IL-10-producing lung interstitial macrophages prevent neutrophilic asthma

Inflammatory responses contribute to host defense against harmful organisms and allergens, whereas a failure of immune tolerance can cause chronic inflammation including asthma. The lung has several innate myeloid cell subsets. Among these subsets, there are two types of macrophages: alveolar macrophages (AMs) and interstitial macrophages (IMs). However, compared with AMs, the role of IMs in lung homeostasis remains poorly understood. In this study, we characterized AMs and IMs in healthy and inflammatory conditions. Pulmonary IMs constitutively produce the anti-inflammatory cytokine IL-10 through activation of the TLR4/MyD88 pathway in a microbiota-independent manner. In addition to IMs, Foxp3⁺ T_reg cells show persistent IL-10 expression in the lung, with IL-10-producing IMs more prevalent than Foxp3⁺ T_reg cells. IMs, but not Foxp3⁺ T_reg cells, increased IL-10 production in house dust mite (HDM)-challenged mice, a model of human asthma. HDM-challenged Il10 ^-/- mice exhibited severe lung pathology characterized by neutrophilia compared with that of wild-type mice. In addition, transplantation of wild-type IMs reduced neutrophilic inflammation, goblet cell mucus production and decreased expression of lung IL-13 and T_h17-related neutrophil-activating cytokines such as IL-17, GM-CSF, and TNF-α. Together these results demonstrate that IL-10-producing IMs negatively regulate T_h2- and T_h17-mediated inflammatory responses, helping prevent neutrophilic asthma.