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<p>Toll-like receptor-4 (TLR-4) is an important pattern-recognition receptor in the testis. It exhibits a context-dependent dual role as both a physiological “sanitiser” and a pathological “killer”. Under normal conditions, TLR-4 is abundantly expressed in Leydig cells, resident tolerogenic (M2-like) macrophages, and also expressed in Sertoli cells. In this quiescent state, it detects pathogen- and damage-associated molecular patterns to mediate localised innate immune surveillance, preserve testicular immune privilege, support spermatogenesis, and maintain steroidogenesis while largely preserving blood-testis barrier integrity. It does this through tightly regulated MyD88- and TRIF-dependent signalling. In testicular ischemia-reperfusion injury (TIRI), however, excessive release of endogenous DAMPs can overwhelm the intrinsic negative regulators such as SOCS-1 and A20. This persistent ligand engagement is associated with sustained activation of NF-κB and IRF pathways, thereby contributing to a cascade of pro-inflammatory mediators, reactive oxygen and nitrogen species, neutrophil infiltration, blood-testis barrier disruption, and both intrinsic and extrinsic germ-cell apoptosis. These events have been implicated in systemic inflammatory spread that may extend damage to the contralateral testis and&#xa0;exacerbate bilateral spermatogenic failure that&#xa0;can consequently lead to infertility. This review examines the&#xa0;current evidence on the molecular architecture of TLR-4 signalling and highlights its built-in regulatory checkpoints, which can serve as precise therapeutic targets. It is noted that elective modulation, rather than global blockade, may offer a promising strategy to attenuate pathological overactivation while preserving the receptor’s homeostatic functions.</p>

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Roles of Toll-like receptor 4 in the normal testis and during testicular ischemia-reperfusion injury: a sanitiser or a killer?

  • 期刊论文

  • 发表日期：

    2026年8月5日

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  • Richard Adedamola Ajike,
  • Precious Abisola Olayiwola,
  • Oladele Ayobami Afolabi,
  • Onaopepo Abdulwakeel Lawal,
  • Oluwaseun Samuel Hezekiah,
  • Olajumoke Stella Olapade,
  • Sofiyat Adenike Akano,
  • Adedamola Emmanuel Ikotun,
  • Peace Peter Adekunleoke,
  • Olubunmi Simeon Oyekunle,
  • Salaudeen Rokeeb Oyetunji

摘要

Toll-like receptor-4 (TLR-4) is an important pattern-recognition receptor in the testis. It exhibits a context-dependent dual role as both a physiological “sanitiser” and a pathological “killer”. Under normal conditions, TLR-4 is abundantly expressed in Leydig cells, resident tolerogenic (M2-like) macrophages, and also expressed in Sertoli cells. In this quiescent state, it detects pathogen- and damage-associated molecular patterns to mediate localised innate immune surveillance, preserve testicular immune privilege, support spermatogenesis, and maintain steroidogenesis while largely preserving blood-testis barrier integrity. It does this through tightly regulated MyD88- and TRIF-dependent signalling. In testicular ischemia-reperfusion injury (TIRI), however, excessive release of endogenous DAMPs can overwhelm the intrinsic negative regulators such as SOCS-1 and A20. This persistent ligand engagement is associated with sustained activation of NF-κB and IRF pathways, thereby contributing to a cascade of pro-inflammatory mediators, reactive oxygen and nitrogen species, neutrophil infiltration, blood-testis barrier disruption, and both intrinsic and extrinsic germ-cell apoptosis. These events have been implicated in systemic inflammatory spread that may extend damage to the contralateral testis and exacerbate bilateral spermatogenic failure that can consequently lead to infertility. This review examines the current evidence on the molecular architecture of TLR-4 signalling and highlights its built-in regulatory checkpoints, which can serve as precise therapeutic targets. It is noted that elective modulation, rather than global blockade, may offer a promising strategy to attenuate pathological overactivation while preserving the receptor’s homeostatic functions.