Immunoreceptor CD300a regulates ischemic tissue damage and adverse remodeling in the mouse heart and kidney
Nanako Nishiyama, Hitoshi Koizumi, Chigusa Nakahashi-Oda, Satoshi Fujiyama, Xuewei Ng, Hanbin Lee, Fumie Abe, Jinao Li, Yan Xu, Takehito Sugasawa, Kazuko Tajiri, Taketaro Sadahiro, Masaki Ieda, Keiji Tabuchi, Kazuko Shibuya, Akira Shibuya
Nanako Nishiyama, Hitoshi Koizumi, Chigusa Nakahashi-Oda, Satoshi Fujiyama, Xuewei Ng, Hanbin Lee, Fumie Abe, Jinao Li, Yan Xu, Takehito Sugasawa, Kazuko Tajiri, Taketaro Sadahiro, Masaki Ieda, Keiji Tabuchi, Kazuko Shibuya, Akira Shibuya
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Research Article Immunology Inflammation

Immunoreceptor CD300a regulates ischemic tissue damage and adverse remodeling in the mouse heart and kidney

Abstract

Acute ischemic organ diseases such as acute myocardial infarction and acute kidney injury often result in irreversible tissue damage and progress to chronic heart failure (CHF) and chronic kidney disease (CKD), respectively. However, the molecular mechanisms underlying the development of CHF and CKD remain incompletely understood. Here, we show that mice deficient in CD300a, an inhibitory immunoreceptor expressed on myeloid cells, showed enhanced efferocytosis by tissue-resident macrophages and decreased damage-associated molecular patterns and pathogenic SiglecFhi neutrophils, resulting in milder inflammation-associated tissue injury than in wild-type mice after ischemia and reperfusion (IR). Notably, we uncovered that CD300a deficiency on SiglecFlo neutrophils increased the signal transducer and activator of transcription 3–mediated production of pro-angiogenic and antifibrotic factors, resulting in milder adverse remodeling after IR. Our results demonstrated that CD300a plays an important role in the pathogenesis of ischemic tissue injury and adverse remodeling in the heart and kidney.

Authors

Nanako Nishiyama, Hitoshi Koizumi, Chigusa Nakahashi-Oda, Satoshi Fujiyama, Xuewei Ng, Hanbin Lee, Fumie Abe, Jinao Li, Yan Xu, Takehito Sugasawa, Kazuko Tajiri, Taketaro Sadahiro, Masaki Ieda, Keiji Tabuchi, Kazuko Shibuya, Akira Shibuya

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Figure 7

Blockade of human CD300A enhances efferocytosis and ameliorates acute renal injury after biIRI.

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Blockade of human CD300A enhances efferocytosis and ameliorates acute re...
(A and B) A public gene expression dataset of patients with CKD of diabetic nephropathy (DN) (n = 9) and focal segmental glomerulosclerosis (FSGS) (n = 19). CD300A expression in comparison with the healthy control group (n = 10) (A) and Spearman’s correlation analysis between the expression of CD300A and renal function of glomerular filtration rate (GFR) and creatinine (B). MDRD, Modification of Diet in Renal Disease formula. (C) Efferocytosis of pHrodo-labeled dead Jurkat cells by human monocytes from 13 donors in the presence of control mAb (Ctrl) and a humanized anti-CD300A mAb (TNAX103). Left: Representative laser scanning confocal microscopy image. Right: Phagocytic index. Scale bars: 100 µm. (D) Schematic diagram of the generation of the humanized mice by transferring of human CD34+ cells to NOG mice with transgenic expression of human GM-CSF and IL-3. These mice were given Ctrl or a humanized anti-CD300A mAb (TNAX103) 2 hours before biIRI. (E) Flow cytometric analysis of CD300A expression on human and mouse CD45+ cells in the kidney in the humanized mice after biIRI. (F and G) Plasma NGAL (F) and BUN and Cre (G) before (0) and 48 hours after biIRI in the humanized mice that had been injected i.v. with TNAX103 mAb or Ctrl (n = 5 or 6, respectively). Data are presented as mean ± SEM and pooled from 2 (F and G) and 3 (C) experiments. Student’s t test (C) and 2-way ANOVA (F and G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.