Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury
Irina A. Leaf, … , William A. Altemeier, Jeremy S. Duffield
Irina A. Leaf, … , William A. Altemeier, Jeremy S. Duffield
Published November 21, 2016
Citation Information: J Clin Invest. 2017;127(1):321-334. https://doi.org/10.1172/JCI87532.
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Research Article Inflammation Nephrology

Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury

Abstract

Fibrotic disease is associated with matrix deposition that results in the loss of organ function. Pericytes, the precursors of myofibroblasts, are a source of pathological matrix collagens and may be promising targets for treating fibrogenesis. Here, we have shown that pericytes activate a TLR2/4- and MyD88-dependent proinflammatory program in response to tissue injury. Similarly to classic immune cells, pericytes activate the NLRP3 inflammasome, leading to IL-1β and IL-18 secretion. Released IL-1β signals through pericyte MyD88 to amplify this response. Unexpectedly, we found that MyD88 and its downstream effector kinase IRAK4 intrinsically control pericyte migration and conversion to myofibroblasts. Specific ablation of MyD88 in pericytes or pharmacological inhibition of MyD88 signaling by an IRAK4 inhibitor in vivo protected against kidney injury by profoundly attenuating tissue injury, activation, and differentiation of myofibroblasts. Our data show that in pericytes, MyD88 and IRAK4 are key regulators of 2 major injury responses: inflammatory and fibrogenic. Moreover, these findings suggest that disruption of this MyD88-dependent pathway in pericytes might be a potential therapeutic approach to inhibit fibrogenesis and promote regeneration.

Authors

Irina A. Leaf, Shunsaku Nakagawa, Bryce G. Johnson, Jin Joo Cha, Kristen Mittelsteadt, Kevin M. Guckian, Ivan G. Gomez, William A. Altemeier, Jeremy S. Duffield

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Figure 2

Activation of NLRP3 inflammasome by pericytes in response to DAMPs.

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Activation of NLRP3 inflammasome by pericytes in response to DAMPs. (A) ...
(A) Concentration of secreted IL-1β in WT and Nlrp3–/– and Casp1/11DKO pericytes 24 hours after treatment with LPS and ATP. (B) Western blot of intracellular pro–IL-1β and secreted mature IL-1β from pericytes 24 hours after treatment with LPS and ATP. (C) Western blot of pericyte cell lysates 24 hours after treatment with LPS, ATP, and DAMPs. (D and E) IL-1β and IL-18 concentration in WT and mutant pericyte supernatants after treatment with DAMPs and ATP. (F) IL-1β concentration in supernatants of WT, TLR2/4DKO, and Myd88–/– pericytes 24 hours after treatment with DAMPs. (G) Immunofluorescence staining for IL-1β, IL-6, and MCP-1 on sections from kidneys on day 1 after IRI. (H) IL-6 and MCP-1 cytokine response to IL-1β treatment in the supernatant of WT and Myd88–/– pericytes. (I) The effect of recombinant IL-1 receptor antagonist (IL1RA) on transcriptional response to DAMPs. (J and K) The effect of siRNA against Il1r1 on Il1r1 expression (J) and Il6 response to DAMPs (K). ND, not detected. KD, knockdown. (Scale bar: 25 μm; n = 3–6 per group; *P < 0.05, 2-tailed Student’s t test or 2-way ANOVA, Bonferroni’s multiple comparisons test.)