Myeloid Trem2 orchestrates nonalcoholic steatohepatitis-associated inflammation and HCC progression by reprogramming recruited macrophages

Abstract Several studies have initially explored the possible role of Trem2 in NASH progression, but the confounding of cellular targeting and differences and limitations in research methods have obscured the precise identity of Trem2. Based on Trem2Flox, Trem2△mye, Trem2creERT Rosa26Tdtomato mice feeding with AMLN/CDAHFD60-driven NASH-HCC progression, we clearly delineate the full-time dynamic landscape of NAFLD-NASH-HCC regulated by myeloid-derived trem2: the absence of myeloid Trem2 leads to the pro-resolution program reprogramming of Ly6Chi monocytes/infiltrating macrophages recruited by NAFLD was partially terminated, resulting in accumulation and proliferation of monocytes and infiltrating macrophages, thereby exacerbating hepatic steatosis and inflammation. Termination of the pro-resolution program resulted in increasing susceptibility to liver fibrosis while impairing Trem2-dependent exocytosis program, inhibiting TGFβ secretion and partially counteracting inflammation-driven activation of stellate cell. Furthermore, myeloid Trem2 deficiency blocks NASH-HCC occurence while reversing the infiltration of Eomes+PD1+CD8+ T cells, thus playing a key role in the progression of NAFLD-NASH-HCC. Our study broaden a new horizon for elucidating how myeloid Trem2 regulates chronic inflammatory liver disease and the corresponding tumor drivens.