lowest BM disease burden. Fewer patients with MYD88(L265P) and CXCR4(WHIM/FS or NS) vs MYD88(L265P)CXCR4(WT) presented with adenopathy (P < .01), further delineating differences in disease tropism based on CXCR4 status. Neither MYD88 nor CXCR4 mutations correlated with SDF-1a (RS1801157) polymorphisms in 54 patients who were genotyped for these variants. Unexpectedly, risk of death was not impacted by CXCR4 mutation status, but by MYD88(WT) status (hazard ratio 10.54; 95% confidence interval 2.4-46.2, P = .0018). Somatic mutations in MYD88 and CXCR4 are important determinants of clinical presentation and impact overall survival in WM. Targeted therapies directed against MYD88 and/or CXCR4 signaling may provide a personalized treatment approach to WM.
Osamu Takeuchi - One of the best experts on this subject based on the ideXlab platform.
-
cutting edge a novel toll il 1 receptor domain containing adapter that preferentially activates the ifn beta promoter in the toll like receptor signaling
Journal of Immunology, 2002Co-Authors: Masahiro Yamamoto, Kiyotoshi Mori, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Kiyoshi TakedaAbstract:MYD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MYD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MYD88 adapter-like, a second adapter harboring the TIR domain, is essential for MYD88-dependent TLR2 and TLR4 signaling pathways, but not for MYD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-β (TRIF). As is the case in MYD88 and TIRAP, overexpression of TRIF activated the NF-κB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-κB activation. Furthermore, TRIF, but neither MYD88 nor TIRAP, activated the IFN-β promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-κB-dependent and IFN-β promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MYD88-independent pathway.
-
cutting edge a novel toll il 1 receptor domain containing adapter that preferentially activates the ifn beta promoter in the toll like receptor signaling
Journal of Immunology, 2002Co-Authors: Masahiro Yamamoto, Kiyotoshi Mori, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Kiyoshi Takeda, Shizuo AkiraAbstract:MYD88 is a Toll/IL-1 receptor (TIR) domain-containing adapter common to signaling pathways via Toll-like receptor (TLR) family. However, accumulating evidence demonstrates the existence of a MYD88-independent pathway, which may explain unique biological responses of individual TLRs, particularly TLR3 and TLR4. TIR domain-containing adapter protein (TIRAP)/MYD88 adapter-like, a second adapter harboring the TIR domain, is essential for MYD88-dependent TLR2 and TLR4 signaling pathways, but not for MYD88-independent pathways. Here, we identified a novel TIR domain-containing molecule, named TIR domain-containing adapter inducing IFN-beta (TRIF). As is the case in MYD88 and TIRAP, overexpression of TRIF activated the NF-kappaB-dependent promoter. A dominant-negative form of TRIF inhibited TLR2-, TLR4-, and TLR7-dependent NF-kappaB activation. Furthermore, TRIF, but neither MYD88 nor TIRAP, activated the IFN-beta promoter. Dominant-negative TRIF inhibited TLR3-dependent activation of both the NF-kappaB-dependent and IFN-beta promoters. TRIF associated with TLR3 and IFN regulatory factor 3. These findings suggest that TRIF is involved in the TLR signaling, particularly in the MYD88-independent pathway.
-
endotoxin can induce MYD88 deficient dendritic cells to support th2 cell differentiation
International Immunology, 2002Co-Authors: Tsuneyasu Kaisho, Osamu Takeuchi, Katsuaki Hoshino, Tomio Iwabe, Teruhito Yasui, Shizuo AkiraAbstract:Toll-like receptor (TLR) signaling activates dendritic cells (DC) to secrete proinflammatory cytokines and up-regulate co-stimulatory molecule expression, thereby linking innate and adaptive immunity. A TLR-associated adapter protein, MYD88, is essential for cytokine production induced by TLR. However, in response to a TLR4 ligand, lipopolysaccharide (LPS), MYD88-deficient (MYD88 ‐/‐ ) DC can up-regulate co-stimulatory molecule expression and enhance their T cell stimulatory activity, indicating that the MYD88-independent pathway through TLR4 can induce some features of DC maturation. In this study, we have further characterized function of LPS-stimulated, MYD88 ‐/‐ DC. In response to LPS, wild-type DC could enhance their ability to induce IFN-g production in allogeneic mixed lymphocyte reaction (alloMLR). In contrast, in response to LPS, MYD88 ‐/‐ DC augmented their ability to induce IL-4 instead of IFN-g in alloMLR. Impaired production of Th1-inducing cytokines in MYD88 ‐/‐ DC cannot fully account for their increased Th2 cell-supporting ability, because absence of Th1-inducing cytokines in DC caused impairment of IFN-g, but did not lead to augmentation of IL-4 production in alloMLR. In vivo experiments with adjuvants also revealed Th2-skewed immune responses in MYD88 ‐/‐ mice. These results demonstrate that the MYD88-independent pathway through TLR4 can confer on DC the ability to support Th2 immune responses.
-
a variety of microbial components induce tolerance to lipopolysaccharide by differentially affecting MYD88 dependent and independent pathways
International Immunology, 2002Co-Authors: Shintaro Sato, Osamu Takeuchi, Kiyoshi Takeda, Takashi Fujita, Hideyuki Tomizawa, Shizuo AkiraAbstract:Exposure of macrophages to lipopolysaccharide (LPS) induces a hypo-responsive state to a second challenge with LPS that is termed LPS tolerance. LPS tolerance is also induced by pre-exposure to lipopeptides and lipoteichoic acid, which trigger Toll-like receptor (TLR) 2-mediated signaling. LPS signaling involves at least two pathways: a MYD88-dependent cascade that is essential for production of inflammatory cytokines and a MYD88-independent cascade that mediates the expression of IFN-inducible genes. We analyzed the induction of LPS tolerance by several microbial components in mouse peritoneal macrophages. Pre-exposure to LPS led to impaired activation of both the pathways. In contrast, mycoplasmal lipopeptides did not affect the MYD88-independent pathway, but impaired the MYD88-dependent signaling by inhibiting LPS-mediated activation of IL-1 receptor-associated kinase (IRAK) 1. The induction of LPS tolerance by recently identified TLR ligands was analyzed. Pretreatment with double-stranded RNA, which triggers the activation of TLR3, led to defective activation of the MYD88-independent, but not the MYD88-dependent, pathway. Imidazoquinoline compounds, which are recognized by TLR7, had no effect on the MYD88-independent pathway, but inhibited LPS-induced activation of MYD88-dependent signaling through down-regulation of IRAK1 expression. Thus, each microbial component induced LPS tolerance in macrophages.
-
Lipopolysaccharide stimulates the MYD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes.
Journal of immunology (Baltimore Md. : 1950), 2001Co-Authors: Taro Kawai, Osamu Takeuchi, Shintaro Sato, Katsuaki Hoshino, Takashi Fujita, Jun-ichiro Inoue, Peter F. Mühlradt, Shizuo AkiraAbstract:Bacterial lipopolysaccharide (LPS) triggers innate immune responses through Toll-like receptor (TLR) 4, a member of the TLR family that participates in pathogen recognition. TLRs recruit a cytoplasmic protein, MYD88, upon pathogen recognition, mediating its function for immune responses. Two major pathways for LPS have been suggested in recent studies, which are referred to as MYD88-dependent and -independent pathways. We report in this study the characterization of the MYD88-independent pathway via TLR4. MYD88-deficient cells failed to produce inflammatory cytokines in response to LPS, whereas they responded to LPS by activating IFN-regulatory factor 3 as well as inducing the genes containing IFN-stimulated regulatory elements such as IP-10. In contrast, a lipopeptide that activates TLR2 had no ability to activate IFN-regulatory factor 3. The MYD88-independent pathway was also activated in cells lacking both MYD88 and TNFR-associated factor 6. Thus, TLR4 signaling is composed of at least two distinct pathways, a MYD88-dependent pathway that is critical to the induction of inflammatory cytokines and a MYD88/TNFR-associated factor 6-independent pathway that regulates induction of IP-10.
