Unveiling The Mechanisms Of NLRs In Negatively Regulating The NF-?B And RLR-IFN Signaling Pathways

As the mechanisms of carcinogenesis being better and better understood, the chronic inflammation has been perceived as an important factor in the initial cell transformation and later tumor progression. The innate immunity, within which the NF-?B and RLR-IFN pathways play essential role in cytokines generation, works as the first defense against pathogen invasion. The activation of both the NF-?B and RLR-IFN pathways during infection require PAMPs recognition by the PRRs, which included the TLRs, NLRs and RLRs. As a result, the signal transductions lead to the secretion of inflammatory cytokines such as TNF-?, IL-6 and type?IFN, which in turn further trigger the activation of an even more complex signal transduction network and finally leads to effective innate immune response. However, increasing evidence suggests that excessive innate immune response give rise to the immunopathological alterations including inflammation related cancer. Thus, it is of great value to better understand the molecular mechanism of negative regulation of the innate immunity. Our work mainly focused on revealing the detailed mechanism for NLRC5 in regulating both the NF-?B and RLR-IFN pathways. Data shown in Part?suggested that NLRC5 complete with NEMO in binding with the IKK?/?molecules and prevent them form been phosphorylated. Knockdown of endogenous NLRC5 significantly increased NF-?B and IL-6 production under LPS stimulation. Besides, we also found that NLRC5 can be unregulated by NF-?B activation, in a MyD88 dependant way, forming a negative feed-back loop. Part II addressed the mechanism of NLRC5 in regulating RLR-IFN pathway, that is, by interacted with RIG-I and blocked the down stream signal transduction. We also showed the dynamic interaction between the endogenous RIG-I and NLRC5 interaction after VSV infection. Knockdown of NLRC5 not only increased the expression of IFNa?/?,but also enhanced the antiviral capability of the RAW264.7 cells. In the last part, we identified the ability of another NLR family member, NLRP4, in negative regulation of the RLR-IFN pathway, its related target and the functional domain. These work well dissected the detailed mechanism of NLRC5 in the negative regulation of the innate immune signal transduction, provided essential knowledge in supporting further utility of the NLR family members in control or healing the innate immune induced inflammatory disorders.