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Objective <p>T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of membrane-bound TIM-3 by the A disintegrin and metalloprotease, however its precise role in inflammation remains largely unclear. This study aims to define the specific function of sTIM-3.</p> Methods <p>In this study, the role of sTIM-3 was investigated using in vivo models of experimental autoimmune encephalomyelitis (EAE) and septic shock. Mechanistic insights were gained through biochemical analyses of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome pathway.</p> Results <p>We found that sTIM-3 alleviated disease severity in both EAE and septic shock. This protective effect was achieved through the inhibition of NLRP3 inflammasome activation. Mechanistically, sTIM-3 interacted with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC), thereby dampening its oligomerization and subsequent assembly of the active NLRP3 inflammasome complex.</p> Conclusion <p>Our findings establish sTIM-3 as a promising therapeutic candidate for mitigating inflammation caused by excessive NLRP3 inflammasome activation, providing novel insights into potential interventions for various inflammatory diseases.</p>

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Novel insights into the effect of sTIM-3 on NLRP3 inflammasome via interacting with ASC

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Xiaodi Zhang,
  • Na Han,
  • Ziqing Xu,
  • Zheng Tong,
  • Xiaolei Ren,
  • Yang Sun,
  • Chunyang Li,
  • Xuetian Yue,
  • Zhuanchang Wu,
  • Xiaohong Liang,
  • Chunhong Ma,
  • Pin Wang,
  • Lifen Gao

摘要

Objective

T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of membrane-bound TIM-3 by the A disintegrin and metalloprotease, however its precise role in inflammation remains largely unclear. This study aims to define the specific function of sTIM-3.

Methods

In this study, the role of sTIM-3 was investigated using in vivo models of experimental autoimmune encephalomyelitis (EAE) and septic shock. Mechanistic insights were gained through biochemical analyses of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome pathway.

Results

We found that sTIM-3 alleviated disease severity in both EAE and septic shock. This protective effect was achieved through the inhibition of NLRP3 inflammasome activation. Mechanistically, sTIM-3 interacted with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC), thereby dampening its oligomerization and subsequent assembly of the active NLRP3 inflammasome complex.

Conclusion

Our findings establish sTIM-3 as a promising therapeutic candidate for mitigating inflammation caused by excessive NLRP3 inflammasome activation, providing novel insights into potential interventions for various inflammatory diseases.