Mast cell populations shift and adapt transcription profiles during the resolution of allergic airway inflammation

Asthma is a chronic lung disease characterized by recurrent acute inflammation and periods of resolution. To determine whether inflammation-induced lung mast cell (MC) populations persist or undergo phenotypic shifts during the resolution phase, we performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) of enriched lineage- CD45+ ST2+ FcεRI+ lung cells and immunofluorescence studies during acute and resolved allergic lung inflammation in mice. During the acute phase, integrin β7+ MC progenitors predominated in the lung epithelium and rapidly matured into mucosal-type MCs, which altered their transcriptional profile and persisted as mouse MC protease-6 (mMCP-6)+ MCs upon resolution of inflammation. A novel MC cluster with a regulatory transcriptional profile, potentially arising from a distinct proliferative MC progenitor population, dominated during the resolution phase. Consistently, MCs expressing the mouse chymase mMCP-4, aryl hydrocarbon receptor (AHR), and IL-10 expanded in a time-dependent manner in the submucosa and parenchyma during the resolution phase. Chymase+ IL-10+ AHR+ regulatory MCs were also identified in lung tissue samples from individuals with asthma. We propose that this population represents a regulatory MC subtype that contributes to the resolution of inflammation. In summary, our study unravels striking transcriptional alterations of MC populations during the resolution of allergic lung inflammation.