TY - JOUR
T1 - C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury
AU - Tanaka, Miyako
AU - Saka-Tanaka, Marie
AU - Ochi, Kozue
AU - Fujieda, Kumiko
AU - Sugiura, Yuki
AU - Miyamoto, Tomofumi
AU - Kohda, Hiro
AU - Ito, Ayaka
AU - Miyazawa, Taiki
AU - Matsumoto, Akira
AU - Aoe, Seiichiro
AU - Miyamoto, Yoshihiro
AU - Tsuboi, Naotake
AU - Maruyama, Shoichi
AU - Suematsu, Makoto
AU - Yamasaki, Sho
AU - Ogawa, Yoshihiro
AU - Suganami, Takayoshi
N1 - Publisher Copyright:
© 2020 Rockefeller University Press. All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia-reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death-triggered, sustained inflammation after acute kidney injury.
AB - Accumulating evidence indicates that cell death triggers sterile inflammation and that impaired clearance of dead cells causes nonresolving inflammation; however, the underlying mechanisms are still unclear. Here, we show that macrophage-inducible C-type lectin (Mincle) senses renal tubular cell death to induce sustained inflammation after acute kidney injury in mice. Mincle-deficient mice were protected against tissue damage and subsequent atrophy of the kidney after ischemia-reperfusion injury. Using lipophilic extract from the injured kidney, we identified β-glucosylceramide as an endogenous Mincle ligand. Notably, free cholesterol markedly enhanced the agonistic effect of β-glucosylceramide on Mincle. Moreover, β-glucosylceramide and free cholesterol accumulated in dead renal tubules in proximity to Mincle-expressing macrophages, where Mincle was supposed to inhibit clearance of dead cells and increase proinflammatory cytokine production. This study demonstrates that β-glucosylceramide in combination with free cholesterol acts on Mincle as an endogenous ligand to induce cell death-triggered, sustained inflammation after acute kidney injury.
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U2 - 10.1084/JEM.20192230
DO - 10.1084/JEM.20192230
M3 - Article
C2 - 32797195
AN - SCOPUS:85089482164
SN - 0022-1007
VL - 217
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20192230
ER -