CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow

Abstract

Chemokine receptor CCR2 mediates monocyte mobilization from the bone marrow (BM) and subsequent migration into target tissues. The degree to which CCR2 is differentially expressed in leukocyte subsets, and the contribution of CCR2 to these leukocyte mobilization from the BM are poorly understood. Using red fluorescence protein CCR2 reporter mice, we found heterogeneity in CCR2 expression among leukocyte subsets in varying tissues. CCR2 was highly expressed by inflammatory monocytes, dendritic cells, plasmacytoid dendritic cells and NK cells in all tissues. Unexpectedly, more than 60% of neutrophils expressed CCR2, albeit at low levels. CCR2 expression in T cells, B cells and NK T cells was greatest in the BM compared to other tissues. Genetic CCR2 deficiency markedly sequestered all leukocyte subsets in the BM, with reciprocal reduction noted in the peripheral blood and spleen. CCR2 inhibition via treatment with CCR2 signaling inhibitor propagermanium produced similar effects. Propagermanium also mitigated lipopolysaccharide-induced BM leukocyte egress. Consistent with its functional significance, CCR2 antibody staining revealed surface CCR2 expression within a subset of BM neutrophils. These results demonstrate the central role CCR2 plays in mediating leukocyte mobilization from the BM, and suggest a role for CCR2 inhibition in managing monocytes/macrophages-mediated chronic inflammatory conditions.

Monocyte infiltration and proliferation reestablish myeloid cell homeostasis in the mouse retina following retinal pigment epithelial cell injury

“…The diminished monocyte recruitment in CCR2-deficient mice also suggests a contribution of CCR2-mediated signaling in the homeostatic recruitment of exogenous monocytes, as has been found for the CCR2-regulated recruitment of monocytes to the peritoneum in a model of peritonitis 67 . However, the differences in monocyte recruitment in CCR2-deficient animals have to be considered together with a reduction of circulating monocytes in these animals 68 , 69 , which can in itself cause to decreased monocyte recruitment to the retina. By comparison, in healthy aged mouse retinas, the expression levels of inflammatory cytokine and CCR2 ligands were however only slightly elevated relative to that in young retina, and concordantly, inner retinal microglia homeostasis was driven primarily by endogenous microglial proliferation, with minimal exogenous monocyte recruitment.…”

Microglial Activation and Inflammation as a Factor in the Pathogenesis of Progressive Supranuclear Palsy (PSP)

“…For example, the pathogenesis of PD is related to an increase in CCL2 ( Grozdanov et al, 2014 ). This chemokine, which stimulates the evolution of myeloid cells from the bone marrow, is interpreted as a concomitant feature of an increase in circulating monocytes ratio ( Fujimura et al, 2015 ). The activation of the triggering receptor of myeloid cells (TREM2) in PSP is associated with microglial activation and subsequent neurodegeneration ( Leyns et al, 2017 ).…”

High expression of C-C chemokine receptor 2 associates with poor overall survival in gastric cancer patients after surgical resection

“…Chemokine (C-C motif) receptor 2 (CCR2) is a 313 amino acid seven transmembrane G protein coupled receptor encoded on chromosome 3 and selectively binds the C-C chemokine CCL2 [ 7 ]. CCR2 was mainly expressed by the inflammatory cells in tissues including monocytes, dendritic cells, plasmacytoid dendritic cells and NK cells etc [ 8 ]. The activated CCR2 could mediate monocytes mobilization from the bone marrow and subsequent migration into target tissues [ 9 ], making it essential for effective control and clearance of infections, as well as pathogenesis of inflammatory, degenerative diseases and tumors [ 10 ].…”