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

Abstract

Background We have shown that rhinovirus (RV), a cause of asthma exacerbations, colocalizes with CD68- and CD11b-positive airway macrophages following experimental infection in humans. We have also shown that RV-induced cytokine expression is abolished in TLR2−/− bone marrow-derived macrophages. Objective We hypothesize that TLR2+ macrophages are required and sufficient for RV-induced airway inflammation in vivo. Methods To determine the requirement and sufficiency of TLR2 for RV-induced airway responses, naïve and ovalbumin-sensitized and challenged C57BL/6 wild-type and TLR2−/− mice were infected with RV1B followed by IgG or anti-TLR2. Bone marrow chimera experiments using OVA-treated C57BL/6 and TLR2−/− mice were also performed. Finally, naïve TLR2−/− mice underwent intranasal transfer of bone marrow-derived wild type macrophages. Results RV1B infection of naïve wild-type mice induced an influx of airway neutrophils and CD11b+ exudative macrophages which was reduced in TLR2−/− mice. In allergen-exposed mice, RV-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 ovalbumin-treated, C57BL/6 mice blocked RV-induced airway responses, whereas transfer of wild type marrow to TLR2−/− mice restored them. Finally, transfer of wild-type macrophages to naïve TLR2−/− mice was sufficient for neutrophilic inflammation after RV infection, whereas macrophages treated with IL-4 (to induce M2 polarization) were sufficient for eosinophilic inflammation, mucous metaplasia and airways hyperresponsiveness. Conclusions TLR2 is required for early inflammatory responses induced by RV, and TLR2+ macrophages are sufficient to confer airway inflammation to TLR2−/− mice, with the pattern of inflammation depending on macrophage activation state.

Advances in environmental and occupational disorders in 2016

“…Han et al found that TLR2 is necessary for rhinovirus-induced airway inflammation in both naïve and allergen-sensitized mice. (40) This was demonstrated by mice lacking TLR2 having decreased airway inflammation in response to rhinovirus infection. Furthermore, transfer of TLR2 + macrophages was sufficient to produce airway inflammation in TLR2 knockout mice.…”

In vivo experimental models of infection and disease

“…145 Efforts to improve the quality and validity of the model made use of a partial purification protocol to generate viral stocks. 146 For mouse models of RV infection or exacerbations, the refined, high-titer, RV purification protocol is the gold standard.…”

“…183 OVA-allergic TLR2 2/2 mice also had reduced macrophage, neutrophil, and eosinophil numbers and suppressed AHR after RV inoculation. 146 Bone marrow transfer experiments demonstrated that TLR2 2/2 bone marrow could protect from exacerbations, while transfer of wild-type bone marrow restored responses in TLR2 2/2 mice. 146 Transfer of wild-type macrophages into TLR2 2/2 mice could also restore exacerbations.…”

“…146 Bone marrow transfer experiments demonstrated that TLR2 2/2 bone marrow could protect from exacerbations, while transfer of wild-type bone marrow restored responses in TLR2 2/2 mice. 146 Transfer of wild-type macrophages into TLR2 2/2 mice could also restore exacerbations. 146 As previously mentioned, a role for TRAIL has also been demonstrated, with HDM-allergic TRAIL-deficient mice (Tnfsf10 2/2 ) protected from RV-induced AHR and induction of airway inflammation.…”

“…146 Transfer of wild-type macrophages into TLR2 2/2 mice could also restore exacerbations. 146 As previously mentioned, a role for TRAIL has also been demonstrated, with HDM-allergic TRAIL-deficient mice (Tnfsf10 2/2 ) protected from RV-induced AHR and induction of airway inflammation. 163 RV-induced asthma exacerbation models have also been used to assess the responses to existing therapies and as preclinical models for novel therapies.…”