Cigarette smoke-induced accumulation of lung dendritic cells is interleukin-1α-dependent in mice

Fernando M Botelho,Yoichiro Iwakura,Donna Finch,Mathieu C Morissette,Roland Kolbeck,Carla Mt Bauer,Alison A Humbles,Martin R Stämpfli,Jake K Nikota

doi:10.1186/1465-9921-13-81

Abstract

BackgroundEvidence suggests that dendritic cells accumulate in the lungs of COPD patients and correlate with disease severity. We investigated the importance of IL-1R1 and its ligands IL-1α and β to dendritic cell accumulation and maturation in response to cigarette smoke exposure.MethodsMice were exposed to cigarette smoke using a whole body smoke exposure system. IL-1R1-, TLR4-, and IL-1α-deficient mice, as well as anti-IL-1α and anti-IL-1β blocking antibodies were used to study the importance of IL-1R1 and TLR4 to dendritic cell accumulation and activation.ResultsAcute and chronic cigarette smoke exposure led to increased frequency of lung dendritic cells. Accumulation and activation of dendritic cells was IL-1R1/IL-1α dependent, but TLR4- and IL-1β-independent. Corroborating the cellular data, expression of CCL20, a potent dendritic cells chemoattractant, was IL-1R1/IL-1α-dependent. Studies using IL-1R1 bone marrow-chimeric mice revealed the importance of IL-1R1 signaling on lung structural cells for CCL20 expression. Consistent with the importance of dendritic cells in T cell activation, we observed decreased CD4+ and CD8+ T cell activation in cigarette smoke-exposed IL-1R1-deficient mice.ConclusionOur findings convey the importance of IL-1R1/IL-1α to the recruitment and activation of dendritic cells in response to cigarette smoke exposure.

Highlights

Evidence suggests that dendritic cells accumulate in the lungs of chronic obstructive pulmonary disease (COPD) patients and correlate with disease severity
Studies by Doz et al demonstrated the importance of IL-1R1, TLR4, and MyD88 to cigarette smoke -induced inflammation [11]; airway neutrophilia was significantly attenuated in IL-1R1, TLR4- and MyD88deficient mouse strains following cigarette smoke exposure
Accumulation and activation of lung dendritic cells in response to cigarette smoke exposure is IL-1R1dependent and TLR4-independent Recent studies by Doz et al have highlighted the importance of IL-1R1 and TLR4 in cigarette smoke-induced lung neutrophilia [11]

Summary

Introduction

Evidence suggests that dendritic cells accumulate in the lungs of COPD patients and correlate with disease severity. We investigated the importance of IL-1R1 and its ligands IL-1α and β to dendritic cell accumulation and maturation in response to cigarette smoke exposure. It is widely accepted that chronic inflammation contributes to airflow limitation observed in COPD; macrophages, neutrophils and T lymphocytes are increased in various parts of the lungs [4]. Studies by Doz et al demonstrated the importance of IL-1R1, TLR4, and MyD88 (an adaptor signaling molecule shared by IL-1R1 and TLR4) to cigarette smoke -induced inflammation [11]; airway neutrophilia was significantly attenuated in IL-1R1-, TLR4- and MyD88deficient mouse strains following cigarette smoke exposure. While increased expression of IL-1α and β was observed following cigarette smoke exposure, mechanistic studies revealed that smoke-induced neutrophilic inflammation was IL-1α-dependent, but independent of IL-1β, and relied on crosstalk between hematopoietic and airway structural cells [12]. Studies by Churg et al further demonstrated that cigarette smoke-induced emphysema formation was, at least in part, IL-1R1-dependent [13]

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