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Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, but the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. Based on these, we explore whether CXCL12-CXCR4 axis regulates the NLRP3 inflammasome in the peripheral nerve. We found that CXCR4/CXCL12, NLRP3 inflammasome-related components, pyroptosis-related proteins and inflammatory factors in the sciatic nerve injured rats were markedly increased compared with the sham-operated group. AMD3100, a CXCR4 antagonist, reverses the activation of NLRP3 inflammasome, Schwann cell pyroptosis and sciatic nerve demyelination. We further treated rat Schwann cells with LPS (lipopolysaccharide) and adenosine triphosphate (ATP) to mimic the cellular inflammation model of sciatic nerve injury, and the results were consistent with those in vivo. In addition, both in vivo and in vitro experiments demonstrated that AMD3100 treatment reduced the phosphorylation of nuclear factor κB (NF-κB) and the expression of thioredoxin interacting protein (TXNIP), which contributes to activating NLRP3 inflammasome. Therefore, our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome and slow the recovery process of the sciatic nerve. Studies have shown that the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is detrimental to the functional recovery of the sciatic nerve, and C-X-C motif chemokine 12 (CXCL12) can bind to C-X-C chemokine receptor type 4 (CXCR4) and participate in a wide range of nerve inflammation by regulating the NLRP3 inflammasome. However, the regulatory mechanisms of the NLRP3 inflammasome in peripheral nerves are unclear. Our findings suggest that, after sciatic nerve injury, CXCL12-CXCR4 axis may promote Schwann cell pyroptosis and sciatic nerve demyelination through activating NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]

• Hypoxia and inflammation are two critical factors that shape the periodontitis. • High levels of interleukin-1β can cause an HGF inflammatory response. • GSDMD-mediated pyroptotic plays an important role in the pathogenesis of periodontitis. • Hypoxia and P. gingivalis -LPS synergistically induced NLRP3 inflammasome activation. To investigate the effects of hypoxia and Porphyromonas gingivalis - lipopolysaccharide (P. gingivalis -LPS) on activation of the NACHT leucine-rich repeat protein 3 (NLRP3) inflammasome in human gingival fibroblasts (HGFs). Periodontitis was optimally simulated using a hypoxic concentration of 1%. HGFs were stimulated using P. gingivalis -LPS (1.0 μg/ml) in normoxia and hypoxia for 3 h and 6 h, respectively. The expression levels of genes and proteins of hypoxia-inducible factor-1α (HIF-1α), interleukin-1β, gasdermin D (GSDMD) and the NLRP3 inflammasome, including NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1 and its activated forms, were measured using quantitative real-time polymerase chain reaction and western blot. ELISA was used to detect and determine levels of the inflammatory factor interleukin-1β in cell supernatants. Lactate dehydrogenase (LDH) release assay, caspase-1 activity assay and Hoechst 33342/Propidium Iodide (PI) staining were performed to further verify the presence of pyroptosis. The NLRP3 inflammasome (i.e., NLRP3, ASC, caspase-1) was not affected by individual stimulation using P. gingivalis -LPS or hypoxia. However, the combination of both hypoxia and P. gingivalis -LPS stimulation significantly enhanced inflammasome activation and promoted the expression of interleukin-1β, gasdermin D and HIF-1α at gene and protein levels; PI positive cells and the release of LDH were also elevated. Hypoxia and P. gingivalis -LPS synergistically induced NLRP3 inflammasome activation in HGFs, and subsequently high levels of interleukin-1β and GSDMD-mediated pyroptosis can cause an HGF inflammatory response, which plays an important role in the pathogenesis of periodontitis. [ABSTRACT FROM AUTHOR]

• Dox:CS/CMCS-NPs had good physicochemical properties and cytocompatibility. • Dox:CS/CMCS-NPs inhibited the growth of Porphyromonas gingivalis. • Dox:CS/CMCS-NPs inhibited the activation of NLRP3 inflammasome in HGFs. • Dox:CS/CMCS-NPs reduced the expression of IL-1β by inhibiting the NLRP3 inflammasome. A polyelectrolyte complex nanoparticle comprising chitosan (CS) and carboxymethyl chitosan (CMCS) was prepared (CS/CMCS-NPs) by ionic gelation, which was then used as a doxycycline carrier (Dox:CS/CMCS-NPs). The obtained CS/CMCS-NPs and Dox:CS/CMCS-NPs were characterized for various parameters and bacteriostatic ability against Porphyromonas gingivalis. The regulation of related genes and proteins of NLRP3 inflammasome and IL-1β in human gingival fibroblasts (HGFs) was characterized by qRT-PCR, western blotting and ELISA. The results showed that Dox:CS/CMCS-NPs had an orderly morphology and an excellent cytocompatibility. P. gingivalis was strongly inhibited by Dox:CS/CMCS-NPs contrasted with control group. Dox:CS/CMCS-NPs effectively down-regulated both gene and protein levels of NLRP3 inflammasome and IL-1β in HGFs. This study provides a new method for rational application of Dox in the clinical treatment of periodontal disease and a new direction for explaining the mechanism of action of Dox:CS/CMCS-NPs and more drug-carrying nanoparticles. [ABSTRACT FROM AUTHOR]

• P. gingivalis -LPS alone could not activate the NLRP3 inflammasome in HGFs. • P. gingivalis -LPS + ATP activates NLRP3 inflammasome in HGFs. • Dox inhibited the activation of NLRP3 inflammasome in HGFs. • Dox reduces the expression of IL-1β by inhibiting the NLRP3 inflammasome. To investigate the effect of adenosine triphosphate (ATP) on inflammasome activation by Porphyromonas gingivalis -lipopolysaccharide (P. gingivalis -LPS) stimulation and the anti-inflammatory eff ;ect of doxycycline (Dox) in human gingival fibroblasts (HGFs). The optimal concentration of P. gingivalis -LPS (1.0 μg/mL) for cellular viability was determined by observing cell morphology and measuring the amount of formazan and the expression of pro-caspase-1. The expression of genes and proteins related to the NAcht Leucine-rich repeat Protein 3 (NLRP3) inflammasome, including NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), caspase-1 and its activated forms, and the inflammatory factor interleukin-1β (IL-1β) and its activated forms were measured. The NLRP3 inflammasome (i.e., NLRP3, ASC, caspase-1) was not affected by stimulation with P. gingivalis -LPS or ATP. However, a combination of P. gingivalis -LPS and ATP significantly enhanced inflammasome activation and IL-1β production at the gene and protein levels as measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Furthermore, doxycycline addition markedly inhibited inflammasome activation and IL-1β production induced by a combination of P. gingivalis -LPS and ATP. LPS, ATP, and doxycycline play critical roles in regulating host immune responses. This evidence provides guidance for the application of tetracycline drugs for the clinical treatment of periodontal disease. [ABSTRACT FROM AUTHOR]

• It focuses on summarizing the regulatory mechanisms of NLRP3 inflammasome in peripheral nerve injury and nerve pain. • The excessive activation of NLRP3 inflammasome exacerbates nerve injury and nerve pain. • There may be CXCL12-CXCR4 autocrine pathway in schwann cells that regulates the activation of NLRP3 inflammasome through some intracellular signaling molecules and participates in the peripheral neuroinflammatory response. • The NLRP3 inflammasome in schwann cells affects the polarization of macrophages. Nerve injury and nerve pain are common diseases caused by neuroinflammation. Numerous studies have shown that the activation of NLRP3 (nod-like receptor family, pyrin domain-containing 3) inflammasome is involved in a various inflammatory response, such as Alzheimer's disease, diabetes, nerve damage and other diseases. The NLRP3 inflammasome is a complex containing NLRP3 protein, ASC (apoptosis-associated speckle-like protein), and pro-caspase-1, which is highly expressed and activated to promote the secretion of IL-1β and IL-18 in response to the stimulation of danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in immune cells such as macrophages and dendritic cells. The activation of NLRP3 inflammasome can cause cell death through caspase-1-mediated cell pyroptosis and plays an important role in the development of nervous system injury and inflammation-related diseases. This discussion aims to summarize the mechanisms of nerve damage and pain caused by excessive activation of the NLRP3 inflammasome. [ABSTRACT FROM AUTHOR]