The sequential role of Mst1/mTORC1/STAT1 activity in chemokine receptor
2-regulated B cell receptor signaling
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.