In the CNS, microglia are the main resident macrophages, which play an important role in the process of secondary injury after SCI, especially by regulating the release of proinflammatory cytokines and chemokines (62). The number of activated microglia was shown to increase on the first day after SCI, which then continued to increase for 7 days until the number of cells stabilized between 2 and 4 weeks (63). In the early stages of SCI, activated microglia release trophic factors that promote axonal growth and regeneration at the lesion site and play a neuroprotective role by limiting lesion site enlargement (64). However, activated microglia can also induce peripheral circulating macrophages to infiltrate the injury site and express several pro-inflammatory cytokines such as IL-1α, IL-1β, and tumor necrosis factor-alpha (TNF-α) to mediate the inflammatory response (65). Both macrophages and microglia exert polarized capability with two major phenotypes, M1 and M2 (65). M1-like cells are classically activated and resemble activated microglia by exerting proinflammatory and destructive effects and producing several proinflammatory cytokines (65). Conversely, alternatively activated M2-like cells have strong protective effects that can promote tissue remodeling, wound healing, and angiogenesis. The microenvironment after SCI is detrimental to M2 macrophages, and the overexpression of TNF can inhibit the conversion of M1 to M2 (66). The ratio of M1 to M2 reflects the proportional balance in the spinal cord microenvironment; a disequilibrium in this proportion causes the release of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α. The interplay between inflammasomes and microglia or macrophages has been described by several studies. Zendedel et al. found that ASC, the inflammasome adaptor protein, was predominantly expressed in microglia after SCI (46). Hu et al. demonstrated that microglial activation triggered NLRP3-related inflammation in the motor cortex after SCI (53). Liu et al. found that oxidation protein products, which served as biomarkers of oxidative stress-triggered inflammatory response after SCI, participated in NLRP3-mediated pyroptosis (67). AIM2 exerts regulatory effects in microglia, which is associated with the development of autoimmune encephalomyelitis in a mouse model (68), indicating that an interplay between AIM2 and microglia may also exist in SCI.

Neutrophils are one of the first immune cells entering the injured site after SCI (69). Infiltrating neutrophils cause damage to the blood-spinal barrier (BBB) and induce the release of many inflammatory factors, triggering a cascade of inflammatory effects (69). Various studies have shown that neuroprotective molecules can protect spinal cord tissue by inhibiting inflammasome activity, which is accompanied by reduced infiltration of neutrophils. OLT1177, a selective inhibitor of the NLRP3 inflammasome, reduced the infiltration of neutrophils and showed a protective role in SCI (70). Similar effects and mechanisms have also been observed for BAY 11-7082 or A438079 (71), topotecan (72), P2X4 receptors (73), asiatic acid (74), and polyphenols (75).

After SCI onset, astrocytes infiltrate the injured tissue, secrete several inflammatory factors, and promote fibrosis (76). Mi et al. found that silencing heat shock protein family A member 8 reduced SCI-caused damage by blocking astrocyte activation and lowing NLRP3 levels; knockdown of this protein protected astrocytes from oxygen and glucose deprivation/reoxygenation-induced injury via the blockade of NF-κB and NLRP3 inflammasome activation (77). ASC-dependent inflammasome formation, especially in resident cells of the spinal cord, including astrocytes, plays a pivotal role in the progression of secondary damage (78). Extracellular vesicles derived from the mesenchymal stem cells have the potential to regulate inflammasome activity after SCI. Moreover, extracellular vesicles stimulate neural progenitor cells and modulate astrocyte activity (79). Oligodendrocyte progenitor cells have significantly higher levels of inflammasome proteins than astrocytes, which may be associated with their high death rates after SCI (80).

Cytokines, which can be classified as proinflammatory or anti-inflammatory mediators, are involved in neuroinflammation (81). Various cytokines such as IL-1, IL-6, TNF-α, and leukocyte inhibitory factors are associated with alterations in the microenvironment in SCI (82). When in low concentrations, several proinflammatory cytokines display protective effects by inducing the expression of neurotrophics (83); however, at higher concentrations, these cytokines also mediate the overexpression of neurotoxic genes, such as inducible nitric oxide synthase, proinflammatory proteases, and cyclooxygenase 2 (84). Moreover, IL-1 overexpression in the spinal cord facilitates vascular permeability and lymphocyte recruitment. Additionally, IL-6 promotes the infiltration and activation of macrophages and microglia (85). High levels of TNF-α are found in neurons, glial cells, and endothelial cells after SCI (86). TNF-α can enlist neutrophils to the lesions by inducing adhesion molecules such as intercellular adhesion molecule-1 and vascular cell adhesion protein-1 (87). Subsequently, the permeability of endothelial cells is altered, thereby leading to the disorder of the blood-spinal cord barrier (88). Moreover, TNF-α can induce the death of oligodendrocytes and cause demyelination (89). Generally, CNS cells maintain low IL-1β levels in the brain and spinal cord that are regulated by preassembled inflammasomes (90). Recently, it was shown that expression of NLRP3 inflammasome components increased in the spinal cord tissue of the mouse model of amyotrophic lateral sclerosis and induced superoxide dismutase 1-mediated microglial IL-1β (35).

A common feature of all cancers is their ability to continuously self-proliferate, which is primarily stimulated by inflammation-driven mechanisms (93). The release of proinflammatory cytokines, such as IL-1β and IL-18, may induce cell proliferation in a paracrine and autocrine manner during acute and chronic inflammation (94, 95). NLRP3 inflammasomes have also been reported to inhibit the function of natural killer cells in the control of carcinogenesis and metastasis (96). In addition, the NLRP3 inflammasome exerts a critical effect on tumorigenesis and may provide prognostic markers and promising therapeutic targets in patients with cancer (97). In the CNS, malignant glioma is the most common primary brain tumor with a poor prognosis. The NLRP3 inflammasome in glioma is also constitutively activated in glioblastoma multiforme cells (98). However, the underlying mechanism of the NLRP3 inflammasome in spinal cord tumorigenesis has not been fully elucidated. Further research is needed to understand the properties of the inflammasome and explore its therapeutic potential in spinal cord tumors. In addition to cytokine maturation, another consequence of inflammasome activation is the cleavage of GSDMD; the cleaved GSDMD forms membrane pores that lead to cytokine release and culminate in cell lysis (99). The exact relevance and function of pyroptosis executor GSDMD during tumorigenesis remain unclear. How these different signals are distributed in different tumor environments and ultimately integrated into different cell types requires further investigation (100).

Tumor metastasis is an elusive process involving a series of successive events, from the spread of tumor cells from the primary lesion to the development of metastatic foci in distant organs (101). The environment of the distant metastatic target organs experiences reprogramming, primarily through the recruitment of immune cells, in favor of tumor growth. Notably, NLRP3 promotes epithelial–mesenchymal transition by enhancing transforming growth factor-β1 (TGF-β1) signaling and activating small mother against decapentaplegic (SMAD) (102, 103). Angiogenesis, a gradual process of the formation of new capillaries and blood vessels arising from pre-existing vascularity, is necessary for tumor progression (104). It is tightly modulated by multiple pro- and anti-angiogenic factors. Inflammasome complexes contribute to the regulation of angiogenesis in different tissues. IL-1β, produced by tumor cells, induces pro-angiogenic factors. IL-1β mediates the upregulation of hypoxia-inducing factor-1α to stimulate the overexpression of vascular endothelial growth factor (105). Notwithstanding these studies demonstrating the angiogenic function of IL-1β, further exploration is necessary to distinguish how different inflammasome complexes modulate the IIL-1β to regulate angiogenesis in tumors.

In response to the invading tumor cells, the immune system initiates a powerful anti-tumor reaction, and inflammatory cells flood the tumor microenvironment (TME) (106). However, cancer cells use several mechanisms to evade the immune system’s surveillance. The release of IL-1β as well as IL-18, is a universally acknowledged process for the immunosuppressive TME during the development of multiple tumors (107, 108). Bone marrow-derived suppressor cells (MDSCs) are crucial components of TME and demonstrate robust immunosuppressive activity (109). NLRP3 is crucial for accumulating MDSCs in tumors and inhibiting the anti-tumor effect of T cells. Moreover, NLRP1 inflammasome promotes the secretion of IL-18 in myeloma, thus resulting in accelerated progression (110).

In summary, the occurrence of tumor is the result of multiple factors, and long-term exposure to the inflammatory microenvironment will increases the risk of tumor development. As an important component of inflammatory response, inflammasome also involve in the occurrence and development of spinal cord tumors, as well as induce the formation of tumor blood vessels, thereby involving in metastasis. Furthermore, inflammasome may prompt the immunosuppression of TME during the development of spinal cord tumors. Although the role of inflammasome in tumors has received considerable attention, studies in spinal cord tumors are still rare. Therefore, further researches focus on the underlying mechanism of inflammasome in spinal cord tumor are quite necessary.

Methylene blue alleviates neuroinflammation post-SCI by inhibiting the activation of the NLRP3 inflammasome in microglia (111). Polydatin, a glycoside of resveratrol, can reduce the activation of the NLRP3 inflammasome and then relieve microglial inflammation, which has a neuroprotective effect on SCI (112). Wogonoside has antioxidant, anti-inflammatory, anti-allergic, and anti-tumor properties (113). Echinoside accelerates the recovery of motor function in rats after SCI by inhibiting the NLRP3 inflammasome (114). Oral glycyrrhizin inhibits NLRP3 inflammasome activation and promotes microglial M2 polarization after a traumatic SC (115). Paeonol may alleviate SCI by regulating the NLRP3 inflammasome and pyroptosis, which is a feasible clinical treatment for SCI (116). Ulinastatin significantly improves neurological function after SCI by regulating the AMP-activated protein kinase/NLRP3 inflammasome signaling pathway (117). MCC950, a small-molecule inhibitor of NLRP3, directly interacts with the Walker B motif within the nucleotide-binding NACHT domain in NLRP3, thereby impeding ATP hydrolysis and inhibiting the synthesis of NLRP3 inflammasome (118, 119). Furthermore, 3,4-methylenedioxy-β-nitrostyrene can block NLRP3-mediated ASC spot formation and oligomerization, but not NLRP3 agonist-induced potassium efflux (120). OLT1177, an orally active β-sulfonyl butyryl molecule, suppresses NLRP3 inflammasome activation. Notably, nanomolar concentrations of OLT1177 can inhibit the secretion of IL-1β and IL-18 following classical and atypical activation of NLRP3 inflammasome in vitro ( 121). Bigford et al. demonstrated that NLRP3 inflammasome was activated in adipose tissue and pancreas in a chronic SCI mouse model (127). Jiang et al. found that topoisomerase 1 inhibition prevented NLRP3 inflammasome activation and pyroptosis to improve recovery after SCI (128). Antioxidants improved peripheral neuropathy in a tumor-bearing mouse model by regulating spinal cord oxidative stress and inflammation (129). Compared with NLRP3, other inflammasomes have been less studied. Vaccari et al. showed that NLRP1 inflammasome proteins presented in the cerebrospinal fluid of patients with SCI and traumatic brain injury (41). Yutaka et al. found an increased expression level of NLRP2 inflammasome in the dorsal root ganglion, which was associated with inflammatory pain hypersensitivity (130).

Production of proinflammatory cytokines such as IL-1β is a pivotal step in the development and progression of various neurological diseases. TNF-α-stimulated gene 6 has been demonstrated to be a promising immunomodulatory target in neurodegenerative diseases (131). In terms of SCI, IL-1β has been proposed as a therapeutic target. In 2020, Tang et al. found that binding of a secretory leukocyte protease inhibitor to the promoter region of TNF-α and IL-8 inhibited the NF-κB signaling pathway, which exerts anti-inflammatory and anti-bacterial effects and promotes recovery after SCI (132). TNF is another pivotal cytokine released after SCI onset, as increased TNF expression has been demonstrated throughout the acute and chronic stages of SCI in the resident cells of spinal tissue. TNF inhibitors, such as adalimumab, infliximab, and etanercept, promoted functional recovery after SCI (122). Yuan et al. found that curcumin inhibited a novel cytokine signaling pathway (TGF-β-SOX9) and improved recovery after SCI (123).

Previous studies have demonstrated that the absence of caspase-1 can alleviate neuroinflammation and neuronal damage during SCI, which implicates the potential significance of caspase-1 inhibitors as a therapeutic target. Pralnacasan (VX-740) and its analog VX-765 are peptide-like caspase-1 inhibitors that act by covalent modification of the catalytic site of caspase-1, thereby suppressing the activation of caspase-1 and the subsequent cleavage of the precursors of IL-1β and IL-18 (124, 125). Chen et al. demonstrated that VX-765 reduced neuroinflammation in an SCI mouse model by inhibiting caspase-1/IL-1β/IL-18 (126).