Background Mast cells are abundant throughout the lung, positioned near the airway epithelium, vasculature, and interstitium where they function as frontline sentinels to inhaled environmental and chemical stimuli. Through rapid release of cytokines, proteases, and lipid mediators, they amplify inflammation, modulate vascular permeability, and shape the recruitment and activation of other immune cells. Although mast cells can influence dendritic cell (DC) positioning and function, their role in regulating DC dynamics during acute chemical-induced lung injury remains poorly defined. Chloropicrin (CP), a highly toxic pulmonary irritant and chemical threat agent, induces severe epithelial damage and inflammation, yet the mast cell–dependent mechanisms governing these responses are not well understood. Materials and methods Two complementary mast cell–deficient mouse models, cKit-dependent (Kit W-sh ) and cKit-independent (Cpa3-Cre; Mcl-1 fl/fl ), were exposed to CP via oropharyngeal aspiration. Lung inflammation, tissue injury, and immune cell composition were assessed using bronchoalveolar lavage, histopathology, and multiparameter flow cytometry. Semi-targeted lipidomics was performed to evaluate mast cell–dependent remodeling of pulmonary oxylipins. Results CP exposure in wild-type mice caused pronounced alveolar disruption, vascular remodeling, and increased bronchoalveolar cellularity, whereas mast cell–deficient mice exhibited attenuated inflammation and preserved lung structure. Mast cells critically regulated DC homeostasis: both cDC1 and cDC2 abundances were markedly elevated in mast cell–deficient mice, while migration of each subset toward the pulmonary vasculature occurred in both genotypes. Lipidomic profiling revealed mast cell–dependent alterations in oxylipins, including elevated leukotriene E 4 and depletion of linoleic acid–derived mediators, identifying a lipid mediator signature associated with mast cell activity. Conclusions Mast cells orchestrate CP-induced lung injury by controlling inflammatory magnitude, dendritic cell abundance and persistence, and oxylipin signaling networks. These findings reveal a previously unrecognized mast cell–dependent regulatory axis governing DC localization and resolution during chemical-induced pulmonary inflammation.
Gibb et al. (Fri,) studied this question.