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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalThe Journal of experimental medicine
Volume217
Issue number11
DOIs
Publication statusPublished - 2020 Nov 2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tanaka, M., Saka-Tanaka, M., Ochi, K., Fujieda, K., Sugiura, Y., Miyamoto, T., Kohda, H., Ito, A., Miyazawa, T., Matsumoto, A., Aoe, S., Miyamoto, Y., Tsuboi, N., Maruyama, S., Suematsu, M., Yamasaki, S., Ogawa, Y., & Suganami, T. (2020). C-type lectin Mincle mediates cell death-triggered inflammation in acute kidney injury. The Journal of experimental medicine, 217(11). https://doi.org/10.1084/jem.20192230