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Gene & Protein in Disease NLRP3 in SCI and CHM

crimes, tumors, and vertebral column degeneration, receptors (TLRs), intracellular receptors such as RIG-
affecting thousands of people worldwide. 3 I-like receptors, and NOD-like receptors (NLRs). The
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These primary mechanical injuries to the spinal cord structure of NLRs is defined by three key components:
trigger a cascade of secondary injuries, resulting in further (i) A central nucleotide-binding NACHT domain, which
tissue damage and neurological impairment. Increasing facilitates self-oligomerization and activation of NLRs in
evidence suggests that the secondary damage linked to SCI adenosine triphosphate (ATP)-dependent manner; (ii) an
is associated with various pathophysiological processes, amino-terminal domain, important for interactions with
many of which remain poorly understood. 4 adaptor proteins; and (iii) a carboxy-terminal leucine-
rich repeat (LRR) domain, which is essential for ligand
Secondary injury involves complex pathological recognition. Based on their N-terminal regions, NLRs are
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alternations in the spinal cord microenvironment that classified into four groups, with the NLRP family being one
occur over a period ranging from minutes to days. The of the most significant. The NLRP family contains a pyrin
activation of inflammatory cells triggers the release domain (PYD) in its N-terminal region and is involved
of cytokines and chemokines, which exacerbate the in pyroptosis, a form of inflammatory cell death that
inflammatory response and impede regenerative processes further amplifies the inflammatory response. Among the
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within the central nervous system (CNS). 5 NLRs, NLRP3 is regarded as one of the most influential.
The NOD-like receptor protein 3 (NLRP3) This protein is expressed in a variety of cells, including
inflammasome, expressed in neurons, microglia, and epithelial cells, osteoblasts, lymphocytes, macrophages,
astrocytes, is activated in response to SCI. This activation dendritic cells, neutrophils, and resident CNS cells such as
induces the secretion of pro-inflammatory cytokines, microglia, astrocytes, and neurons. 15
which modulate the pathological progression of SCI. 6 The NLRP3 inflammasome is a cytoplasmic
While inflammation is a crucial cellular defense supramolecular complex composed of three major parts:
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mechanism in SCI, excessive cytokine production can (i) The sensor component, NLRP3 itself; the adaptor,
be detrimental to the body. Therefore, the activation of apoptosis-associated speck-like protein (ASC), and
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the NLRP3 inflammasome must be tightly regulated to (iii) the effector, protease caspase-1. The ASC adaptor
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maintain hemostasis. 7 contains a caspase activation and recruitment domain
that associates with the CARD domain of caspase-1, as well
Spinal cord repair is a complex process involving as a PYD that interacts with NLRP3’s PYD. 18
various biological and cellular factors, and the underlying
mechanisms remain poorly understood. The formation of the active NLRP3 inflammasome is
initiated when NLRP3 is activated by infection or stress-
Despite the exploration of several treatment options, related stimuli. This activation leads to interactions
such as surgery, pharmacotherapy, cellular therapy, and between ASC, NLRP3, and procaspase-1, culminating in
rehabilitation, no treatment with high efficacy has been the assembly of the inflammasome and the activation of
identified. Due to the limitations and adverse effects caspase-1. Active caspase-1 is essential for converting
6
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of these therapies, there has been growing interest in the inactive precursors, pro-interleukin (IL)-1β and
alternative medicine, particularly natural medicines pro-IL-18, into their active forms (IL-1β and IL-18), which
and herbal drugs. Chinese herbal medicine (CHM) has are then released from the cell. Furthermore, caspase-1
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garnered attention and has been reported as an effective promotes the formation of gasdermin D, which forms
treatment for SCI in animal models. 9 pores in the cell membrane, triggering pyroptosis, a form
Hence, this article reviews recent studies to investigate of inflammatory cell death. 20
whether the inhibition of NLRP3 inflammasome activation The activation of NLRP3 inflammasome occurs in two
by CHM could provide novel insights into SCI treatment. stages: priming and activation. During the priming phase,
2. The NOD-like receptor protein 3 (NLRP3) the expression of NLRP3, pro-IL-1β, pro-IL-18, and other
inflammasome pro-inflammatory cytokines is induced by microbial and
endogenous stimuli, such as TLR ligands, IL-1β, and tumor
The innate immunity system, as the body’s initial line of necrosis factor (TNF). These stimuli activate the pro-
defense, is equipped with pattern recognition receptors inflammatory transcription factor nuclear factor kappa-
(PRRs) that detect pathogen-associated molecular light-chain-enhancer of activated B cells (NF-κB). 21,22
patterns and damage-associated molecular patterns Several studies also suggest that FAS-associated death
(DAMPs). 10,11 PRRs can be categorized into several types, domain protein, along with caspase-8, promotes the
including transmembrane receptors such as Toll-like expression of NLRP3 during this priming phase. 16,23 In

Volume 4 Issue 3 (2025) 2 doi: 10.36922/gpd.4827