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Publications

Journal Article Epublish

PubMed: 39966955 DOI: 10.1186/s12967-025-06204-z

Targeting the NLRP3 in macrophages contributes to senescence cell clearance in radiation-induced skin injury.

J Transl Med 23(1):196

Authors: Gaoyu Liu, Yan Chen, Shijie Dai, Gang Wu, Fulong Wang, Wanchao Chen, Lingling Wu, Peng Luo, Chunmeng Shi

Affiliations

  • Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China. Key Laboratory of Extreme Environmental Medicine of Ministry of Education, Institute of Medicine and Equipment for High Altitude Region, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
  • Institute of Rocket Force Medicine, State Key Laboratory of Trauma and Chemical Poisoning, Third Military Medical University (Army Medical University), Chongqing, 400038, China.

Abstract

BACKGROUND

The persistent accumulation of senescence cells is one of the characteristics of radiation-induced skin injury (RISI), leading to fibrosis and impaired healing. However, the reasons why these senescence cells are resistant to clearance remain unclear.

METHODS

The mouse RISI model was established using an X-ray generator, and a shield was used to cover all areas except the skin of the right leg or back for protecting surrounding tissue. ScRNA sequencing, immunohistochemistry, immunofluorescence, qPCR, western blot, primary cell co-culture system and fluorescence microsphere phagocytosis assay were performed for the functional and mechanistic investigations.

RESULTS

The dynamic changes of senescence cell levels and multiple immune cell levels during RISI were evaluated, we found that macrophages could remove senescence cells from the dermis, and the clearance ability gradually strengthens over time. ScRNA sequencing revealed that macrophages with high senescence clearance capacity exhibited increased NOD-like receptor family pyrin domain-containing 3 (NLRP3) expression compared to those with low senescence clearance capacity. Inhibition or conditional knockout of Nlrp3 in macrophages led to senescence cell clearance dysfunction and impaired healing. Further studies found that interleukin-33 secreted by senescence cells inhibited the expression of NLRP3 in macrophages and their ability to phagocytize senescence cells, especially in the early stages after radiation. In addition, Nocardia rubra cell wall skeleton (Nr-CWS), an approved immunomodulator, was found to activate macrophage NLRP3 expression, reduce senescence cell burden, and accelerate the healing of RISI.

CONCLUSION

This study underscored NLRP3 in macrophages as a critical intervention target for senescence cell immunosurveillance and emphasized Nr-CWS as a potential therapeutic agent for accelerating senescence cell clearance in RISI.

MeSH

Skin, Cells, Biomedical Research, Macrophages, Cellular Senescence