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

• Published in: The Journal of experimental medicine 2020-11, Vol.217 (11)
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - immunology; Acute Kidney Injury - metabolism; Animals; Cell Death - genetics; Cytokines - metabolism; Disease Models, Animal; Female; Glucosylceramidase - metabolism; Green Fluorescent Proteins - genetics; Inflammation - metabolism; Innate Immunity and Inflammation; Lectins, C-Type - deficiency; Lectins, C-Type - genetics; Lectins, C-Type - metabolism; Ligands; Macrophages - immunology; Macrophages - metabolism; Male; Membrane Proteins - deficiency; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction - genetics; Signal Transduction - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20192230

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.