Th17/Treg imbalance: a key driver of neutrophilic inflammation in severe asthma

Severe asthma, characterized by neutrophilic airway inflammation, poses a significant clinical obstacle, primarily due to its frequent association with glucocorticoid resistance. This review provides a systematic analysis of how the imbalance between T helper 17 (Th17) cells and regulatory T (Treg) cells contributes to this glucocorticoid-resistant phenotype. We emphasize three interconnected mechanisms that transcend traditional cytokine networks: immunometabolic reprogramming, which promotes glycolytic adaptation in Th17 cells while simultaneously impairing oxidative metabolism in Tregs; microbiome dysregulation, acting via the "gut-lung axis", which disrupts local and systemic immune tolerance; and Treg plasticity, wherein inflammatory signals transform suppressive Tregs into pro-inflammatory Th17-like cells, thereby exacerbating immune imbalance. Consequently, these processes establish a self-perpetuating inflammatory environment that sustains neutrophilic infiltration and impairs glucocorticoid sensitivity. On this basis, we evaluate emerging therapeutic strategies targeting the Th17/Treg axis, including Interleukin-17/Interleukin-23 (IL-17/IL-23) blockade, Janus kinase inhibitors, and Treg-enhancing approaches. We conclude that biomarker-guided patient stratification, rather than a "one-size-fits-all" strategy, will be essential to translate these mechanistic insights into effective precision immunotherapy for severe neutrophilic asthma.