Involvement of MST1/mTORC1/STAT1 activity in the regulation of B‐cell receptor signalling by chemokine receptor 2

Abstract

Background CCR2 is involved in maintaining immune homeostasis and regulating immune function. This study aims to elucidate the mechanism by which CCR2 regulates B‐cell signalling. Methods In Ccr2 ‐knockout mice, the development and differentiation of B cells, BCR proximal signals, actin movement and B‐cell immune response were determined. Besides, the level of CCR2 in PBMC of SLE patients was analysed by bioinformatics. Results CCR2 deficiency reduces the proportion and number of follicular B cells, upregulates BCR proximal signalling and enhances the oxidative phosphorylation of B cells. Meanwhile, increased actin filaments aggregation and its associated early‐activation events of B cells are also induced by CCR2 deficiency. The MST1/mTORC1/STAT1 axis in B cells is responsible for the regulation of actin remodelling, metabolic activities and transcriptional signalling, specific MST1, mTORC1 or STAT1 inhibitor can rescue the upregulated BCR signalling. Glomerular IgG deposition is obvious in CCR2‐deficient mice, accompanied by increased anti‐dsDNA IgG level. Additionally, the CCR2 expression in peripheral B cells of SLE patients is decreased than that of healthy controls. Conclusions CCR2 can utilise MST1/mTORC1/STAT1 axis to regulate BCR signalling. The interaction between CCR2 and BCR may contribute to exploring the mechanism of autoimmune diseases.

Targeting chemokine receptors signalling of immune cells in autoimmune diseases

“…CCR2 is a chemokine receptor that transduces signals in inflammatory diseases and the inflammatory response against cancer, upon binding of the chemokine (C‐C motif) ligand 2 (CCL2) that mediates monocyte chemotaxis. Liu and colleagues observe an increased CCR2 expression in the peripheral blood mononuclear cells (PBMC) of systemic lupus erythematosus (SLE) patients compared to healthy individuals 2 . This study follows the line of another paper published earlier by the same group about the role of the CCL2 ligand in modulating the B cell receptor (BCR) signalling and B cell differentiation 3 .…”

“…mononuclear cells (PBMC) of systemic lupus erythematosus (SLE) patients compared to healthy individuals. 2 This study follows the line of another paper published earlier by the same group about the role of the CCL2 ligand in modulating the B cell receptor (BCR) signalling and B cell differentiation. 3 The new work provides a large amount of data supporting the function of CCR2 in the development of B cell populations, mainly impacting the development of peripheral populations, and decreasing the circulation of plasma cells and memory cells.…”

“…Altogether, cell populations of more dedifferentiated phenotypes are observed, and more mature circulating subtypes are reduced. These Ccr2‐/‐ cells show higher levels of mTOR and Akt activation, as well as an overall higher level of phosphorylated targets, and appear to be involved in the emergence of autoimmune disorders 2 . This outcome correlates with a low expression of CCR2 in PBMC observed in SLE patients compared to healthy controls.…”

“…Recently, the work of Liu and colleagues presented new data that support the role of the Mst1/Akt/STAT axis in the development of central and peripheral B cell populations in CC chemokine receptor type 2 (CCR2) wild‐type and knockout mice 2 . CCR2 is a chemokine receptor that transduces signals in inflammatory diseases and the inflammatory response against cancer, upon binding of the chemokine (C‐C motif) ligand 2 (CCL2) that mediates monocyte chemotaxis.…”

“…8,13 Caution should be taken in the interpretation of results presented by Liu and colleagues because most of the experiments were performed in vitro using cells recovered from spleens, bone marrow, and the peritoneal cavity of mice. 2 The CCR2 levels were evaluated in both SLE patients and healthy individuals; however, further characterization is needed to prove that the Mst1/Akt/STAT axis works the way suggested by the results in mice. It is in fact crucial to demonstrate that the proposed mechanism would work in healthy conditions and would be altered in SLE patients, as well as to show which implications it may have in the development and pathogenesis of the disease.…”