AUTHOR=Zhang Weiwei , Zhu Baoling , Ding Suling , Wang Xiangfei , Wu Jian , Zhu Xiaowei , Zou Yunzeng , Ge Junbo , Tong Minghong , Yang Xiangdong 

TITLE=Disruption of STAT6 Signal Promotes Cardiac Fibrosis Through the Mobilization and Transformation of CD11b+ Immature Myeloid Cells

JOURNAL=Frontiers in Physiology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.579712

DOI=10.3389/fphys.2020.579712

ISSN=1664-042X

ABSTRACT=The roles of STAT6 signal in allergy, immune regulation, tumorigenesis, and renal fibrosis have been documented. However, the function and mechanism of STAT6 signal in sympathetic overactivation-induced cardiac fibrosis have not been fully elucidated. This study explores the novel role of STAT6 signal in isoproterenol (ISO)-induced cardiac fibrosis through the regulation of inflammatory response and the differentiation of macrophages from immature myeloid cells. The expression levels of STAT6, β1-AR, and inflammatory factors in CD11b+ myeloid cells were analyzed with a microarray study. The levels of IL-6 and TGF-β1 in the CD11b+ myeloid cells-derived  macrophages were detected with RT-PCR. STAT6-KO and WT mice were used to establish a murine cardiac fibrosis model. Cardiac fibroblasts were isolated from the hearts of newborn mice, and STAT6 expression was measured by western blotting and RT-PCR. α-SMA expression was detected by immunofluorescence and immunohistochemistry staining. Cardiac function and pathological characteristics were examined by echocardiography and immunohistochemistry staining, respectively. Immunohistochemistry staining with anti-CD11b was performed to detect the infiltration of CD11b+ myeloid cells in heart tissue. Flow cytometry analysis was used to measure the percentages of CD11b+ myeloid cells and CD11b+Ly6C+ macrophages in the peripheral blood. Results showed that STAT6 was highly expressed in CD11b+ myeloid cells located in injured hearts, and STAT6 expression in cardiac fibroblasts was down-regulated after ISO treatment. STAT6 deficiency further aggravated ISO-induced increased expression of α-SMA in cardiac fibroblasts, myocardial fibrosis and cardiac dysfunction. The activation of ISO/β1-AR signal aggravated cardiac inflammatory infiltration, promoted CD11b+ myeloid cell mobilization and enhanced CD11b+Ly6C+/low macrophage differentiation, which was further exacerbated by STAT6 deficiency. Furthermore, β1-AR mRNA expression significantly increased in splenic CD11b+ myeloid cells compared to their bone marrow-derived controls, and STAT6 deficiency promoted β1-AR expression in an MI-induced sensitive cardiac fibrosis mouse model. The spleen-derived CD11b+ myeloid cells of STAT6-KO mice produced more IL-1α, IL-18 and TGF-β than their WT counterparts. Taken together, these results suggest that STAT6 signal plays a critical role in ISO-induced β1-AR overactivation and systemic inflammatory cascades, contributing to cardiac fibrogenesis. STAT6 should be a promising cardioprotective target against myocardial fibrosis and heart failure after β1-AR overactivation-induced myocardial injury.