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Gene & Protein in Disease NLRP3 in SCI and CHM

addition to its transcriptional regulation, the priming phase activation can occur through various mechanisms,
involves post-translational modifications of NLRP3, such either independently or in conjunction with others.
as phosphorylation and ubiquitination, which are critical It induces metabolic disturbances by forming pores,
for controlling its activation. The second phase involves integrating cellular stress, ionic redistribution, lysosomal
24
the activation of the NLRP3 inflammasome, which can rupture, inflammation, mitochondrial dysfunction, and
be triggered by a variety of stimuli. These stimuli include non-canonical signaling pathways. 38-40 In general, the
pathogens (e.g., viruses, bacteria, fungi, and protozoa) components of NLRP3 inflammasome – NLRP3, ASC,
and sterile inflammation caused by cellular events such and caspase-1 – are initially separated, but they assemble
as reactive oxygen species (ROS) production, lysosomal into a functional inflammasome when activated. 27,41 Under
damage, mitochondrial dysfunction, ion flux (e.g., calcium normal conditions, the expression of genes associated with
ions [Ca ], chloride ions [Cl ], and potassium ions [K ]), the NLRP3 inflammasome (ASC, NLRP3, and caspase-1)
-
2+
+
and the presence of DAMPs. Numerous regulators of is maintained at low levels. 42,43 However, these genes are
25
NLRP3 inflammasome activation have been identified, upregulated at both the protein and mRNA levels at the
including guanylate-binding protein 5, double-stranded lesion site following SCI. 6,44-47 ASC-dependent activation
RNA-dependent protein kinase, and NIMA-related protein in spinal cord cells, especially astrocytes, contributes to
kinase 7. 8,26 neuronal death pathways, thereby developing secondary
injury. 31,1,48,49 Notably, NLRP3 has also been implicated in
3. SCI and role of NLRP3 inflammasome neuropathic pain, 50-53 although the relationship between
SCI consists of two primary stages: primary and secondary pyroptosis and pain remains unclear. 50
injury. 27,28 The primary injury occurs due to a direct NOD-, LRR-, and pyrin domain-containing protein 3
external force, resulting in mechanical damage to the is upregulated in both high-impact and low-impact SCI
27
spinal cord. Subsequently, a second injury follows, models at 1, 3, and 7 days post-injury, with no significant
driven by pathophysiological processes such as apoptosis, difference in the extent of damage between these groups. 27,43
inflammation, cell proliferation, and differentiation. In addition, NLRP3 inflammasome may act as a deleterious
29
While the damage caused by primary injury is irreversible, factor for functional recovery after injury. 27,54 Deficits in
secondary damage, which usually develops over time, is motor function after SCI may be associated with NLRP3
induced by various factors, including pro-inflammatory inflammasome activation in motor neurons, triggered
cytokines, glutamate, and tissue acidosis. The initiation of by the activation of microglia in the motor cortex. 37,55
secondary injury has neurotoxic effects that can worsen Notably, hyperactivation of NLRP3 inflammasome can
spinal cord functions. Trauma to the spinal cord leads to lead to sustained damage to neuronal fiber tracts. 56,57 The
microvascular permeability, edema, cellular injury, tissue release of NLRP3 is rapidly increased within 6 h post-
remodeling, and neuroinflammation. 28,30,31 Within minutes SCI, continuing to rise until 72 h post-injury, peaking on
6
of trauma, a series of neuroimmune interactions occur. 31,32 day 2. After day 3, its levels begin to decline gradually until
58
Inflammation is essential for restoring homeostasis after day 7. 6,27,54 Moreover, the increase in pro-caspase-1 follows
injury. However, a deficiency in this response can hinder a similar trend to that of NLRP3. Host cell recognition
6
regeneration. 31,33 The immune-inflammatory response of ligands for PRRs, including DAMPs, stimulates the
not only reflects the injury but also serves as a potential NLRP3 inflammasome. 1,59,60 After SCI onset, DAMPs,
endogenous recovery mechanism. 27,34 It is worth noting particularly ATP, are elevated in microglia, astrocytes,
61
that the immunity-dependent mechanisms in spinal cord and macrophages. At the secondary stage of injury,
1
trauma are not fully understood. high lipocalin-2 promotes the secretion of inflammatory
The inflammasome is an innate immune sensor that cytokines, neuronal and astrocyte dysfunction, and
triggers inflammatory responses, contributing to further immune cell infiltration by triggering the priming and
functional damage. SCI can disrupt the homeostasis activation phases of NLRP3-related inflammation. 56
1,19
of the cellular microenvironment, a process in which Several factors contribute to the second signaling
inflammasomes play a significant role. Consequently, pathway of NLPR3 activation after SCI, including
inflammasomes are crucial in the imbalance of cholesterol, ionic disruptions such as Ca signals or K +
2+
microenvironmental components and in impairing efflux, and non-canonical cytoarchitectural changes,
neuronal recovery, myelin repair, and the regulation of the including mitochondrial and lysosomal dysfunction.
1,38
immune system. 35 ROS, acting as secondary messengers, directly trigger
62
The NLRP3 inflammasome is expressed by mitochondrial impairment and the release of mitochondrial
macrophages, microglial cells, and neurons. 35-37 NLRP3 DNA (mtDNA). 63,64 The binding of oxidized mtDNA to

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