Platelet-derived serotonin epigenetically programs macrophage alternative activation to orchestrate type 2 airway inflammation

Abstract Type 2 inflammation (T2I) drives chronic airway diseases such as eosinophilic chronic rhinosinusitis (eCRS) and asthma, which are frequently accompanied by coagulation activation and platelet recruitment. However, whether and how these associated processes actively contribute to shaping inflammation remain largely unknown. Here, using single-cell transcriptomic profiling of human nasal polyp samples from eCRS patients with or without comorbid asthma, we identified a TGM2 hi macrophage population enriched in inflamed tissues and strongly correlated with local eosinophilia and systemic disease burden. Using dust mite-induced type 2 airway inflammation models in mice, we showed that the loss of Tgm2 , either globally or in macrophages, selectively impaired alternative macrophage activation and attenuated both eosinophilic inflammation and epithelial remodeling. Mechanistically, TGM2 catalyzes the recently described histone modification H3Q5 serotonylation (H3Q5Ser), promoting an epigenetically permissive chromatin state for alternative macrophage activation. We further revealed a transcellular circuit driven by the activated platelet-derived monoamine metabolite serotonin (5-HT), which acts as a critical paracrine signal to fuel this epigenetic reprogramming of macrophages. Crucially, pharmacological inhibition of platelet 5-HT release or TGM2 activity ameliorated both nasal and pulmonary pathology in a mouse model of type 2 inflammation, underscoring the therapeutic potential of this pathway. Our findings establish a serotonin-TGM2-H3Q5Ser axis that couples platelet activation to macrophage epigenetic programming. This transcellular mechanism drives type 2 inflammation and reveals novel therapeutic opportunities across airway diseases.