Introduction
B cells are derived from bone marrow (BM) and travel to peripheral
lymphoid organs to fight
pathogens.1 Following B
cell receptor (BCR) activation, sequential signaling pathways involving
adaptors, kinases, second messengers, and phosphatases produce a variety
of B cell responses.2-4Actin cytoskeleton is a major target of BCR signaling that can regulate
B cell morphological features, immune synapse formation, and BCR
internalization.5,
6
As a member of the chemokine family, the contribution of chemokine (C-C
motif) receptor 2 (CCR2) in autoimmunity has been previously
demonstrated. A previous study suggested that CCR2 expressed on
regulatory T cells (Tregs) can restrain the proliferation of T cellin vitro. 7Furthermore, CCR2 was shown to mediate arthritis progression by
enhancing Tregs
migration.8 Although not
as well studied as T cells, a growing body of evidence indicate a
potential connection between CCR2 and B cell regulation. While CXCR4 as
well as functional and constitutive CCR2 are expressed in B cells, the
transcription of CCR2 occurs in immature B cells and dampens in mature B
cells.9 Furthermore,
mice lacking CCR2 are a specifically well suited animal model to
investigate B cell expansion under infection and non-infection
condition.10 Following
infections, the lymphatic follicles are notably enlarged, which
represents an increased B cell proliferation and
outgrowth.11Additionally, in CCR2 deficient immature B cells, actin polymerization
is increased, as well as the migration and homing to the lymph nodes,
all of which being mediated by the interaction between CCR2 and its
ligand CCL2.12. Taken
together, these studies suggest that CCR2 might play an important role
in the B cell downstream signaling pathways.
Several downstream pathways dominated by BCR activation are particularly
prominent in autoimmunity. First, the mammalian target of rapamycin
(mTOR) was shown to be involved in the autoimmune pathogenesis, while
rapamycin has been demonstrated to represent an effective treatment of
rheumatism.13,
14 MTOR aids the expanded T follicular
helper (TFH) cells to facilitate B cell activation and autoantibody
production.15Furthermore, CCR2 can mediate HIF-1α expression via the PI3K-Akt-mTOR
pathway; thus, controlling the cell metabolic
process.16 Another
pathway mainly regulated by Mst1 plays an essential role in lymphocyte
migration and adhesion during immunosurveillance. During T
cell-regulated B cell activation, Mst1 functions as a molecular brake to
balance immune tolerance, and its depletion leads to
hypergammaglobulinemia in
mice.17 Mst1 deficient
mice exhibited peripheral lymphoid tissue hypertrophy, decreased
marginal zone (MZ) B cells in the spleen, and the emigration of
single-positive thymocytes was also
influenced.18 Moreover,
Mst1 depleted B cells show an attenuated response to mitogens and a
down-regulated BCR signaling as well as
clustering.19Additionally, the Janus kinase/signal transduction and activator of
transcription (JAK/STAT) signaling pathway is involved in the
development of systemic lupus erythematosus (SLE), which is supported by
the effective use of JAK inhibitor as a therapeutic
method.20 CCL2-CCR2 has
been shown to associate with the JAK/STAT signaling pathway by
activating STAT1, STAT3, and
STAT5.21 Furthermore,
CCL2 and CCR2 dimerization induce tyrosine phosphorylation of
STAT5.22 However, the
interaction between these three main pathways during the course of
autoimmunity and the manner in which they are regulated by CCR2 and B
cell signaling activity, remains unknown.
Therefore, we hypothesized that CCR2 interacts with BCR signaling
potentially through sequential Mst1-mTOR-STAT1 activation. Herein, we
utilized CCR2 deficient mice and revealed that the loss of CCR2 leads to
up-regulation of BCR proximal signaling molecules, enhancement of the
F-actin remodeling related BCR clustering, and increased expression
levels of various transcriptional factors.
Changes being underlined by the
effect of CCR2 on PI3K-Akt-mTORC1, Mst1-mTORC1-Dock8-WASP, and
Mst1-mTORC1-STAT1 axes, respectively.