The TREM2 paradox in fibrosis: a unified mechanism for opposite outcomes across organs.

Organ fibrosis, a debilitating outcome of chronic diseases, results from the maladaptive interaction between inflammatory activation and tissue repair mechanisms. Triggering receptor expressed on myeloid cells 2 (TREM2), which is primarily expressed on macrophages, has emerged as a crucial regulator of this process. However, its seemingly contradictory roles across various fibrotic contexts have impeded the development of a cohesive understanding. This review seeks to transcend a simplistic organ-based categorization by proposing that the dual role of TREM2 in fibrosis is dictated by its central function in orchestrating macrophage functional polarization, immunometabolic reprogramming, and multicellular communication within the damaged microenvironment. First, we elucidate the molecular foundations of TREM2 signaling. We subsequently integrate evidence from pulmonary, renal, hepatic, cardiac, and dermal fibrosis to support the premise that TREM2 serves as a pivotal determinant in directing macrophages toward either resolving or perpetuating fibrosis through these fundamental pathways. Furthermore, we critically assessed the translational implications, including the potential of soluble TREM2 (sTREM2) as a dynamic biomarker and the promise of innovative therapeutic approaches.