Poly I:C-induced monocyte-macrophages alleviate type 2 immunopathology in a murine asthma model.

RATIONALE: Pathogen-associated molecular patterns (PAMPs) are known to initiate pro-inflammatory responses, but emerging evidence has revealed their roles in inducing macrophage-dependent immunomodulatory pathways that dampen inflammation. OBJECTIVES: We explored the interactions between the asthma-associated type 2 immunopathology and immune response to poly I:C, a PAMP mimicking double-stranded RNA, in ovalbumin (OVA) sensitized and challenged mice. METHODS: Following intranasal co-administration of Poly I:C during OVA challenges, we performed immunophenotyping of the lung and measured airway responses to inhaled methacholine (MCh). We characterized the pulmonary macrophages by flow cytometry and examined the effects of monocyte-derived (Ly6C+) macrophage depletion and c-c motif chemokine receptor 2 (CCR2) deficiency on inflammation and responses to MCh. The role of IL-10 was assessed by antibody inhibition of the IL-10 receptor. MEASUREMENTS AND MAIN RESULTS: Poly I:C attenuated allergen-induced type 2 immunopathology and airway hyperresponsiveness. Unexpectedly, the poly I:C receptors and poly I:C-induced cytokines were suppressed in the co-administered group compared to poly I:C only group. We observed an enrichment of lung Ly6C+ macrophages in co-administrated mice, which featured alternatively activated- (M2) and a myeloid-derived suppressor cell-like phenotype, expressed immunoregulatory factor IL-10, and inhibited in vitro T cell activation. Poly I:C did not inhibit Th2 immunopathology in mice depleted of Ly6C+ macrophages or deficient in CCR2, which mediates monocyte recruitment. Lastly, the blockade of the IL-10 receptor reversed the Th2-suppressing effect of co-administered poly I:C. CONCLUSIONS: Concurrent poly I:C and allergen exposure at the airway mucosa evokes macrophage-mediated immunomodulation that suppresses allergic airway reactions.