Maxing Shigan Decoction Alleviates Lung Heat Syndrome by Inhibiting α4β7-Mediated γδT17 Cell Migration Across the Gut-Lung-Nasal Axis

Jingyi Zhao, Junge Wang, Xinyu Yan, Suying Guo, Man Wang Department of Otolaryngology, Beijing Hospital of Traditional Chinese Medicine, Beijing, People’s Republic of ChinaCorrespondence: Junge Wang, Email [email protected]: Lung Heat Syndrome (LHS), a pathological state in Traditional Chinese Medicine characterized by pulmonary inflammation, lacks mechanistic understanding of its gut-lung-nasal axis involvement. Maxing Shigan decoction (MXSGD) clinically resolves LHS, but its immunomodulatory mechanisms remain unclear. This study aimed to elucidate the specific immunomodulatory mechanism through which MXSGD alleviates LHS, focusing on its role in regulating γδT17 cell migration along the gut-lung-nasal axis via the α 4β 7 pathway.Methods: Network pharmacology and molecular docking identified MXSGD’s bioactive components and targets. Mice were randomized into Control, LHS, and different doses of MXSGD groups. LHS was induced by cold stress with intratracheal lipopolysaccharide, and MXSGD was administered orally. Water intake, respiratory rate, and locomotor activity were monitored. CFSE-labeled γδT17 cells were adoptively transferred. CCL25 levels were manipulated using recombinant protein or neutralizing antibody, and α 4β 7 integrin was blocked with specific antibody. Tissues were analyzed by H&E staining, flow cytometry, ELISA and RT-PCR.Results: Network pharmacology analysis identified 142 shared targets between MXSGD and LHS, with significant enrichment in interleukin-17A (IL-17A) and T cell receptor signaling pathways. MXSGD significantly alleviated reduced water intake and attenuated neutrophil infiltration in ileum and lung. MXSGD inhibited γδT17 cell migration in the lungs and nose, while downregulating IL-17A production in the ileum and lungs and RORγt expression across all tissues. Recombinant CCL25 increased the frequencies of γδT17 cells in the ileum and lungs and α 4β 7+γδT17 cells in the lungs, and elevated IL-17A levels in all tissues. These effects were reversed by CCL25 neutralization. α 4β 7 blockade inhibited γδT17 recruitment and IL-17A production in nose.Conclusion: MXSGD alleviated LHS by inhibiting CCL25/α 4β 7-dependent γδT17 cell migration and IL-17 production. The study demonstrated γδT17 trafficking as the cellular basis for gut-lung-nasal axis interaction in LHS, while positioning MXSGD as a promising therapy for IL-17-driven respiratory inflammation. Keywords: maxing Shigan decoction, lung heat syndrome, γδT17 cells, gut-lung-nasal axis, C-C motif chemokine 25, α 4β 7 integrin