Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair
Dong Im Cho, Hye-jin Kang, Ju Hee Jeon, Gwang Hyeon Eom, Hyang Hee Cho, Mi Ra Kim, Meeyoung Cho, Hye-yun Jeong, Hyen Chung Cho, Moon Hwa Hong, Yong Sook Kim, Youngkeun Ahn
Dong Im Cho, Hye-jin Kang, Ju Hee Jeon, Gwang Hyeon Eom, Hyang Hee Cho, Mi Ra Kim, Meeyoung Cho, Hye-yun Jeong, Hyen Chung Cho, Moon Hwa Hong, Yong Sook Kim, Youngkeun Ahn
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Research Article Cardiology Inflammation

Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair

Abstract

Mesenchymal stem cells (MSCs) can suppress pathological inflammation. However, the mechanisms underlying the association between MSCs and inflammation remain unclear. Under coculture conditions with macrophages, MSCs highly expressed angiopoietin-like 4 (ANGPTL4) to blunt the polarization of macrophages toward the proinflammatory phenotype. ANGPTL4-deficient MSCs failed to inhibit the inflammatory macrophage phenotype. In inflammation-related animal models, the injection of coculture medium or ANGPTL4 protein increased the antiinflammatory macrophages in both peritonitis and myocardial infarction. In particular, cardiac function and pathology were markedly improved by ANGPTL4 treatment. We found that retinoic acid–related orphan receptor α (RORα) was increased by inflammatory mediators, such as IL-1β, and bound to ANGPTL4 promoter in MSCs. Collectively, RORα-mediated ANGPTL4 induction was shown to contribute to the antiinflammatory activity of MSCs against macrophages under pathological conditions. This study suggests that the capability of ANGPTL4 to induce tissue repair is a promising opportunity for safe stem cell–free regeneration therapy from a translational perspective.

Authors

Dong Im Cho, Hye-jin Kang, Ju Hee Jeon, Gwang Hyeon Eom, Hyang Hee Cho, Mi Ra Kim, Meeyoung Cho, Hye-yun Jeong, Hyen Chung Cho, Moon Hwa Hong, Yong Sook Kim, Youngkeun Ahn

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Figure 9

RORα positively regulates ANGPTL4 induction in MSCs.

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RORα positively regulates ANGPTL4 induction in MSCs. (A) Rora mRNA expre...
(A) Rora mRNA expression was assessed in hMSCs with or without coculture with THP-1 macrophages. n = 4. hMSCs were transfected with control siRNA or RORα siRNA before coculture with THP-1 macrophages, and expression levels of RORα and ANGPTL4 mRNA (B, n = 4) and protein (C, n = 3) were measured in hMSCs. (D) Expression levels of CXCL10 and CXCL11 in macrophages were assayed after coculture with hMSCs transfected with control siRNA or ANGPTL4 siRNA. n = 4. (E) The mRNA levels of Rora and Angptl4 were assessed in hMSCs treated with IL-1β or TNF-α. n = 4. (F) The mRNA levels of Rora and Angptl4 were assessed in siRORα-transfected hMSCs treated with IL-1β or TNF-α. n = 4. (G) hMSCs were treated with SR1001, an inverse agonist of RORα and RORγ, or SR3335, a selective inverse agonist of RORα, with or without coculture with THP-1 macrophages. Inductions of RORα and ANGPTL4 were assessed by real-time PCR. n = 4. (H) hMSCs were stimulated with Veh or CCM, and binding of RORα to ANGPTL4 promoter was determined by ChIP assay. n = 3. (I) Deletion analysis of the ANGPTL4 promoter activity. HEK293T cells were transfected with the ANGPTL4-LUC reporter constructs and stimulated with Veh or CCM to analyze promoter activities. n = 4. Data are represented as mean ± SEM. #P < 0.05; ##P < 0.01; ###P < 0.001 (by Student’s t test or 1-way ANOVA with Bonferroni’s multiple-comparisons test).