Toll-like receptor 2-expressing macrophages are required and sufficient for rhinovirus-induced airway inflammation.

Abstract

We have shown that rhinovirus, a cause of asthma exacerbation, colocalizes with CD68⁺ and CD11b⁺ airway macrophages after experimental infection in human subjects. We have also shown that rhinovirus-induced cytokine expression is abolished in Toll-like receptor (TLR2)^-/- bone marrow-derived macrophages. We hypothesize that TLR2⁺ macrophages are required and sufficient for rhinovirus-induced airway inflammation in vivo. Naive and ovalbumin (OVA)-sensitized and challenged C57BL/6 wild-type and TLR2^-/- mice were infected with RV1B, followed by IgG or anti-TLR2, to determine the requirement and sufficiency of TLR2 for rhinovirus-induced airway responses. Bone marrow chimera experiments using OVA-treated C57BL/6 and TLR2^-/- mice were also performed. Finally, naive TLR2^-/- mice underwent intranasal transfer of bone marrow-derived wild-type macrophages. RV1B infection of naive wild-type mice induced an influx of airway neutrophils and CD11b⁺ exudative macrophages, which was reduced in TLR2^-/- mice. After allergen exposure, rhinovirus-induced neutrophilic and eosinophilic airway inflammation and hyperresponsiveness were reduced in TLR2^-/- and anti-TLR2-treated mice. Transfer of TLR2^-/- bone marrow into wild-type, OVA-treated C57BL/6 mice blocked rhinovirus-induced airway responses, whereas transfer of wild-type marrow to TLR2^-/- mice restored them. Finally, transfer of wild-type macrophages to naive TLR2^-/- mice was sufficient for neutrophilic inflammation after rhinovirus infection, whereas macrophages treated with IL-4 (to induce M2 polarization) were sufficient for eosinophilic inflammation, mucous metaplasia, and airways hyperresponsiveness. TLR2 is required for early inflammatory responses induced by rhinovirus, and TLR2⁺ macrophages are sufficient to confer airway inflammation to TLR2^-/- mice, with the pattern of inflammation depending on the macrophage activation state.