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Review
. 2022 Oct 27:13:986565.
doi: 10.3389/fendo.2022.986565. eCollection 2022.

Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications

Affiliations
Review

Potential therapeutic role of pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications

Xiang Li et al. Front Endocrinol (Lausanne). .

Abstract

As a new way of programmed cell death, pyroptosis plays a vital role in many diseases. In recent years, the relationship between pyroptosis and type 2 diabetes (T2D) has received increasing attention. Although the current treatment options for T2D are abundant, the occurrence and development of T2D appear to continue, and the poor prognosis and high mortality of patients with T2D remain a considerable burden in the global health system. Numerous studies have shown that pyroptosis mediated by the NLRP3 inflammasome can affect the progression of T2D and its complications; targeting the NLRP3 inflammasome has potential therapeutic effects. In this review, we described the molecular mechanism of pyroptosis more comprehensively, discussed the most updated progress of pyroptosis mediated by NLRP3 inflammasome in T2D and its complications, and listed some drugs and agents with potential anti-pyroptosis effects. Based on the available evidence, exploring more mechanisms of the NLRP3 inflammasome pathway may bring more options and benefits for preventing and treating T2D and drug development.

Keywords: NLRP3 inflammasome; complications; pyroptosis; therapy; type 2 diabetes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Molecular mechanism of pyroptosis. In the caspase-1-dependent pathway, PAMPs and DAMPs mediate inflammasome assembly and activate caspase-1, which cleaves GSDMD and pro-IL-1β/18. N-GSDMD forms non-selective pores on the cell membrane surface, and IL-1β and IL-18 are secreted out of the cell membrane through the pores formed by N-GSDMD, which further leads to cell lysis and death. In the caspase-1-independent pathway, LPS of bacteria activates caspase-4/5/11 and cleaves GSDMD to trigger pyroptosis. However, caspase-4/5/11 can also activate inflammasome assembly and caspase-1 to induce pyroptosis. In addition, in the caspase-8-mediated pathway, TNF-α induces the activation of caspase-8, cleavage of GSDMD leads to pyroptosis, and caspase-8 can also cleave GSDMC and GSDME, Furthermore, the NLRP3 inflammasome also activate Caspase-8. Granzyme also mediates pyroptosis, such as GzmB released from CAR T cells induces pyroptosis by activating caspase-3 and cleaving GSDME. In the caspase-9-mediated pathway, chemotherapy drugs and iron cause mitochondrial stress, activate caspase-3/9, and cleave GSDMB/E to mediate pyroptosis. Furthermore, GzmA in cytotoxic leukomonocyte enters target cells via perforin and cleaves GSDMB resulting in cell pyroptotic death. Similarly, GSDMB/C/E also forms pores to mediate the secretion of inflammatory mediators out of the membrane, amplify the inflammatory response, and promote cell death.
Figure 2
Figure 2
Classical and non-classical inflammasome assembly. The canonical pathway is mediated by caspase-1. When NLRP1, NLRC4, NLRP3, AIM, and Pyrin inflammatory sensors receive different stimuli, recruiting ASC and caspase-1 to mediate the assembly of inflammasomes and activate caspase-1. Among them, the assembly of NLRP3 and NLRC4 inflammasomes requires the participation of NEK7 and NAIPs, respectively, and NLRP1 and NLRC4 can directly activate case page-1 due to their CARD domains. After activation of Caspase-1, GSDMD and pro-IL-1β/18 is cleaved, and the pore formed by GSDMD on the cell membrane surface mediates secretion of IL-1β/18 out of the cell and induces pyroptosis. The non-canonical pathway is mediated by caspase-4/5/11; LPS of Gram-negative bacteria directly induces caspase-4/5/11 activation and cleaves GSDMD and Pannexin-1. N-GSDMD induces caspase-1 activation by activating NLRP3 inflammasome assembly, which mediates the release of inflammatory mediators and pyroptosis.
Figure 3
Figure 3
Pyroptosis mediated by the NLRP3 inflammasome in type 2 diabetes and its complications.

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