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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

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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 4

Myd88 deletion specifically in pericytes attenuates injury and fibrotic responses following IRI.

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Myd88 deletion specifically in pericytes attenuates injury and fibrotic ...
(A–C) Transcription of inflammatory genes in kidneys from control and day 5 post-IRI kidneys from WT and Foxd1+/Cre Myd88fl/fl (referred to as mutant) mice. (D) Quantification of Ly6G+ neutrophils on kidney sections. (E–H) Representative images of kidney sections stained with Ly6G antibody, TUNEL, PAS, or Sirius red. (F) TUNEL+ cells are labeled green. (G) Necrotic tubules in PAS-stained sections are labeled with arrowheads. (H) Fibrosis is detected as red stain. (I–K) Graphs quantifying apoptotic (TUNEL+) cells (I), tubular injury score based on PAS-stained sections (J), and fibrosis score based on Sirius red staining (K). (L and M) Transcription of Col1a1 and Acta2. (Scale bars: 50 μm; n = 6 per group; *P < 0.05, 2-tailed Student’s t test or 2-way ANOVA, Bonferroni’s multiple comparisons test.)

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