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 chap... read moreters 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
