CXCL2 Impairs Functions of Bone Marrow Mesenchymal Stem Cells and Can Serve as a Serum Marker in High-Fat Diet-Fed Rats

Abstract

In modern society excessive consumption of a high-fat diet (HFD) is a significant risk factor for many diseases such as diabetes, osteoarthritis and certain cancers. Resolving cellular and molecular mechanisms underlying HFD-associated disorders is of great importance to human health. Mesenchymal stem cells (MSCs) are key players in tissue homeostasis and adversely affected by prolonged HFD feeding. Low-grade systemic inflammation induced by HFD is characterized by increased levels of pro-inflammatory cytokines and alters homeostasis in many organs. However, whether, which and how HFD associated inflammatory cytokines impair MSCs remain unclear. Here we demonstrated that HFD induced serum cytokines disturbances, especially a continuous elevation of serum CXCL2 level in rats. Coincidentally, the differentially expressed genes (DEGs) of bone marrow MSCs (BMSCs) which functions were impaired in HFD rats were enriched in cytokine signaling. Further mechanism analysis revealed that CXCL2 treatment in vitro suppresses the adipogenic potential of BMSCs via Rac1 activation, and promoted BMSC migration and senescence by inducing over-production of ELMO1 and reactive oxygen species (ROS) respectively. Moreover, we found that although glycolipid metabolism indicators can be corrected, the CXCL2 elevation and BMSC dysfunctions cannot be fully rescued by diet correction and anti-inflammatory aspirin treatment, indicating the long-lasting deleterious effects of HFD on serum CXCL2 levels and BMSC functions. Altogether, our findings identify CXCL2 as an important regulator in BMSCs functions and may serve as a serum marker to indicate the BMSC dysfunctions induced by HFD. In addition, our findings underscore the intricate link among high-fat intake, chronic inflammation and BMSC dysfunction which may facilitate development of protective strategies for HFD associated diseases.

New evidence for dietary fatty acids in the neutrophil traffic between the bone marrow and the peripheral blood

“…In the short-term exposure to the HFD-SFAs (4 weeks), we observed the induction of apoptosis in bone marrow neutrophils, which could be probably due to an excessive engulfment of TGs ( Ortega-Gomez et al, 2017 ) and not to the trafficking of senescent neutrophils back to the bone marrow, as CXCR4 expression in circulating and bone marrow neutrophils and CXCL12 expression in bone marrow cells at fasting were unaffected ( De Filippo & Rankin, 2018 ). In addition, we found that the HFD-SFAs induced a remarkable elevation of fasting serum CXCL2, which is a chemokine associated with the onset of inflammation and recently identified to cause early senescence and a functional decline of stem cells from bone marrow mesenchymal niche during the development of obesity in rats ( Bi et al, 2021 ). These findings are in line with previous in vitro reports showing that palmitic acid was involved in mediating apoptosis and pro-inflammatory response in immune cells, which were effects not observed with oleic acid, EPA or DHA ( Hidalgo et al, 2021 , Radzikowska et al, 2019 ).…”

Early infiltrating NKT lymphocytes attenuate bone regeneration through secretion of CXCL2

“…The expression of CXCL2 was negatively correlated with BMD ( 17 ). Neutralization of CXCL2 prevented bone destruction in lipopolysaccharide-challenged mice ( 36 ), while supplement of CXCL2 in culture medium led to cellular senescence and impaired differentiation of MSCs ( 37 ). In our study, differential gene analysis showed that the expression of Cxcl2 was significantly up-regulated at 1 day.…”

Investigating the Causal Association Between Characteristic Genes and Osteoarthritis: A Mendelian Randomization and Bioinformatics Approach

“…They induce chemotaxis in cells like neutrophils, lymphocytes, and monocytes, and are intimately linked to vasculitis progression, mediating early OA synovitis [22]. CXCL2 belongs to the chemokine superfamily, with its encoded secreted protein playing a role in immune modulation and in ammation [23]. CXCL8 promotes chondrocyte apoptosis and inhibits their proliferation by in uencing the JAK-STAT, NF-kB, and JNK MAPK signaling pathways and enhancing the expression of other pro-in ammatory cytokines [24].…”