Abstract
Background :
Chemokine (C-C motif) receptor 2 (CCR2) contributes to autoimmune
pathogenesis. However, the effect of CCR2 on B cell signaling and its
role in autoimmunity remains unclear. Herein, we investigated the role
of CCR2 in the B cell receptor (BCR) signaling pathway and aimed to
illustrate its potential molecular mechanisms of action.
Methods : To investigate the alterations in B cell signaling and
the immune response, we used flow cytometry, western blotting,
microscopic techniques, Seahorse assay, and immunofluorescence assay on
samples from C57BL/6 mice and germinal CCR2-deletion mice.
Results : The absence of CCR2 disturbed follicular B cell
development. Furthermore, CCR2 absence was correlated with increased
mTORC1-mediated energy metabolism and enhanced early B cell activation,
which were induced by the up-regulation of BCR proximal signaling and
F-actin accumulation. Mst1 and STAT1 were key factors in up-regulating
the B cell activation in CCR2 deficient mice. The disrupted peripheral B
cell differentiation and enhanced B cell signaling were associated with
the inhibition mTORC1, Mst1, and STAT1. Moreover, loss of CCR2 caused a
weakened T cell dependent antigen response, resulting in decreased
antibody secreting cells and diminished antigen specific IgM levels.
Conclusion : CCR2 is involved in the regulation of BCR signaling
pathway by sequentially activating signaling pathways dominated by Mst1,
mTORC1, and STAT1. Our study suggests that CCR2 might represent a novel
therapeutic targeted for autoimmune diseases.
Key words :
Autoimmune
diseases; B cell receptor; CCR2; Mst1; mTOR