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 4

CD300a deficiency upregulates pro-angiogenic and antifibrotic genes in SiglecFlo neutrophils.

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CD300a deficiency upregulates pro-angiogenic and antifibrotic genes in S...
(A–D) CD31+ capillary density in peri-infarct area (A), the percentage of FSP1+ cells (B), LVFS and LVEF (C), and the percentage of scar areas (D) in isotype control (Ctrl)– or anti-Ly6G mAb–administered Cd300a–/– and WT mice (Ctrl, n = 6–8 [A and B], 10–12 [C], and 13–16 [D]). Scale bars: 1 mm. (E) CD31+ capillary density in the peri-infarct area in the heart of mice into which WT or Cd300a–/– neutrophils were transferred. Scale bars: 100 μm. (F) Flow cytometric analysis of SiglecFhi and SiglecFlo neutrophils in the cardiac tissue in WT (n = 12) and Cd300a–/– (n = 11) mice. (G) The correlation between LVEF and the percentages of SiglecFlo neutrophils. (H) Principal component analysis plot of RNA expression of SiglecFhi and SiglecFlo neutrophils in the cardiac tissue from WT and Cd300a–/– mice (n = 8 in each group). (I) GSEA profiles of enrichment gene sets associated with angiogenesis in Cd300a–/– and WT SiglecFlo neutrophils. (J) Heatmap of enriched genes associated with angiogenesis. (K) Prok2 and Chil1 mRNA expression in SiglecFhi and SiglecFlo neutrophils in cardiac tissue in Cd300a–/– and WT mice (n = 10 or 7). (L) Heatmap of enriched genes associated with degradation of the extracellular matrix. (M) Mmp9 mRNA expression in SiglecFlo neutrophils in the cardiac tissue in Cd300a–/– and WT mice (n = 7 or 10). Data are presented as mean ± SEM and pooled from 2 (E–G) and more than 5 (A–D, K, and M) experiments. Two-way ANOVA (A–D and K) and unpaired Student’s t test (E, F, and M). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.