NLRP3 Inflammasome Targeting Offers a Novel Therapeutic Paradigm for Sepsis-Induced Myocardial Injury

Abstract

Cardiac or myocardial dysfunction induced by sepsis, known as sepsis-induced cardiomyopathy or sepsis-induced myocardial injury (SIMI), is a common complication of sepsis and is associated with poor outcomes. However, the pathogenesis and molecular mechanisms underlying SIMI remain poorly understood, requiring further investigations. Emerging evidence has shown that NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes contribute to SIMI. Compounds that inhibit NLRP3-associated pyroptosis may exert therapeutic effects against SIMI. In this review, we first outlined the principal elements of the NLRP3 signaling cascade and summarized the recent studies highlighting how NLRP3 activation contributes to the pathogenesis of SIMI. We outlined selective small-molecule modulators that function as NLRP3 inhibitors and delineated their mechanisms of action to attenuate SIMI. Finally, we discuss the major limitations of the current therapeutic paradigm and propose possible strategies to overcome them. This review highlights the pharmacological inhibition of SIMI as a promising therapeutic strategy.

Keywords: NLRP3; bioactive compounds; pyroptosis; sepsis; sepsis-induced myocardial injury.

Figure 1

NLRP3 priming, activation, and downstream effectors NLRP3 activity is initiated by extracellular signaling derived from damage-associated molecular patterns (DAMPs)/pathogen-associated molecular patterns (PAMPs), cytokines, or neuronal hormones. Integrated signals promote the activity of the NF-kB and IRF3 transcription factors, promoting the expression of the NLRP3 protein components and substrates. Lysosomal degradation of insoluble particulates/crystals, potassium efflux, calcium influx, chloride efflux, viral infection, and mitochondrial ROS generation promote the assembly of the mature NLRP3 complex. Once mature and active, the NLRP3 complex cleaves pro-IL-1b, pro-IL-18, and GSDMD to initiate pyroptosis and the paracrine spread of pro-inflammatory cytokines.

Figure 2

Mechanisms underlying NLRP3 activation in cardiac-associated cells In addition to cardiomyocytes, NLRP3 activation in cardiac fibroblasts and macrophages is crucial for the onset and progression of sepsis-induced myocardial injury (SIMI). Cardiac fibroblasts are primarily regulated by the lipopolysaccharide (LPS), peroxynitrite/PKR, and paracrine pathways. Macrophages are regulated by reactive oxygen species (ROS)/M1 polarization, metabolic reprogramming, and exosomal exposure. Finally, cardiomyocytes are regulated by nuclear factor-kappaB (NF-kB) pathway activity, cGAS-STING pathway activity, and the balance between pro/anti-pyroptotic protein expression.

Figure 3

Chemical structures of small molecules targeting NLRP3 to treat SIMI.

Figure 4

Pharmacology of NLRP3 antagonists against SIMI Multiple generic classes of NLRP3 inhibitors have been identified. Some compounds have been found to repress upstream toll-like receptor 4 (TLR4) signaling, repress the transcription of NLRP3-associated genes, inhibit NLRP3 complex assembly/maturation, and prevent downstream NLRP3-induced pyroptosis.