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

Abstract

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.

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

“…More importantly, treatment with bindarit also alleviated bone damage in the tibial epiphysis of CHIKV-infected mice. This finding is, at first glance, inconsistent with a recent report of disease exacerbation, including cartilage damage, during the chronic stage of disease in CCR2-deficient mice infected with CHIKV (69). However, it is worth noting that CCR2 is a promiscuous receptor that interacts not only with CCL2 but also with seven other ligands, including CCL7 and CCL12 (70), which may suggest that other ligands for CCR2 play an inhibitory role in CHIKV, particularly in terms of cartilage damage.…”

Chikungunya virus non-structural protein 2-mediated host shut-off disables the unfolded protein response

“…and ample CHIKV RNA replication in the first 3 days p.i. (Gardner et al, 2010;Metz et al, 2013;Poo et al, 2014;Rudd et al, 2012) (Fig. 2c and data not shown).…”

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

“…These data suggest that macrophages are a source of persistent virus and contribute to CHIKV-induced arthropathy. Plasmacytoid dendritic cells, NK cells, and neutrophils also infiltrate infected tissues during acute CHIKV infection (8,(143)(144)(145)(146), but their role in CHIKV control remains to be clarified.…”

“…CHIKVinfected humans, mice, and NHPs develop potent and neutralizing IgM and IgG antibodies that control viremia and confer cross-protection against secondary CHIKV infections in animal models (125,137,143,147,(150)(151)(152). In humans, IgM levels are detected within 5-7 days after the onset of symptoms (153), peak several weeks after infection (154), and begin to wane over the next several months (154).…”