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Hao Zhou_Ph D dissertation_Final.pdf (6.3 MB)

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The Regulatory Role of Interleukin-1 Receptor Associated Kinase M in Toll-Like Receptor Signaling

Zhou, Hao
http://rave.ohiolink.edu/etdc/view?acc_num=csu1459209358

Abstract Details

2016, Doctor of Philosophy in Regulatory Biology, Cleveland State University, College of Sciences and Health Professions.
Toll-like receptors (TLRs) are one of the major groups of pattern recognition receptors. TLRs are able to recognize the pathogen-associated molecular patterns and transduce their signals through the adaptor molecule MyD88 and members of the IL-1R-associated kinase family (IRAK1, 2, M and 4). IRAKM was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signaling. However, we now found that IRAKM was also able to interact with MyD88-IRAK4 to form IRAKM Myddosome to mediate TLR7-induced MEKK3-dependent second wave NF¿B activation. As a result, the IRAKM-dependent pathway only induced expression of genes that are not regulated at the posttranscriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and I¿Ba), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK2, IRAKM inhibited TLR7-mediated production of cytokines and chemokines at translational levels. While the TLR-mediated inflammatory response is critical for innate immunity and host defense against infections, uncontrolled inflammation is detrimental to the host, leading to chronic inflammatory diseases. Alcohol-induced liver injury is induced by necrosis of hepatocytes and increased translocation of endotoxin from the intestinal tract into hepatic portal system, which trigger chronic inflammation that is damaging to the liver together. We found that mice deficient of IRAKM, are protected from alcohol-induced liver injury. IRAKM mediates the up-regulation of Mincle, a receptor for danger signals release by damaged cells, in response to low level of LPS. Biochemical analysis revealed that low-dose LPS preferentially induces the formation of IRAKM Myddosome, leading to MEKK3-dependent NF¿B activation. Mincle-deficient mice are also protected from alcohol-induced liver injury. We found IRAKM deficiency and Mincle deficiency drastically reduced alcohol feeding induced inflammasome activation in the mouse liver. Ex vivo studies showed that both IRAKM and Mincle are required for inflammasome activation by endogenous Mincle ligand, SAP130, which is a danger signal release by damaged hepatocytes. Taken together, we identifies an IRAKM-Mincle axis critical for the pathogenesis of alcohol induced liver disease through the activation of inflammasome.
Xiaoxia Li, Ph.D (Committee Chair)
George Stark, Ph.D (Committee Member)
Crystal Weyman, Ph.D (Committee Member)
Mazumder Barsanjit , Ph.D (Committee Member)
Nagy Laura , Ph.D (Other)
190 p.
Biochemistry; Biology; Biomedical Research; Cellular Biology; Immunology
Immunology; IRAK; Toll-like Receptor; IL-1 Receptor; Mincle

Recommended Citations

Citations

  • Zhou, H. (2016). The Regulatory Role of Interleukin-1 Receptor Associated Kinase M in Toll-Like Receptor Signaling [Doctoral dissertation, Cleveland State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=csu1459209358

    APA Style (7th edition)

  • Zhou, Hao. The Regulatory Role of Interleukin-1 Receptor Associated Kinase M in Toll-Like Receptor Signaling. 2016. Cleveland State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=csu1459209358.

    MLA Style (8th edition)

  • Zhou, Hao. "The Regulatory Role of Interleukin-1 Receptor Associated Kinase M in Toll-Like Receptor Signaling." Doctoral dissertation, Cleveland State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=csu1459209358

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Cleveland State University and OhioLINK.