Inflammasomes are intracellular multiprotein complexes of the innate immune system that respond to damage associated molecular patterns (DAMPs) generated during cellular stress and tissue injury, as well as pathogen associated molecular patterns (PAMPs) associated with microbial infection.
Among them, the NLRP3 inflammasome has received particular attention because of its role in regulating inflammation and its potential involvement in impaired wound healing. Once activated, NLRP3 promotes caspase 1 activation, leading to maturation and release of the inflammatory cytokines IL 1β and IL 18. Caspase 1 also cleaves gasdermin D, promoting pore formation and pyroptosis, an inflammatory form of programmed cell death.
Importantly, inflammasome activity is not inherently harmful. During acute wound healing, controlled and transient activation contributes to the normal inflammatory response and early tissue repair. The concern arises when this signaling becomes excessive or fails to resolve.
In diabetic wounds, increased NLRP3, caspase 1, and IL 1β signaling has been demonstrated in human tissue. Experimental studies suggest that persistent inflammasome activation can contribute to prolonged inflammation, impaired fibroblast function, abnormal extracellular matrix remodeling, pyroptotic cell injury, and altered vascular repair.
Preclinical studies also demonstrate that targeting NLRP3 or IL 1β can improve several aspects of diabetic wound healing. However, inflammasome directed therapy remains investigational and is not currently an established treatment for chronic wounds.
The therapeutic objective may therefore not be to suppress inflammation broadly, but to restore its appropriate timing, intensity, and resolution.
Indicative References
Weinheimer-Haus, E. M., Mirza, R. E., & Koh, T. J. (2015). Nod-like receptor protein-3 inflammasome plays an important role during early stages of wound healing. PloS one, 10(3), e0119106. https://lnkd.in/d3YwVWWx
Zhang, X., Dai, J., Li, L., Chen, H., & Chai, Y. (2017). NLRP3 Inflammasome Expression and Signaling in Human Diabetic Wounds and in High Glucose Induced Macrophages. Journal of diabetes research, 2017, 5281358. https://lnkd.in/d2b_s_vP
Mirza, R. E., Fang, M. M., Ennis, W. J., & Koh, T. J. (2013). Blocking interleukin-1β induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes, 62(7), 2579–2587. https://lnkd.in/dfAFq_EG
Dai, J., Shen, J., Chai, Y., & Chen, H. (2021). IL-1β Impaired Diabetic Wound Healing by Regulating MMP-2 and MMP-9 through the p38 Pathway. Mediators of inflammation, 2021, 6645766. https://lnkd.in/dHu_F_RC
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