TLR2 and TLR4 bridge physiological and pathological inflammation in the reproductive system

Toll-like receptors (TLRs), particularly TLR2 and TLR4, are critical components of the innate immune system that play significant roles in reproductive biology beyond their well-established functions in immune defense. These receptors recognize distinct pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), triggering signaling cascades that impact diverse reproductive processes. TLR2-induced physiological inflammation, characterized by transient and precisely controlled inflammatory responses, is essential for facilitating sperm-triggered uterine clearance and promoting embryo implantation, thus maintaining reproductive homeostasis. This homeostasis represents a dynamic equilibrium of immune, endocrine, and cellular interactions essential for successful reproduction. Conversely, pathological inflammation, often driven by TLR4, can result in severe tissue damage, impairing fertility and pregnancy outcomes. This review highlights the shared and distinct signaling pathways of TLR2 and TLR4, their interplay mediated by co-receptors (TLR1 and TLR6) and regulatory molecules such as SOCS-1 and A20, and the implications of their dimerization. Understanding how physiological and pathological inflammation overlap and influence reproductive processes is critical for advancing fertility treatments. Targeting these pathways presents a promising therapeutic approach to address inflammation-related infertility and improve reproductive health.