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

• DOI: 10.1128/jvi.03364-13
• Publication Date: 2014-04-03T05:13:22Z
• Authors: Yee Suan Poo; Helder Nakaya; Joy Gardner; Thibaut Larcher; Wayne A. Schroder; Thuy T. Le; Lee D. Major; Andreas Suhrbier
• Keywords: 1109 Insect Science; chikungunya; Neutrophils; Receptors, CCR2; Interleukin-1beta; Mice; 03 medical and health sciences; 0302 clinical medicine; Chemokine receptor Ccr2; 616; Granulocyte Colony-Stimulating Factor; Animals; Humans; Neutrophil infiltration; Mice, Knockout; 2403 Immunology; Alphavirus Infections; Arthritis; 2404 Microbiology; Interleukin-10; 3. Good health; Santé publique et épidémiologie; Neutrophil Infiltration; [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie; 2406 Virology; Chikungunya Fever; [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie; arthrite; Chikungunya virus

ABSTRACTChikungunya 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-1β [IL-1β], 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.