TREM2 defends the liver against alveolar echinococcosis by driving fibrous shell formation.

Immunosuppression and extensive fibrosis around the lesions are important features of alveolar echinococcosis (AE) caused by E. multilocularis. Recent studies have suggested that TREM2 is involved in tumor immunosuppression and tissue fibrosis. However, the function and mechanism of TREM2 in AE remain to be determined. Here, TREM2 expression was assessed in human and mouse lesions by immunostaining. A variety of E. multilocularis infection models were established in wild-type and Trem2-/- mice. RNA sequencing, ATAC sequencing, and in vitro assays were conducted to explore the underlying roles of TREM2+ macrophages. Potential drugs were screened and tested in vivo. We show that TREM2+ macrophages accumulated at the periparasitic borders of human and mouse metacestode lesions in the liver. Trem2 deficiency exacerbated the parasitic burden and weakened the fibrous shells surrounding the lesions, whereas Trem2 overexpression enhanced peri-lesional fibrosis in mouse models. E. multilocularis vesicle fluid (EmVF) can induce TREM2 expression via TGF-β/Smad signaling. Trem2 deficiency abolished the macrophage migration and fibroblast proliferation induced by EmVF. Drug screening revealed that resiquimod promoted periparasitic fibrosis, whereas SB431542, a TGF-β signaling inhibitor, had the opposite effect. Thus, TREM2-mediated fibrous shell formation plays a protective role in patients with AE. Activation of TREM2 signaling represents a novel potential therapeutic strategy for AE.