TLR Signaling Beyond Immunity: Emerging Roles in Cell Migration, Metabolism, Development, and Host-Microbiome Crosstalk.

Recent findings support a broader view of TLR signaling as an integrative signaling hub that links immunity with cell migration, metabolism, development, and host-microbiome crosstalk. In cell migration, TLRs exert context-dependent effects through chemokine receptor regulation, adhesion and cytoskeletal modulation, and indirect cytokine-mediated signaling. In metabolism, TLRs orchestrate insulin resistance, obesity, and glucose homeostasis in a receptor- and tissue-specific manner. In tissue injury and development, TLR signaling exerts dual roles; it is detrimental in ischemia-reperfusion injury, but beneficial in vascular remodeling and neurogenesis. We then examine the bidirectional interplay between TLRs and the gut microbiome, where TLRs shape microbial community structure and intestinal immune homeostasis. Finally, we survey the therapeutic landscape of TLR modulators, highlighting that while TLR agonists are predominantly explored in oncology, TLR antagonists show promise in autoimmune diseases such as inflammatory bowel disease. Special attention is given to insights from organoid, rodent and zebrafish models, which have provided powerful in vitro and in vivo evidence for multiple roles of TLR signaling under both physiological and pathological conditions. A deeper understanding of these non-canonical functions will be essential for developing next-generation therapeutic strategies that selectively modulate TLR signaling in infectious, inflammatory, metabolic, and microbiome-associated diseases.