C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury.

Tanaka, Miyako; Saka-Tanaka, Marie; Ochi, Kozue; Fujieda, Kumiko; Sugiura, Yuki; Miyamoto, Tomofumi; Kohda, Hiro; Ito, Ayaka; Miyazawa, Taiki; Matsumoto, Akira; Aoe, Seiichiro; Miyamoto, Yoshihiro; Tsuboi, Naotake; Maruyama, Shoichi; Suematsu, Makoto; Yamasaki, Sho; Ogawa, Yoshihiro; Suganami, Takayoshi

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.