CCL2 regulation of MST1-mTOR-STAT1 signaling axis controls BCR signaling and B-cell differentiation

Lü, Yang; Li, Na; Yang, Di; Tang, Jianlong; Jing, Yukai; Kang, Danqing; Jiang, Panpan; Dai, Xin; Luo, Lei; Chen, Qiuyue; Chang, Jiang; Liu, Ju; Gu, Heng; Huang, Yanmei; Chen, Qianglin; Li, Zhenzhen; Zhu, Yaowu; Miller, Heather; Chen, Yan; Qiu, Liru; Mei, Heng; Hu, Yu; Gong, Quan; Liu, Chaohong

doi:10.1038/s41418-021-00775-2

Cited by 23 publications

(21 citation statements)

References 27 publications

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“…CCL2 has been confirmed as a negative regulator of BCR signal 24 . In this study, we complemented the role of CCR2, thus linking CCL2‐CCR2 and clarifying the role of this axis in BCR signalling.…”

Section: Discussionmentioning

confidence: 68%

“…CCL2 has been confirmed as a negative regulator of BCR signal. 24 In this study, we complemented the role of CCR2, thus linking CCL2‐CCR2 and clarifying the role of this axis in BCR signalling. Defects in the CCL2‐CCR2 signalling axis upregulate B‐cell signalling, actin remodelling and B‐cell metabolic activity in mice.…”

Section: Discussionmentioning

confidence: 87%

“…Cell lysates were obtained using a mixed RIPA buffer, as previously described. 24 Lysates were run through SDS‐PAGE and western blotting. Abs from Cell Signaling Technology: BTK (8547S), pAKT (4060L), AKT (9272S), SHIP‐1 (2728S), pFOXO1 (9461S), FOXO1 (2880S), pS6 (4856S), S6 (2217S), pPI3K (4228S), PI3K (4292S), pMST1 (3681S), MST1 (PA5‐22015), pmTOR (5536S), mTOR (2983S), pEZRIN (3726S), STAT1 (14994S), P65 (4764S), pIKKB (2697S), IKKB (8943S), and anti‐human‐CCR2 (12199S).…”

Section: Methodsmentioning

confidence: 99%

“…Purified splenic B cells (2 × 10 6 ) were activated at 37°C with sAg for 5, 10 and 30 min. Cell lysates were obtained using a mixed RIPA buffer, as previously described 24 . Lysates were run through SDS‐PAGE and western blotting.…”

Section: Methodsmentioning

confidence: 99%

“…Purified splenic B cells (2 × 10 6 ) were incubated with 5 μM Celltrace Violet (CTV, C34557, Thermo Fisher) before being seeded into 96‐well plates with 250 μl complete RPMI1640 medium, as previously described 24 . Lipopolysaccharide (LPS, 5 μg/ml) or C P G (10 μg/ml) were added into medium to stimulate cells for 72 h, F(ab') 2 anti‐mouse Ig (M + G) (3 μg/ml), anti‐CD40 (10 μg/ml) and IL‐4 (5 ng/ml) were added to stimulate cells for 96 h. Cells apoptosis were measured after incubation with anti‐Annexin V and PI (70‐AP101‐100, Multiscience Biotech).…”

Section: Methodsmentioning

confidence: 99%

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

Zhu

Lü

et al. 2022

Clinical & Translational Med

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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.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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

Zhu

Lü

et al. 2022

Clinical & Translational Med

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PGRN Inhibits Early B‐cell Activation and IgE Production Through the IFITM3‐STAT1 Signaling Pathway in Asthma

Zhang,

Ruan,

Yang

et al. 2024

Advanced Science

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Progranulin (PGRN) plays a critical role in bronchial asthma and the function of various immune cells. However, the mechanisms by which PGRN influences B‐cell receptor (BCR) signaling and immunoglobulin E(IgE) production are not fully understood. The study aimed to elucidate the molecular mechanisms through which PGRN affects BCR signaling, B‐cell differentiation, and IgE production. A PGRN knockout mouse model, along with techniques including flow cytometry, the creation of a bone marrow chimeric mouse model, total internal reflection fluorescence (TIRF), and Western blot (WB) analysis is employed, to investigate the link between PGRN and various aspects of B‐cell biology. It is discovered that the absence of PGRN in mice alters peripheral B‐cell subpopulations, promotes IgE class switching in a cell‐intrinsic manner, and affects B‐cell subpopulations. Additionally, PGRN modulates B‐cell functions by regulating BCR signaling pathways, metabolic processes, and the actin cytoskeleton during early B‐cell activation. Significantly, PGRN deficiency results in diminished production of NP‐specific antibodies. Moreover, it is found that PGRN inhibits B‐cell activation and IgE production through the PGRN‐IFITM3‐STAT1 signaling pathway. The findings provide new strategies for the targeted treatment of bronchial asthma, highlighting the crucial role of PGRN in B‐cell signaling and IgE production.

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Targeting chemokine receptors signalling of immune cells in autoimmune diseases

López

Barberis

2022

Clinical and Translational Dis

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The study of molecular signalling pathways in the fate of immune cells has gained relevance for their potential dysregulation in the onset of diseases of the immune system. Indeed, the signalling and metabolic pathways involved in the proliferation, development, and differentiation of different immune cell types have attracted the interest of the scientific and patient communities. In recent years, new evidence about the involvement of particular cell populations in the development of autoimmune disorders has been shown. An example is given by T cells, which metabolic status we have recently proposed to be the tipping point underlying the imbalance among T cell types in healthy versus immunocompromised patients. 1 Thus, understanding the context of the development of T and B cell subtypes in different tissues, and the cues responsible for their emergence, appears to be crucial when treating autoimmune disorders.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) wildtype 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. Liu and colleagues observe an increased CCR2 expression in the peripheral bloodThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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CCL2 regulation of MST1-mTOR-STAT1 signaling axis controls BCR signaling and B-cell differentiation

Cited by 23 publications

References 27 publications

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

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

PGRN Inhibits Early B‐cell Activation and IgE Production Through the IFITM3‐STAT1 Signaling Pathway in Asthma

Targeting chemokine receptors signalling of immune cells in autoimmune diseases

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