J Immunol. 2025 Nov 9:vkaf280. doi: 10.1093/jimmun/vkaf280. Online ahead of print.

ABSTRACT

Cigarette smoke is the primary cause of chronic obstructive pulmonary disease (COPD), an incurable condition characterized by irreversible airflow obstruction and alveolar destruction driven by chronic inflammation of the lungs and airways. The inflammatory response caused by cigarette smoke is typified by the recruitment of innate and adaptive immune cells to the lung. Paradoxically, many of these immune cells are functionally impaired by smoke. Notable among these are lung macrophages, which have reduced ability to clear apoptotic lung epithelial cells and neutrophils by efferocytosis when exposed to cigarette smoke. Lung macrophages may express the aryl hydrocarbon receptor (AhR), a receptor/transcription factor highly expressed in barrier organs including the lungs. The AhR protects against the damaging effects of cigarette smoke by attenuating pulmonary neutrophilia via an unknown mechanism. We used our preclinical cigarette smoke models, mutant AhR mice and techniques such as flow cytometry, Western blot and reverse transcription quantitative polymerase chain reaction (RT-qPCR) to show that the AhR promotes the resolution of cigarette smoke-induced inflammation in mice via enhanced efferocytosis. Moreover, the ability of macrophages to engulf apoptotic neutrophils in the lungs is due to a non-genomic AhR pathway that involves signaling through the IL-10/JAK/STAT pathway. Finally, we show that the non-toxic endogenous AhR ligand FICZ promotes macrophage uptake of neutrophils. Taken together, these results support the importance of AhR activity in mediating its anti-inflammatory functions in response to cigarette smoke. Further investigation of the precise mechanisms by which the AhR exerts its anti-inflammatory function may open the possibility for therapeutic agents to treat chronic inflammatory diseases.

PMID:41206959 | DOI:10.1093/jimmun/vkaf280