Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury
Xiaohong Wang, Wa Du, Yutian Li, Hui-Hui Yang, Yu Zhang, Rubab Akbar, Hannah Morgan, Tianqing Peng, Jing Chen, Sakthivel Sadayappan, Yueh-Chiang Hu, Yanbo Fan, Wei Huang, Guo-Chang Fan
Xiaohong Wang, Wa Du, Yutian Li, Hui-Hui Yang, Yu Zhang, Rubab Akbar, Hannah Morgan, Tianqing Peng, Jing Chen, Sakthivel Sadayappan, Yueh-Chiang Hu, Yanbo Fan, Wei Huang, Guo-Chang Fan
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Research Article Cardiology Immunology

Macrophage-enriched Sectm1a promotes efficient efferocytosis to attenuate ischemia/reperfusion-induced cardiac injury

Abstract

Efficient clearance and degradation of apoptotic cardiomyocytes by macrophages (collectively termed efferocytosis) is critical for inflammation resolution and restoration of cardiac function after myocardial ischemia/reperfusion (I/R). Here, we define secreted and transmembrane protein 1a (Sectm1a), a cardiac macrophage–enriched gene, as a modulator of macrophage efferocytosis in I/R-injured hearts. Upon myocardial I/R, Sectm1a-KO mice exhibited impaired macrophage efferocytosis, leading to massive accumulation of apoptotic cardiomyocytes, cardiac inflammation, fibrosis, and consequently, exaggerated cardiac dysfunction. By contrast, therapeutic administration of recombinant SECTM1A protein significantly enhanced macrophage efferocytosis and improved cardiac function. Mechanistically, SECTM1A could elicit autocrine effects on the activation of glucocorticoid-induced TNF receptor (GITR) at the surface of macrophages, leading to the upregulation of liver X receptor α (LXRα) and its downstream efferocytosis-related genes and lysosomal enzyme genes. Our study suggests that Sectm1a-mediated activation of the Gitr/LXRα axis could be a promising approach to enhance macrophage efferocytosis for the treatment of myocardial I/R injury.

Authors

Xiaohong Wang, Wa Du, Yutian Li, Hui-Hui Yang, Yu Zhang, Rubab Akbar, Hannah Morgan, Tianqing Peng, Jing Chen, Sakthivel Sadayappan, Yueh-Chiang Hu, Yanbo Fan, Wei Huang, Guo-Chang Fan

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Figure 8

rSec protects against myocardial I/R injury by promoting cardiac macrophage efferocytosis.

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rSec protects against myocardial I/R injury by promoting cardiac macroph...
(A) Schematic illustration of the experimental procedure. (B) Representative flow cytometry histograms and (C) their quantification results showing the increased red mCherry intensity in cardiac macrophages of rSec-treated mice, compared with control mice (n = 5; *, P < 0.05). (D) Representative flow cytometry histograms and (E) their quantification results of MERTK levels on the surface of macrophages (n = 5; *, P < 0.05). (F) Representative images and (G) quantitative results of the TUNEL staining in rSec-treated and control mouse hearts after in vivo 45 minutes of LAD occlusion followed by 4 days of reperfusion (I/R-D4). Green: TUNEL-positive nuclei (pointed by white arrows); red: mCherry-expressing cardiomyocytes; blue: DAPI. (n = 6 hearts and 2 sections for each heart; *, P < 0.05.) (H) Caspase-3 activity was measured in heart homogenates of rSec-injected and control-treated mice subjected to in vivo myocardial I/R (I/R-D4) (n = 6). (I) The circulating Troponin I (TnI) was measured in the sera collected from rSec-injected and control-treated mice at day 4 post-I/R (n = 6; *, P < 0.05). The numbers of cardiac Ly6G+ neutrophils (J) and cardiac Ly6C-high monocytes (K) were measured in rSec-injected and control-treated mice at day 4 post-I/R by flow cytometry assay (n = 5; *, P < 0.05). (L) Representative images of Masson’s trichrome and (M) their quantification results of cardiac fibrosis in rSec-injected and control-treated mice at 1 month post-I/R (n = 6; *, P < 0.05). (N) Representative echocardiography images and (O) quantification results of myocardial contractile function in rSec-injected and control-treated mice at 1 month post-I/R (n = 6; *, P < 0.05). All data are presented as mean ± SEM and analyzed by Student’s t test. R.O., retro-orbital.