Kinase Activities of RIPK1 and RIPK3 Direct Host Immune Cytokine Production that Manifests Independent of Cell Death
Saleh, Danish.
2017
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Abstract: Macrophages function as a crucial component of the innate immune
system in sensing bacterial pathogens and promoting local and systemic inflammation. RIPK1
and RIPK3 are serine/threonine kinases that have been well-characterized as key regulators
of programmed necrotic cell death or necroptosis that is dependent on downstream
pseudokinase MLKL. The work presented in the ensuing chapt... read moreers describes a new function of
these kinases as master regulators of cytokine gene expression and the synthesis of
inflammatory mediators in primary macrophages activated by LPS, in the absence of caspase-8
activation. RIPK1 and RIPK3 kinase-dependent cytokine production requires the Toll-like
receptor 4 (TLR4) adaptor molecule, TRIF, and proceeds independently of MLKL and the
well-documented death functions of these kinases. Mechanistically, RIPK1 and RIPK3 kinases
promote sustained activation of at least two canonical cytokine response axes: the acute
inflammatory response mediated by downstream factors, Erk1/2, c-Fos, and NFᴋB; and the
Type-I interferon (IFN-I) response pathway mediated by TBK1/IKKε and IRF3/7. The evidence
summarized here suggests that detergent-insoluble complexes of RIPK1 and RIPK3 (necrosomes)
serve as a signaling platform to engage downstream signaling molecules. Using genetic and
pharmacologic tools, the data reveals that RIPK1 and RIPK3 kinase functions account for a
major fraction cytokine elicited by LPS challenge in vivo. Notably, in contrast to the
circumstance observed in vitro, the regulation in vivo did not require exogenous
manipulation of caspase-8 activity, suggesting that RIPK1 and RIPK3 kinase-dependent
cytokine responses may serve as a feature of the host-inflammatory response in
gram-negative bacterial (GNB) infection. Intriguingly, in primary macrophages, RIPK1 and
RIPK3 kinase-dependent synthesis of IFNβ can be markedly induced by a variety of
gram-negative bacterial species (Yersinia and Klebsiella). Furthermore, data show that
RIPK1 and RIPK3 kinase-dependent IFNβ synthesis is strongly induced by avirulent strains of
gram-negative bacteria, Yersinia and Klebsiella, and less-so by their wild-type
counterparts. Similarly, RIPK1 kinase-dependent TNFα synthesis is more pronounced following
in vivo infection with an avirulent strain of Klebsiella compared to the wild type. These
data suggest that TRIF-RIPK1-RIPK3 kinase-dependent signaling may be a mechanism of
immune-surveillance employed against non-pathogens or commensal bacteria. Conversely,
TRIF-RIPK1-RIPK3 signaling may be selectively suppressed by invading microbes to facilitate
bacterial pathogenesis. Consistent with this hypothesis, GNB species are armed with
specific mechanisms to attenuate RIPK1 and RIPK3 kinase-dependent signaling. As a result,
exogenous activation of TRIF-RIPK-RIPK3 kinase-dependent signaling may aid in the clearance
of GNB infection. Importantly, the findings reported here identify new drug-targetable
activities that may be relevant to infection and/or inflammatory pathologies associated
with inappropriate RIPK1 and RIPK3 kinase activation.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Neuroscience.
Advisor: Alexei Degterev.
Committee: Rob Jackson, Larry Feig, Joan Mecsas, and James Schwob.
Keywords: Immunology, Biochemistry, and Microbiology.read less - ID:
- 2227n168h
- Component ID:
- tufts:23412
- To Cite:
- DCA Citation Guide EndNote
