Lysophosphatidylserine (LysoPS) is an amphipathic lysophospholipid that mediates a broad spectrum of inflammatory responses through a poorly characterized mechanism. Because LysoPS levels can rise in a variety of pathological conditions, we sought to investigate LysoPS’s potential role in airway epithelial cells that actively participate in lung homeostasis. Here, we report a previously unappreciated function of LysoPS in production of a mucin component, MUC5AC, in the airway epithelial cells. LysoPS stimulated lung epithelial cells to produce MUC5AC via signaling pathways involving TACE, EGFR, and ERK. Specifically, LysoPS- dependent biphasic activation of ERK resulted in TGF-α secretion and strong EGFR phosphorylation leading to MUC5AC production. Collectively, LysoPS induces the expression of MUC5AC via a feedback loop composed of proligand synthesis and its proteolysis by TACE and following autocrine EGFR activation. To our surprise, we were not able to find a role of GPCRs and TLR2, known LyoPS receptors in LysoPS-induced MUC5AC production in airway epithelial cells, suggesting a potential receptor-independent action of LysoPS during inflammation. This study provides new insight into the potential function and mechanism of LysoPS as an emerging lipid mediator in airway inflammation.

Jo SH, et al. Allergy Asthma Immunol Res. 2026 Mar;18(2):204-223. https://doi.org/10.4168/aair.2026.18.2.204

Secreted airway mucins form a mucous gel consisting of MUC5AC and MUC5B and maintain airway homeostasis for appropriate mucociliary clearance and airway defense. There is conceivably a global mechanism to counteract excessive mucin production in response to incessant exposure to external and internal stimuli, which otherwise leads to goblet metaplasia and mucus hyperproduction. Here, we report that butyrate, a short-chain fatty acid (SCFA), strongly suppresses MUC5AC production at as low as sub-to micromolar concentrations in NCI-H292, airway epithelial cells. Butyrate transcriptionally inhibits MUC5AC mRNA and protein that are induced by a variety of stimuli including EGF and LPS. In line, butyrate upregulates FOXA2, which is known to block goblet cell metaplasia. The mode of the inhibition by butyrate appears to be independent of the known receptors of butyrate. In addition, butyrate does not alter the EGFR signaling pathway. Chromatin immunoprecipitation analysis demonstrates that histone H3K27 acetylation level is increased upon stimulation with EGF and returns to baseline in the presence of butyrate. We propose that butyrate, a metabolic product of gut microbiota, plays a central role in maintaining homeostasis of airway mucous gel by counteracting mucin production resulting from repeated provocation of airway epithelium. National Research Foundation of Korea (NRF) funded by the Korean government (MSIT), NRF-2022R1A2B5B01002127.