CCR2 deficiency promotes exacerbated chronic erosive neutrophil-dominated chikungunya virus arthritis

Yee Suan Poo (1) , Helder Nakaya (2) , Joy Gardner (1) , Thibaut Larcher (3) , Wayne Schroder (1) , Thuy Le (4) , Lee Major (5) , Andreas Suhrbier (6)

1 Australian Infectious Diseases Research Centre
2 Yerkes National Primate Research Center [Lawrenceville, GA]
3 PAnTher - Physiopathologie Animale et bioThérapie du muscle et du système nerveux
4 Australian Infectious Disease Research Center
5 Australian Infectious Diseases Resaerch Centre
6 Australian Infectious Research Centre

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. The arthritic disease is usually characterised 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 treating certain inflammatory conditions, including autoimmune and viral arthritides. Herein 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 anti-viral immunity, arthritic disease was substantially increased and prolonged in CCR2-/- mice when compared with 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 expression of multiple inflammatory mediators (including CXCL1, CXCL2, G-CSF, IL-1β, IL-10). Loss of anti-inflammatory macrophages and their activities (eg efferocytosis) was also implicated in the 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+ monocyte/macrophages can contribute to inflammation, they also appear 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.

Domaines: Santé publique et épidémiologie

Yee Suan Poo, Helder Nakaya, Joy Gardner, Thibaut Larcher, Wayne Schroder, et al.. CCR2 deficiency promotes exacerbated chronic erosive neutrophil-dominated chikungunya virus arthritis. Journal of Virology, 2014, 88 (12), pp.6862-6872. ⟨10.1128/JVI.03364-13⟩. ⟨hal-01222894⟩