In vivo imaging implicates CCR2+ monocytes as regulators of neutrophil recruitment during arthritis

Wang, Baomei; Zinselmeyer, Bernd H.; Runnels, Herbert A.; LaBranche, Timothy P.; Morton, Phillip A.; Kreisel, Daniel; Mack, Matthias; Nickerson‐Nutter, Cheryl; Allen, Paul M.; Miller, Mark J.

doi:10.1016/j.cellimm.2012.07.005

Cited by 29 publications

(25 citation statements)

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“…What does emerge from these studies is that in CHIKV arthritis (and perhaps other viral arthritides [1]), inflammation-recruited CCR2 ϩ monocytes/macrophages appear to be important for limiting neutrophil recruitment into infected and inflamed joint tissues. This contrasts with observations in other arthritis models, where these cells promoted neutrophil recruitment (60).…”

Section: This Paper Describes the First Analysis Of Viral Arthritis Icontrasting

confidence: 93%

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Poo

Nakaya

Gardner

et al. 2014

J Virol

122

143

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Chikungunya virus (CHIKV) is a member of a globally distributed group of arthritogenic alphaviruses that cause weeks to months of debilitating polyarthritis/arthralgia, which is often poorly managed with current treatments. Arthritic disease is usually characterized by high levels of the chemokine CCL2 and a prodigious monocyte/macrophage infiltrate. Several inhibitors of CCL2 and its receptor CCR2 are in development and may find application for treatment of certain inflammatory conditions, including autoimmune and viral arthritides. Here we used CCR2 ؊/؊ mice to determine the effect of CCR2 deficiency on CHIKV infection and arthritis. Although there were no significant changes in viral load or RNA persistence and only marginal changes in antiviral immunity, arthritic disease was substantially increased and prolonged in CCR2 ؊/؊ mice compared to wild-type mice. The monocyte/macrophage infiltrate was replaced in CCR2 ؊/؊ mice by a severe neutrophil (followed by an eosinophil) infiltrate and was associated with changes in the expression levels of multiple inflammatory mediators (including CXCL1, CXCL2, granulocyte colony-stimulating factor [G-CSF], interleukin-1␤ [IL-1␤], and IL-10). The loss of anti-inflammatory macrophages and their activities (e.g., efferocytosis) was also implicated in exacerbated inflammation. Clear evidence of cartilage damage was also seen in CHIKV-infected CCR2 ؊/؊ mice, a feature not normally associated with alphaviral arthritides. Although recruitment of CCR2 ؉ monocytes/macrophages can contribute to inflammation, it also appears to be critical for preventing excessive pathology and resolving inflammation following alphavirus infection. Caution might thus be warranted when considering therapeutic targeting of CCR2/CCL2 for the treatment of alphaviral arthritides. IMPORTANCEHere we describe the first analysis of viral arthritis in mice deficient for the chemokine receptor CCR2. CCR2 is thought to be central to the monocyte/macrophage-dominated inflammatory arthritic infiltrates seen after infection with arthritogenic alphaviruses such as chikungunya virus. Surprisingly, the viral arthritis caused by chikungunya virus in CCR2-deficient mice was more severe, prolonged, and erosive and was neutrophil dominated, with viral replication and persistence not being significantly affected. Monocytes/macrophages recruited by CCL2 thus also appear to be important for both preventing even worse pathology mediated by neutrophils and promoting resolution of inflammation. Caution might thus be warranted when considering the use of therapeutic agents that target CCR2/CCL2 or inflammatory monocytes/macrophages for the treatment of alphaviral (and perhaps other viral) arthritides. Individuals with diminished CCR2 responses (due to drug treatment or other reasons) may also be at risk of exacerbated arthritic disease following alphaviral infection.

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Section: This Paper Describes the First Analysis Of Viral Arthritis Icontrasting

confidence: 93%

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Poo

Nakaya

Gardner

et al. 2014

J Virol

122

143

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“…Notably, neutrophils are readily distinguishable from monocytes and macrophages, as they are 5-10 times brighter than CD11b + , Ly6G -monocytes with the brightest GFP + cells (>2 logs over background) being preferentially detected with our imaging settings. These cells are more than 95% neutrophils based on flow cytometric analysis (37,38) and intravital microscopy analysis of LysM-GFP mice injected with a neutrophil-specific anti-Ly6G antibody (1A8) (Supplemental Figure 4, A-C). The right kidney was surgically exteriorized and imaged (39), and tissue perfusion was verified by bright-field observation of robust capillary flow and by injection of Q-dots into the retro-orbital sinus.…”

Section: Abl1 Regulates F-actin Polymerization Needed For Neutrophil mentioning

confidence: 99%

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

Nishi

Furuhashi

Culleré

et al. 2017

Journal of Clinical Investigation

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“…For example, recent evidence implicated monocytes as key regulators of neutrophil and eosinophil recruitment to the gut and joint. 34,54 In the context of infection, monocytes can promote antigen delivery to the lymph nodes, thus contributing to T cell priming. 38 Thus, monocytes/MΦ have broad contributions to immunity and influence other immune cells in a variety of inflammatory conditions ranging from infection to autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…Our data therefore suggest that monocyte depletion attenuated the characteristic influx of neutrophils into the inflamed colon in DSS-induced colitis. 54,60 …”

Section: Discussionmentioning

confidence: 99%

A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis

Becker

Kurmaeva

Gavins

et al. 2016

Inflammatory Bowel Diseases

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Background Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MΦ) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MΦ to the development of intestinal inflammation and IAL. Methods Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2−/− mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4+CD45RBhigh T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. Results We demonstrated that intestinal MΦ expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2−/− mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. Conclusions We propose a dual role of MΦ in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MΦ, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MΦ independently, to restore lymphatic clearance and reduce inflammation.

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In vivo imaging implicates CCR2+ monocytes as regulators of neutrophil recruitment during arthritis

Cited by 29 publications

References 50 publications

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

CCR2 Deficiency Promotes Exacerbated Chronic Erosive Neutrophil-Dominated Chikungunya Virus Arthritis

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis

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