Kuziel, W.A. et al. Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc. Natl. Acad. Sci. USA 94, 12053-12058
ABSTRACT CC chemokine receptor 2 (CCR2) is a prominent receptor for the monocyte chemoattractant protein (MCP) group of CC chemokines.
Mice generated by gene targeting to lack CCR2 exhibit normal leukocyte rolling but have a pronounced defect in MCP-1-induced
leukocyte firm adhesion to microvascular endothelium and reduced leukocyte extravasation. Constitutive macrophage trafficking
into the peritoneal cavity was not significantly different between CCR2-deficient and wild-type mice. However, after intraperitoneal
thioglycollate injection, the number of peritoneal macrophages in CCR2-deficient mice did not rise above basal levels, whereas
in wild-type mice the number of macrophages at 36 h was ≈3.5 times the basal level. The CCR2-deficient mice showed enhanced
early accumulation and delayed clearance of neutrophils and eosinophils. However, by 5 days neutrophils and eosinophils in
both CCR2-deficient and wild-type mice had returned to near basal levels, indicating that resolution of this inflammatory
response can occur in the absence of macrophage influx and CCR2-mediated activation of the resident peritoneal macrophages.
After intravenous injection with yeast β-glucan, wild-type mice formed numerous large, well-defined granulomas throughout
the liver parenchyma, whereas CCR2-deficient mice had much fewer and smaller granulomas. These results demonstrate that CCR2
is a major regulator of induced macrophage trafficking in vivo.
Full-textDOI: · Available from: Klaus Ley, Aug 19, 2015
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- "presented here confirms these results with respect to the expression of MCP-1, IL-6, and IL-8 but further demonstrates expression at the protein level and documents synergy with OSM stimulation. The demonstration that MCP-1 and macrophages were present in atherosclerotic plaques  and that MCP-1 causes monocyte/macrophage chemoattraction and extravasation  has implicated MCP-1 in the atherosclerotic process. Mice lacking both the LDL receptor and the MCP-1 genes were found to be protected from atherosclerosis compared to LDL receptor knockout mice . "
ABSTRACT: Accumulating evidence suggests that adventitial fibroblasts play a significant role in contributing to inflammation of the arterial wall and pathogenesis of atherosclerosis. The effects of gp130 cytokines on these cells (including oncostatin M-[OSM] and IL-6), some of which have been implicated in atherosclerosis, are currently unknown. Experiments were performed to determine whether gp130 cytokines regulate human aortic adventitial fibroblasts (HAoAFs) or smooth muscle cells (HAoSMCs) alone or in context of TLR-4 ligands (also implicated in atherosclerosis). HAoAFs and HAoSMCs were stimulated with LPS and/or one of OSM, IL-6, IL-11, IL-31, or LIF. ELISAs performed on cell supernatants showed that stimulation with OSM alone caused increased MCP-1, IL-6, and VEGF levels. When combined, LPS and OSM synergized to increase MCP-1, IL-6, VEGF protein, and mRNA expression as assessed by qRT-PCR, in both HAoAFs and HAoSMCs, while LPS-induced IL-8 levels were reduced. Such effects were not observed with other gp130 cytokines. Signalling pathways including STATs, MAPKinases, and NF κ B were activated, and LPS induced steady state mRNA levels of the OSM receptor chains OSMR β and gp130. The results suggest that OSM is able to synergize with TLR-4 ligands to induce proinflammatory responses by HAoAFs and HAoSMCs, supporting the notion that OSM regulation of these cells contributes to the pathogenesis of atherosclerosis.Mediators of Inflammation 11/2013; 2013:317503. DOI:10.1155/2013/317503 · 3.24 Impact Factor
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- "Genetic deletion of Csf1r or Csf1 also results in loss of monocytes and tissue macrophages, but experiments in these mice are difficult to interpret because of additional severe pleiotropic effects, including infertility, osteoporosis , neural development, low body weight, and severe skeletal abnormalities (Wiktor-Jedrzejczak et al., 1990; Dai et al., 2002). The most frequently used mouse model to study monocyte function is the Ccr2 / mouse (Boring et al., 1997; Kuziel et al., 1997), wherein monocytes accumulate in the bone marrow due to a defect in migration (Boring et al., 1997; Peters et al., 2004; Serbina and Pamer, 2006; Tsou et al., 2007; Hohl et al., 2009; Nakano et al., 2009). Most importantly , however, CCR2 is also expressed on CD103 + DCs, NK cells, mature T cells, and activated Th1 cells (Kim et al., 2001; Egan et al., 2009; Hohl et al., 2009; Zhang et al., 2010), and therefore the precise role of monocytes in Ccr2 / and Ccr2 DTR mice is difficult to discern with confidence. "
ABSTRACT: Dendritic cells (DCs), monocytes, and macrophages are closely related phagocytes that share many phenotypic features and, in some cases, a common developmental origin. Although the requirement for DCs in initiating adaptive immune responses is well appreciated, the role of monocytes and macrophages remains largely undefined, in part because of the lack of genetic tools enabling their specific depletion. Here, we describe a two-gene approach that requires overlapping expression of LysM and Csf1r to define and deplete monocytes and macrophages. The role of monocytes and macrophages in immunity to pathogens was tested by their selective depletion during infection with Citrobacter rodentium. Although neither cell type was required to initiate immunity, monocytes and macrophages contributed to the adaptive immune response by secreting IL-12, which induced Th1 polarization and IFN-γ secretion. Thus, whereas DCs are indispensable for priming naive CD4(+) T cells, monocytes and macrophages participate in intestinal immunity by producing mediators that direct T cell polarization.Journal of Experimental Medicine 09/2013; 210(10). DOI:10.1084/jem.20130903 · 13.91 Impact Factor
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- "À/À mice to determine whether CCR2-dependent migration of candidate progenitor cells, including monocytes and hematopoietic progenitors, contribute to the recovery of tissue-resident macrophages after turnover (Boring et al., 1997). Consistent with prior work (Kuziel et al., 1997; Serbina and Pamer, 2006), Ccr2 À/À mice indeed had lower circulating monocyte numbers (Figure S3A) and also lower steady-state monocyte numbers in the lung and spleen (Figure S3B and data not shown) than did Ccr2 +/À littermates, but they had comparable numbers of BM and lung macrophages (Figures 3B and 3C). Consistent with the lack of a CCR2-depen- dent contribution to steady-state tissue macrophages, we also found that both the extent of the depletion and the kinetics of the recovery were equivalent in DT-infused CD169 "
ABSTRACT: Despite accumulating evidence suggesting local self-maintenance of tissue macrophages in the steady state, the dogma remains that tissue macrophages derive from monocytes. Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significant contribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lung macrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in a macrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependent manner but independently of interleukin-4. We also found that after bone marrow transplantation, host macrophages retained the capacity to expand when the development of donor macrophages was compromised. Expansion of host macrophages was functional and prevented the development of alveolar proteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state.Immunity 04/2013; 38(4):792-804. DOI:10.1016/j.immuni.2013.04.004 · 19.75 Impact Factor