SR-A1 cooperates with TLR4-NF-κB signaling to drive macrophage TGF-β1 expression and Treg induction during schistosome infection

Helminths induce regulatory T cells (Tregs) to establish chronic infections, promoting long-term persistence of both parasites and hosts. TGF-β1 is essential for Treg induction by initiating Foxp3 expression. Helminth infections are typically associated with high TGF-β1 levels, yet the mechanisms by which helminths drive its production are not fully understood. Here, we uncover a mechanism whereby the scavenger receptor class A1 (SR-A1) cooperates with TLR4 signaling to drive TGF-β1 production by macrophages. Mechanistically, schistosome egg antigens activate TLR4-p50 (NF-κB1) while concurrently engaging SR-A1 to upregulate c-Jun, thereby assembling c-Jun-p50 transcription complexes at the Tgfb1 promoter and enhancing TGF-β1 expression, subsequently inducing Tregs and mitigating liver immunopathology in Schistosoma japonicum-infected mice. Thus, we identify a previously unrecognized host-parasite interaction wherein SR-A1-TLR4 cooperation enables helminths to manipulate macrophage transcriptional programs for TGF-β1 expression and Treg induction, identifying a potential therapeutic target in the host for inflammatory helminthiasis.