TY - JOUR
T1 - Pericyte MyD88 and IRAK4 control inflammatory and fibrotic responses to tissue injury
AU - Leaf, Irina A.
AU - Nakagawa, Shunsaku
AU - Johnson, Bryce G.
AU - Cha, Jin Joo
AU - Mittelsteadt, Kristen
AU - Guckian, Kevin M.
AU - Gomez, Ivan G.
AU - Altemeier, William A.
AU - Duffield, Jeremy S.
N1 - Funding Information:
These studies were funded by Biogen, by NIH grants (DK087389, DK093493, DK094768, HL122895, TR000504), and by an American Heart Association grant (12040023).
PY - 2017/1/3
Y1 - 2017/1/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85008354898&partnerID=8YFLogxK
U2 - 10.1172/JCI87532
DO - 10.1172/JCI87532
M3 - Article
C2 - 27869651
AN - SCOPUS:85008354898
SN - 0021-9738
VL - 127
SP - 321
EP - 334
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -