Neuronal tetraspanin TSP-6 suppresses intestinal innate immunity by modulating dense-core vesicle release in Caenorhabditis elegans

Immunomodulation plays a pivotal role in maintaining immune homeostasis, defending against pathogens, and regulating various biological processes. Tetraspanins (TSPs), a highly conserved transmembrane protein superfamily, are predominantly expressed on the surface of more than 50% of mammalian immune cells, where they critically control the immune responses. However, the underlying mechanisms by which TSPs modulate immunity remain poorly elucidated. Through a systematic screening of TSPs in Caenorhabditis elegans, it was found that knockdown or knockout of tsp-6 significantly enhanced innate immunity against Pseudomonas aeruginosa PA14 in the intestine. Moreover, tissue-specific rescue of tsp-6 in AWA neurons eliminated resistance to this pathogenic bacterium, a process dependent on UNC-31-mediated synaptic vesicle release. Our findings further supported that TSP-6 controlled innate immunity through the DAF-16/FOXO and p38 mitogen-activated protein kinase (MAPK) pathways. Collectively, our results have indicated that the tetraspanin TSP-6 in C. elegans regulates intestinal innate immune responses against P. aeruginosa PA14 through neuronal modulation, suggesting a novel mechanism by which tetraspanins contribute to neuro-immune crosstalk.