Baicalin restores innate lymphoid immune imbalance during exacerbation of COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by immune dysregulation, including altered innate lymphoid cell (ILC) immune responses, particularly during exacerbations (ECOPD). Baicalin, a natural compound prevalent in various herbal medicines, has shown promise as a therapeutic candidate in ECOPD. However, its potential and molecular mechanism for addressing ILC immune imbalance during ECOPD remain poorly understood. First, this study conducted a cross-sectional analysis of ILC immune responses in stable COPD patients and those experiencing exacerbations. Then, clinical findings of skewed ILC immunity were validated in cigarette smoke and lipopolysaccharide-induced ECOPD mouse models. Lastly, the therapeutic effect of baicalin on restoring ILC immune homeostasis was investigated in experimental ECOPD mouse models. Significant downregulation of ILC2 immunity was observed during COPD exacerbations, accompanied by increased ILC1 and ILC3 responses, particularly in cases associated with bacterial infections. Notably, elevated IL-22 levels were observed in this group. Administration of recombinant IL-22 in ECOPD mouse models disrupted lung ILC homeostasis, specifically inhibiting the accumulation of ILC2. Proteomics and transcriptomics analyses suggested IL-22 as a mediator of type 2 immune suppression by creating a molecular environment that favors type 1 and type 3 immunity. Treatment with baicalin effectively restored ILC2 immunity by enhancing the recruitment and activation of lung ILC2 while suppressing ILC1 and ILC3 responses. Importantly, baicalin attenuated IL-22 production from lung ILC3, highlighting its potential as an IL-22 inhibitor. Baicalin demonstrates potential as a therapeutic strategy for addressing ILC immune imbalance in COPD exacerbations, particularly by restoring ILC2 immunity and partially inhibiting IL-22 production. Clinical registration The cross-sectional study was registered with the Chinese Clinical Trial Registry (ChiCTR2100050683).