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Review
. 2024 Jun 14:17:3839-3864.
doi: 10.2147/JIR.S465203. eCollection 2024.

Pyroptosis in Diabetic Peripheral Neuropathy and its Therapeutic Regulation

Abdullah Al Mamun  1   2 , Chuxiao Shao  1 , Peiwu Geng  1 , Shuanghu Wang  1 , Jian Xiao  1   2   3
Affiliations
Review

Pyroptosis in Diabetic Peripheral Neuropathy and its Therapeutic Regulation

Abdullah Al Mamun et al. J Inflamm Res. .

Abstract

Pyroptosis is a pro-inflammatory form of cell death resulting from the activation of gasdermins (GSDMs) pore-forming proteins and the release of several pro-inflammatory factors. However, inflammasomes are the intracellular protein complexes that cleave gasdermin D (GSDMD), leading to the formation of robust cell membrane pores and the initiation of pyroptosis. Inflammasome activation and gasdermin-mediated membrane pore formation are the important intrinsic processes in the classical pyroptotic signaling pathway. Overactivation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome triggers pyroptosis and amplifies inflammation. Current evidence suggests that the overactivation of inflammasomes and pyroptosis may further induce the progression of cancers, nerve injury, inflammatory disorders and metabolic dysfunctions. Current evidence also indicates that pyroptosis-dependent cell death accelerates the progression of diabetes and its frequent consequences including diabetic peripheral neuropathy (DPN). Pyroptosis-mediated inflammatory reaction further exacerbates DPN-mediated CNS injury. Accumulating evidence shows that several molecular signaling mechanisms trigger pyroptosis in insulin-producing cells, further leading to the development of DPN. Numerous studies have suggested that certain natural compounds or drugs may possess promising pharmacological properties by modulating inflammasomes and pyroptosis, thereby offering potential preventive and practical therapeutic approaches for the treatment and management of DPN. This review elaborates on the underlying molecular mechanisms of pyroptosis and explores possible therapeutic strategies for regulating pyroptosis-regulated cell death in the pharmacological treatment of DPN.

Keywords: Caspase-1; Diabetes mellitus; Diabetic peripheral neuropathy; GSDMD; IL-1β and IL-18; Inflammation; NLRP3; Pyroptosis.

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Conflict of interest statement

The authors declare no competing interests in this work.

Figures

None
Graphical abstract
Figure 1
Figure 1
Cellular and molecular mechanisms of pyroptosis-related signaling pathways. Pyroptotic signaling pathways are mainly activated by the stimulation of damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), leading to the activation of a variety of inflammasome signals. The activated inflammasome proteins further activate the Caspase-1 signaling pathway. Then, activated Caspase-1 splits GSDMD protein molecules to produce GSDMD N-fragment and plasma membrane pores, resulting in pyroptosis-dependent cell death. Furthermore, the Caspase-1 pathway triggers the formation and maturation of IL-1β and IL-18 inflammatory factors. In addition, LPS binds to Caspase-4/5/11 precursor, which further activates pyroptosis-regulated cell death through the formation of GSDMD-dependent pores in the cytoplasmic region. Caspase-3/GSDME can also induce pyroptosis-mediated cell death. Furthermore, mitochondrial and death receptors can trigger the Caspase-3 pathway. The activated Caspase-3 splits GSDME to produce GSDME N-fragment, which further creates plasma membrane pores, cell contraction and rupture, resulting in pyroptosis-mediated cell death.
Figure 2
Figure 2
Pathophysiological roles of pyroptosis-dependent cell death in the course of the pathogenesis of DPN. Hyperglycemia, insulin resistance and hyperlipidemia stimulate NLRP3/ASC inflammasome signals, further activating pro-caspase-1 into Caspase-1 form. Then, activated Caspase-1 induces the generation and maturation of inflammatory factors including IL-1β and IL-18, resulting in low-grade inflammation and peripheral nerve injury, eventually advancing DPN.
Figure 3
Figure 3
Schematic illustration of therapeutic implications by several experimental compounds/drugs targeting inflammasome and pyroptosis-related signaling pathways for novel therapeutic strategies in the treatment and management of DPN.
See this image and copyright information in PMC

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Grants and funding

This review work was partially supported by the grants of the Zhejiang Provincial Natural Science Foundation of China (LQ21H09000, the National Natural Science Foundation of China (Grants 82172428 and 81972150), the Key Research and Development Project of Lishui (2023zdyf15), the Public Welfare Technology Research Funding Project of Zhejiang (LTGY24H100002) and the Post-Doctoral Research Start-up Fund of Lishui People’s Hospital, Zhejiang, China (2023bsh001).

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