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 5

CD300a suppresses STAT3 phosphorylation in SiglecFlo neutrophils.

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CD300a suppresses STAT3 phosphorylation in SiglecFlo neutrophils. (A–C) ...
(A–C) WT or Cd300a−/− BM neutrophils were cultured for 2 days in the presence of the culture supernatant of the naive cardiac tissue, which had been stimulated or not with HMGB-1 or IL-1α (A) and analyzed for SiglecF expression by flow cytometry (B). (C) The GM-CSF and G-CSF levels in the culture supernatant of the cardiac tissue after stimulation with HMGB-1 or IL-1α. (D) Flow cytometric analysis of SiglecF expression on WT or Cd300a−/− BM neutrophils after stimulation with GM-CSF or G-CSF. (E) Ingenuity Pathway Analysis based on differentially expressed genes from Cd300a–/– and WT SiglecFlo neutrophils. (F and G) Flow cytometric analysis of phosphorylated STAT3 (p-STAT3) in neutrophils of the cardiac tissue of Cd300a–/– (n = 7) and WT (n = 6) mice (F) and WT or Cd300a–/– BM neutrophils stimulated with or without the cardiac tissue supernatant (G). (H and I) Prok2 and Chil1 mRNA expression in BM neutrophils of WT or Cd300a–/– mice stimulated with the cardiac tissue supernatant after MI/R (H) or with G-CSF together with STAT3 inhibitor (STAT3i) or control vehicle (Vehicle) (I). (J) LVEF after MI/R in Cd300a–/– (vehicle, n = 5; STAT3i, n = 4) and WT mice (n = 3 in each group) treated with STAT3i or vehicle. Data are presented as mean ± SEM, representative of 2 experiments (B, D, G, and H) and pooled from 2 (C, F, and I) and 4 (J) experiments. One-way (B–D) and 2-way ANOVA (F, G, I, and J) and unpaired Student’s t test (H). *P < 0.05; **P < 0.01; ****P < 0.0001.