Collagen XV Promotes ER Stress-Induced Inflammation through Activating Integrin β1/FAK Signaling Pathway and M1 Macrophage Polarization in Adipose Tissue

Abstract

Collagen XV (Col XV), a basement membrane (BM) component, is highly expressed in adipose tissue, and studies have found that Col XV is related to extracellular matrix (ECM) remodeling involving in adipose tissue fibrosis and inflammation. Furthermore, the ECM is essential for maintaining normal development and tissue function. In this study, we found that Col XV is related to the endoplasmic reticulum stress (ERS) and inflammation of adipose tissue. Moreover, we found that overexpression of Col XV in mice could cause macrophages to infiltrate white adipose tissue (iWAT). At the same time, the expression of the ERS sensor IRE1α (Inositol-Requiring Enzyme-1α) was significantly up-regulated, which intensified the inflammation of adipose tissue and the polarization of M1 macrophages after the overexpression of Col XV in mice. In addition, after overexpression of Col XV, the intracellular Ca2+ concentration was significantly increased. Using focal adhesion kinase (FAK) inhibitor PF573228, we found that PF-573228 inhibited the phosphorylation of FAK and reversed the upward trend of Col XV-induced protein expression levels of IRE1α, C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). After treatment with IRE1α inhibitor STF-083010, the results showed that the expression of adipocyte inflammation-related genes interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) significantly were decreased. Our results demonstrate that Col XV induces ER-stress in adipocytes by activating the Integrinβ1/FAK pathway and disrupting the intracellular Ca2+ balance. At the same time, Col XV regulates the inflammation induced by ER stress in adipocytes by promoting IRE1α/XBP1 (X-Box binding protein 1) signaling. Our study provides new ideas for solving the problems of adipose tissue metabolism disorders caused by abnormal accumulation of ECM.

Macrophage‐mediated extracellular matrix remodeling after fat grafting in nude mice

“…18 Adipose ECM remodeling is always associated with increased macrophage infiltration and upregulation of adipose tissue inflammation. 18,38,39 Generally, inflammatory factors in the microenvironment can recruit macrophages that secrete MMPs, which in turn degrade the ECM. 40,41 Our results showed that, over time, the number of nucleated cells in the graft gradually increased from the periphery to the center, and on the third day after transplantation, there were already M1-macrophage infiltrating the periphery of the graft and subsequently migrated gradually toward the center of the graft.…”

“…In the fat transplantation model, the grafted ECM is disrupted and undergoes remodeling in the post‐transplantation period 18 . Adipose ECM remodeling is always associated with increased macrophage infiltration and upregulation of adipose tissue inflammation 18,38,39 . Generally, inflammatory factors in the microenvironment can recruit macrophages that secrete MMPs, which in turn degrade the ECM 40,41 .…”

Translation from Microgravity Research to Earth Application

“…The topic “Translation from Microgravity Research to Earth Application” comprises publications focusing on space life sciences, gravitational biology and space medicine [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. It covers publications reporting the impact of altered environmental conditions, such as microgravity (µ g ), cosmic radiation and isolation on organisms down to the level of cells [ 3 , 4 , 5 , 7 , 8 , 10 , 11 , 12 , 13 , 14 ].…”

“…The topic “Translation from Microgravity Research to Earth Application” comprises publications focusing on space life sciences, gravitational biology and space medicine [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. It covers publications reporting the impact of altered environmental conditions, such as microgravity (µ g ), cosmic radiation and isolation on organisms down to the level of cells [ 3 , 4 , 5 , 7 , 8 , 10 , 11 , 12 , 13 , 14 ]. In addition, the topic collects studies validating causal diagrams of human health risks for spaceflight [ 1 ], hypergravity studies [ 2 ] and investigations about the impact of extreme isolation in the Antarctica on the human body [ 6 ].…”

“…These data can improve our knowledge about macrophage function in s-µ g , but validation under real spaceflight conditions is necessary. Another interesting study showed that collagen type XV is related to endoplasmic reticulum stress and inflammation of adipose tissue [ 13 ]. The FAK/integrin β1 signaling pathway and M1 macrophages are involved in this process and should be addressed in mice or rats exposed to s-µ g or in space.…”