Berberine alleviates T cell-driven lung inflammation by inhibiting cytokine secretion and regulating pulmonary microbiota.

Berberine exhibits diverse biological activities including inhibition of T cell function to alleviate inflammatory diseases. However, the evidence and mechanisms by whether berberine directly regulates CD4+ T cells in vitro and in vivo remain unclear. Using an OVA-stimulated primary T cell activation model in vitro, berberine directly targeted T cells to suppress Th1 and Th17 differentiation. Moreover, berberine inhibited early T cell activation and proliferation while modestly promoting T cell apoptosis by downregulating Bcl2 expression. Mechanistically, transcriptomic analysis revealed that berberine controls the pro-inflammatory cytokine production by modulating JAK-STAT, PI3K/Akt, and NF-κB signals. Notably, inhibition of PTEN, a key negative regulator of these pathways, completely reversed the reduced cytokine release induced by berberine. In vivo experiments showed that berberine significantly improves pulmonary inflammation. In an OVA-specific T cell-mediated lung inflammation model, berberine markedly reduced activated CD4+ T cell infiltration and cytokine production in lung, as well as impaired their capacity to recruit other immune cells. Furthermore, berberine alters the social community and diversity of lung microbiota rather than inhibiting bacterial abundance, which potentially contribute to improved lung inflammation. Collectively, our findings elucidate the role and mechanisms of berberine in T cell differentiation and demonstrated its therapeutic effects in ameliorating lung inflammation through suppression of T cell function and modulation of pulmonary microbiota.