Background Neutrophil intravasation from the bone marrow into the peripheral blood is a critical step in innate immune responses, tightly regulated by the CXCR4/CXCL12 signaling axis. However, the upstream inflammatory signals governing this process during systemic inflammation remain poorly understood. Objectives This study aimed to investigate whether and how NLRP3 regulates neutrophil intravasation from the bone marrow during systemic inflammation. Methods To investigate the role of NLRP3 in neutrophil intravasation, we employed LPS-induced and Pseudomonas aeruginosa PAO1-induced inflammation models in WT and Nlrp3 KO mice. The numbers of BM and blood neutrophils, cell surface protein expression, and cytokine expression were analyzed by flow cytometry. Moreover, bulk RNA sequencing was performed to identify NLRP3-mediated transcriptional changes in BM neutrophils. Results We demonstrate that NLRP3 promotes neutrophil intravasation by suppressing CXCR4-mediated BM retention signaling during inflammation. Mechanistically, NLRP3 drives IFN-γ accumulation in the BM milieu through enhanced IFN-γ production in dendritic cells and macrophages, while simultaneously promoting IFN-γ responsiveness in BM neutrophils, thereby collectively downregulating CXCR4 expression on BM neutrophils. This regulation was selective for CXCR4, as IFN-γ did not alter CXCR2 expression on BM neutrophils. Furthermore, the NLRP3-IFN-γ axis operated independently of G-CSF signaling, suggesting that at least two independent upstream pathways converge on CXCR4-mediated retention signaling to regulate neutrophil intravasation. Conclusions These findings reveal a previously unrecognized NLRP3-IFN-γ-CXCR4 axis linking innate immune activation to neutrophil intravasation during systemic inflammation, suggesting its potential as a therapeutic target for inflammatory diseases.

Colchicine, a well-known anti-inflammatory drug, has emerged as a therapeutic option in various inflammatory diseases. However, its role in chronic kidney disease (CKD) remains unclear. This study aims to investigate the reno-protective effects of colchicine in an experimental CKD model and its potential role in modulating the NOD-like receptor, pyrin domain containing protein 3 (NLRP3) inflammasome pathway. A CKD animal model was established in C57BL/6 mice by feeding a 0.2

Background: Anakinra, a recombinant human interleukin-1 receptor antagonist (hIL-1Ra), is a widely used anti-inflammatory biologic for conditions like rheumatoid arthritis and gout. However, its limited potency and dose-dependent side effects restrict broader therapeutic application, highlighting a need for more potent and stable IL-1R antagonists. Methods: To develop improved IL-1R antagonists, we rationally designed six hIL-1Ra variants using structure-guided mutagenesis. Molecular dynamics simulations and thermodynamic integration predicted enhanced binding stability, with an average binding free energy improvement of -7.8 ± 0.9 kcal/mol compared to wild-type hIL-1Ra (hIL-1Ra WT). We assessed variant functions in microglia-derived HMC-3 cells by measuring IL-1β and IL-6 mRNA suppression and evaluated their ability to attenuate IL-1β-induced NMDAR hyperactivation in cultured cortical neurons using electrophysiological recordings. In vivo validation was performed using Nlrp3 D301N knock-in mice, a model of chronic neuroinflammation. Results: All six hIL-1Ra variants demonstrated enhanced anti-inflammatory activity, suppressing IL-1β and IL-6 expression by 25-53% in HMC-3 cells. The E127Q variant exhibited the greatest efficacy. In primary cultured neurons, hIL-1Ra E127Q more effectively inhibited IL-1β-induced NMDAR-mediated postsynaptic responses at lower concentrations than hIL-1Ra WT. Furthermore, acute administration of hIL-1Ra E127Q, but not hIL-1Ra WT, reversed elevated NMDAR activity in the medial prefrontal cortex of Nlrp3 D301N knock-in mice. Conclusion: This study successfully developed next-generation hIL-1Ra variants with superior receptor binding and anti-inflammatory activity. E127Q emerged as a promising therapeutic candidate, effectively attenuating inflammatory signaling and neuroinflammatory responses both in vitro and in vivo. These findings underscore the significant therapeutic potential of engineered IL-1R antagonists for treating inflammation-driven neurological and systemic disorders, paving the way for improved anti-inflammatory therapies.

Circadian rhythm disruption has been associated with the exaggerated inflammatory responses in peripheral tissues; however, its impact on neuroinflammation and blood-brain barrier (BBB) integrity remains unclear. Here, we identify the astrocytic circadian clock as a key regulator of BBB homeostasis during systemic inflammation. In a mouse model, circadian rhythm disruption for three weeks markedly increased BBB permeability in male mice, as evidenced by Evans blue leakage and myeloid cell infiltration into the brain parenchyma following lipopolysaccharide (LPS) challenge. Transcriptomic analyses using public datasets revealed that astrocytes exhibit the highest expression of core circadian clock genes among brain cell types. Accordingly, we generated tamoxifen-inducible, astrocyte-specific Bmal1-knockout (KO) mice. Deletion of Bmal1 in astrocytes significantly enhanced BBB leakage, astrogliosis and pericyte loss after LPS administration. Mechanistically, Bmal1-deficient astrocytes produced elevated levels of the chemokine CXCL5, which promoted CXCR2-dependent neutrophil recruitment into the brain. Pharmacological blockade of CXCR2 with SB225002 restored pericyte coverage and attenuated BBB disruption in astrocytic Bmal1 KO mice. Functionally, these mice exhibited impaired excitatory synaptic transmission following systemic inflammation, suggesting that astrocytic Bmal1 loss compromises neurovascular and synaptic integrity. Taken together, our findings demonstrate that astrocytic Bmal1 maintains BBB integrity and synaptic stability under inflammatory stress. This work also highlights astrocyte-intrinsic circadian regulation as a critical mechanism linking chemokine production to neurovascular vulnerability.

Neuroinflammation is a well-established risk factor for various neurological disorders and cognitive decline. However, the precise molecular mechanisms linking inflammation with neuropsychiatric symptoms remain unclear. Here, using NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) conditional knockin (cKI) mice harboring a D301N point mutation originating in patients with autoinflammatory diseases, we found that activation of the NLRP3 inflammasome by administration of lipopolysaccharide induced anxiety-like and repetitive behaviors frequently found in patients with neuropsychiatric disorders, as well as increasing NMDAR (N-methyl-D-aspartate receptor)-mediated excitatory synaptic functions in the medial prefrontal cortex of mice. In addition, interleukin 1β (IL-1β), a downstream cytokine of the NLRP3 inflammasome, enhanced NMDAR activation and increased surface levels of the selective NMDAR subunit GluN2A in cultured cortical neurons. Strikingly, treatment with an NMDAR antagonist or IL-1 receptor antagonist completely normalized the specific behavioral deficits in Nlrp3D301N-cKI mice. Collectively, our results demonstrate that NLRP3-mediated neuroinflammation elicits repetitive behavior through impaired NMDAR functions.

Blood-brain barrier (BBB) disintegration is a key contributor to neuroinflammation; however, the biological processes governing BBB permeability under physiological conditions remain unclear. Here, we investigate the role of NLRP3 inflammasome in BBB disruption following peripheral inflammatory challenges. Repeated intraperitoneal lipopolysaccharide administration causes NLRP3-dependent BBB permeabilization and myeloid cell infiltration into the brain. Using a mouse model with cell-specific hyperactivation of NLRP3, we identify microglial NLRP3 activation as essential for peripheral inflammation-induced BBB disruption. Conversely, NLRP3 and microglial gasdermin D (GSDMD) deficiency markedly attenuates lipopolysaccharide-induced BBB breakdown. Notably, IL-1β is not required for NLRP3-GSDMD-mediated BBB disruption. Instead, microglial NLRP3-GSDMD axis upregulates CXCL chemokines and matrix metalloproteinases around BBB via producing GDF-15, promoting the recruitment of CXCR2-containing neutrophils. Inhibition of neutrophil infiltration and matrix metalloproteinase activity significantly reduces NLRP3-mediated BBB impairment. Collectively, these findings reveal the important role of NLRP3-driven chemokine production in BBB disintegration, suggesting potential therapeutic targets to mitigate neuroinflammation. The biological mechanisms regulating blood-brain barrier integrity remain unclear. Here, the authors identify microglial NLRP3-gasdermin D signaling as a driver of blood-brain barrier disruption during peripheral inflammation in mice, mediated by CXCL-dependent neutrophil recruitment.

NLRP3 is an intracellular sensor molecule that affects neutrophil functionality and infiltration in brain disorders such as experimental autoimmune encephalomyelitis (EAE). However, the detailed molecular mechanisms underlying the role of NLRP3 in these processes remain unknown. We found that NLRP3 is crucial for neutrophil infiltration, whereas dispensable for neutrophil priming. Notably, NLRP3 activation in neutrophils induced blood-brain barrier (BBB) disruption and neutrophil infiltration into the brain via CXCL1/2 secretion and subsequent activation of the CXCL1/2-CXCR2 signaling axis. Moreover, CXCL1 and CXCL2 in the inflamed brain directly reduced Claudin-5 expression, which regulates BBB permeability in brain endothelial cells. Furthermore, neutrophil-specific NLRP3 activation aggravated EAE pathogenesis by promoting CXCR2-mediated infiltration of both neutrophils and CD4+ T cells into the central nervous system at disease onset. Thus, the CXCL1/2-CXCR2 axis plays a role in EAE progression. Therefore, this chemokine axis could be a potential therapeutic target for attenuating neuroinflammatory diseases through modulating of neutrophil and CD4+ T cell infiltration and BBB disruption.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, yet the role of type I interferon (IFN) signaling in seizure pathogenesis remains elusive. In this study, we show that deficiency of type I IFN signaling reduces seizure severity in a kainic acid-induced mouse model. Ifnar1-/- mice exhibited significantly lower seizure scores at multiple time points (e.g., U = 88.5, p = 0.0078 at 110 min), along with decreased neuronal excitability and microglial activation in these mice in response to kainic acid stimulation. Conversely, intracerebroventricular injection of IFN-β exacerbated kainic acid-induced seizure severity. In vitro calcium imaging demonstrated that IFN-β treatment enhanced neuronal excitability, although no significant difference in basal neuronal excitability were observed between wild-type and Ifnar1-/- neurons. Additionally, Ifnar1-/- mice showed reduced activation of the mammalian target of rapamycin (mTOR) pathway in the brain following kainic acid administration-a pathway known to contribute to epileptogenesis. Consistent with this finding, IFN-β treatment increased mTOR activation, as indicated by S6 phosphorylation in in vitro mixed glial cultures. Taken together, these findings highlight a critical role of type I IFN signaling in seizure progression, potentially via mTOR modulation, and suggest that targeting type I IFNs may offer a promising therapeutic strategy for epilepsy.

Hyperglycemia has been shown to modulate the immune response of peripheral immune cells and organs, but the impact of hyperglycemia on neuroinflammation within the brain remains elusive. In the present study, we provide evidences that streptozotocin (STZ)-induced hyperglycemic condition in mice drives a phenotypic switch of brain astrocytes to a proinflammatory state, and increases brain vulnerability to mild peripheral inflammation. In particular, we found that hyperglycemia led to a significant increase in the astrocyte proliferation as determined by flow cytometric and immunohistochemical analyses of mouse brain. The increased astrocyte proliferation by hyperglycemia was reduced by Glut1 inhibitor BAY-876. Transcriptomic analysis of isolated astrocytes from Aldh1l1CreERT2;tdTomato mice revealed that peripheral STZ injection induced astrocyte reprogramming into proliferative, and proinflammatory phenotype. Additionally, STZ-induced hyperglycemic condition significantly enhanced the infiltration of circulating myeloid cells into the brain and the disruption of blood-brain barrier in response to mild lipopolysaccharide (LPS) administration. Systemic hyperglycemia did not alter the intensity and sensitivity of peripheral inflammation in mice to LPS challenge, but increased the inflammatory potential of brain microglia. In line with findings from mouse experiments, a high-glucose environment intensified the LPS-triggered production of proinflammatory molecules in primary astrocyte cultures. Furthermore, hyperglycemic mice exhibited a significant impairment in cognitive function after mild LPS administration compared to normoglycemic mice as determined by novel object recognition and Y-maze tasks. Taken together, these results demonstrate that hyperglycemia directly induces astrocyte reprogramming towards a proliferative and proinflammatory phenotype, which potentiates mild LPS-triggered inflammation within brain parenchymal regions.

Circadian arrhythmia has been linked to increased susceptibility to multiple inflammatory diseases, such as sepsis. However, it remains unclear how disruption of the circadian clock modulates molecular aspects of innate immune responses, including inflammasome signaling. Here, we examined the potential role of the circadian clock in inflammasome-mediated responses through myeloid-specific deletion of BMAL1, a master circadian clock regulator. Intriguingly, Bmal1 deficiency significantly enhanced pyroptosis of macrophages and lethality of mice under noncanonical inflammasome-activating conditions but did not alter canonical inflammasome responses. Transcriptome analysis of enriched peritoneal myeloid cells revealed that Bmal1 deficiency led to a marked reduction in Rev-erbα expression at steady state and a significant increase in serum amyloid A1 (SAA1) expression upon poly(I:C) stimulation. Notably, we found that the circadian regulator Rev-erbα is critical for poly(I:C)- or interferon (IFN)-β-induced SAA1 production, resulting in the circadian oscillation pattern of SAA1 expression in myeloid cells. Furthermore, exogenously applied SAA1 markedly increased noncanonical inflammasome-mediated pyroptosis of macrophages and lethality of mice. Intriguingly, our results revealed that type 1 IFN receptor signaling is needed for poly(I:C)- or IFN-β-induced SAA1 production. Downstream of the type 1 IFN receptor, Rev-erbα inhibited the IFN-β-induced association of C/EBPβ with the promoter region of Saa1 , leading to the reduced transcription of Saa1 in macrophages. Bmal1 -deficient macrophages exhibited enhanced binding of C/EBPβ to Saa1 . Consistently, the blockade of Rev-erbα by SR8278 significantly increased poly(I:C)-stimulated SAA1 transcription and noncanonical inflammasome-mediated lethality in mice. Collectively, our data demonstrate a potent suppressive effect of the circadian clock BMAL1 on the noncanonical inflammasome response via the Rev-erbα-C/EBPβ-SAA1 axis.

Abstract Type Ⅰ interferon (IFN) signaling has emerged as a significant factor in brain development and homeostasis. Also, its dysregulation has been associated with various central nervous system (CNS) diseases, including Alzheimer's disease. According to a recent study, microglia in kainic acid-induced seizures show an increase in interferon beta responsiveness. However, the specific role of type Ⅰ IFN signaling in seizure-related processes remains elusive. Therefore, in this study, we aimed to investigate the function of type Ⅰ IFN signaling in seizures. Here, we found the upregulation of interferon beta and interferon-stimulated genes in the hippocampus of mice subjected to kainic acid, which indicates the involvement of type Ⅰ IFN signaling in seizure events. To examine the specific roles of type Ⅰ IFN signaling in seizures, we induced seizures in C57BL/6 wild-type mice and IFNAR1 knockout mice and compared the severity of seizures and subsequent events. Interestingly, IFNAR1 knockout mice showed rapid rises in seizure severity in the early stages, but later exhibited a decrease in severity compared to the wild-type. On the other hand, interferon signaling did not have a significant impact on late-phase gliosis after seizures. These data provide novel insights into the crucial role of the interferon pathway in seizure progression, suggesting its potential as a therapeutic target for the treatment of seizures and epilepsy.

Viruses have evolved to control mitochondrial quality and content to facilitate viral replication. Mitophagy is a selective autophagy, in which the damaged or unnecessary mitochondria are removed, and thus considered an essential mechanism for mitochondrial quality control. Although mitophagy manipulation by several RNA viruses has recently been reported, the effect of mitophagy regulation by varicella zoster virus (VZV) remains to be fully determined. In this study, we showed that dynamin-related protein-1 (DRP1)-mediated mitochondrial fission and subsequent PINK1/Parkin-dependent mitophagy were triggered during VZV infection, facilitating VZV replication. In addition, VZV glycoprotein E (gE) promoted PINK1/Parkin-mediated mitophagy by interacting with LC3 and upregulating mitochondrial reactive oxygen species. Importantly, VZV gE inhibited MAVS oligomerization and STING translocation to disrupt MAVS- and STING-mediated interferon (IFN) responses, and PINK1/Parkin-mediated mitophagy was required for VZV gE-mediated inhibition of IFN production. Similarly, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-mediated mitophagy induction led to increased VZV replication but attenuated IFN production in a three-dimensional human skin organ culture model. Our results provide new insights into the immune evasion mechanism of VZV gE via PINK1/Parkin-dependent mitophagy.

Epilepsy is a chronic neurological disorder characterized by recurrent seizures, yet the role and mechanisms of type I interferon (IFN) signaling in seizure conditions remain elusive. In this study, we demonstrate that type I IFN signaling exacerbates seizure phenotypes in a kainic acid-induced seizure mouse model. We found that the absence of type I IFN signaling in Ifnar1-/- mice led to decreased neuronal excitability and microglial activation in response to kainic acid stimulation. Conversely, intracerebroventricular injection of IFN-β heightened the severity of kainic acid-induced seizures. In vitro calcium imaging revealed that IFN-β treatment amplified both basal and kainic acid-induced neuronal excitability, though no significant difference was observed in basal neuronal excitability between wild-type and Ifnar1-/- neurons. Furthermore, Ifnar1-/- mice exhibited reduced mTOR activation in the brain following kainic acid administration. Consistent with this finding, IFN-β treatment induced mTOR activation, as indicated by S6 phosphorylation in in vitro mixed glial cultures. Taken together, these results demonstrate the critical role of type I IFN signaling in seizure pathogenesis and suggest that targeting type I IFNs could be a promising therapeutic strategy for reducing seizure severity and mitigating epilepsy. ### Competing Interest Statement The authors have declared no competing interest.

Abstract Circadian arrhythmia has been linked to the increased susceptibility of multiple inflammatory diseases. However, it remains elusive how disruption of circadian clock modulates innate immune responses including inflammasome signaling. Here, we examined a potential role of circadian clock on inflammasome-mediated responses through myeloid-specific deletion of BMAL1, a master circadian clock regulator. Intriguingly, Bmal1 deficiency significantly enhanced macrophage pyroptosis and lethality of mice under noncanonical inflammasome-activating conditions, but did not alter canonical inflammasome responses. Transcriptome analysis revealed that Bmal1 deficiency led to a marked reduction in Rev-erbα expression at steady state and a significant increase in serum amyloid A1 (SAA1) expression upon poly(I:C) stimulation. We found that Rev-erbα is critical for poly(I:C)-induced SAA1 production, resulting in the circadian oscillation pattern of SAA1 expression in myeloid cells. Mechanistically, Rev-erbα inhibited poly(I:C)-induced association of C/EBPβ to the promoter region of Saa1 leading to the reduced transcription of Saa1 in macrophages. Bmal1-deficient macrophages exhibited enhanced binding of C/EBPβ to Saa1. Collectively, our data demonstrate a potent suppressive role of circadian clock BMAL1 on noncanonical inflammasome response via Rev-erbα-C/EBPβ-SAA1 axis and further suggest that circadian arrhythmia can enhance the susceptibility to noncanonical inflammasome-mediated toxicity.

Inflammation is a series of host defense processes in response to microbial infection and tissue injury. Inflammatory processes frequently cause extracellular acidification in the inflamed region through increased glycolysis and lactate secretion. Therefore, the immune cells infiltrating the inflamed region encounter an acidic microenvironment. Extracellular acidosis can modulate the innate immune response of macrophages; however, its role for inflammasome signaling still remains elusive. In the present study, we demonstrated that macrophages exposed to an acidic microenvironment exhibited enhanced caspase-1 processing and IL-1β secretion compared with those under physiological pH. Moreover, exposure to an acidic pH increased the ability of macrophages to assemble the NLR family pyrin domain containing 3 (NLRP3) inflammasome in response to an NLRP3 agonist. This acidosis-mediated augmentation of NLRP3 inflammasome activation occurred in bone marrow-derived macrophages but not in bone marrow-derived neutrophils. Notably, exposure to an acidic environment caused a reduction in the intracellular pH of macrophages but not neutrophils. Concordantly, macrophages, but not neutrophils, exhibited NLRP3 agonist-mediated translocation of chloride intracellular channel protein 1 (CLIC1) into their plasma membranes under an acidic microenvironment. Collectively, our results demonstrate that extracellular acidosis during inflammation can increase the sensitivity of NLRP3 inflammasome formation and activation in a CLIC1-dependent manner. Thus, CLIC1 may be a potential therapeutic target for NLRP3 inflammasome-mediated pathological conditions.

Neutrophil extracellular traps (NETs) exert a novel function of trapping pathogens. Released NETs can accumulate in inflamed tissues, be recognized by other immune cells for clearance, and lead to tissue toxicity. Therefore, the deleterious effect of NET is an etiological factor, causing several diseases directly or indirectly. NLR family pyrin domain containing 3 (NLRP3) in neutrophils is pivotal in signaling the innate immune response and is associated with several NET-related diseases. Despite these observations, the role of NLRP3 in NET formation in neuroinflammation remains elusive. Therefore, we aimed to explore NET formation promoted by NLRP3 in an LPS-induced inflamed brain. Wild-type and NLRP3 knockout mice were used to investigate the role of NLRP3 in NET formation. Brain inflammation was systemically induced by administering LPS. In such an environment, the NET formation was evaluated based on the expression of its characteristic indicators. DNA leakage and NET formation were analyzed in both mice through Western blot, flow cytometry, and in vitro live cell imaging as well as two-photon imaging. Our data revealed that NLRP3 promotes DNA leakage and facilitates NET formation accompanied by neutrophil death. Moreover, NLRP3 is not involved in neutrophil infiltration but is predisposed to boost NET formation, which is accompanied by neutrophil death in the LPS-induced inflamed brain. Furthermore, either NLRP3 deficiency or neutrophil depletion diminished pro-inflammatory cytokine, IL-1β, and alleviated blood-brain barrier damage. Overall, the results suggest that NLRP3 exacerbates NETosis in vitro and in the inflamed brain, aggravating neuroinflammation. These findings provide a clue that NLRP3 would be a potential therapeutic target to alleviate neuroinflammation.

Inflammation is an essential host defense mechanism in response to microbial infection and tissue injury. In addition to its well-established role in infection, inflammation is actively involved in the repair of damaged tissues and restoration of homeostatic conditions after tissue injury. The intensity of the inflammatory response and types of cells involved in inflammation have a significant impact on the quality of tissue repair. Numerous immune cell subtypes participate in tissue repair and regeneration. In particular, immune cell-derived secretants, including cytokines and growth factors, can actively modulate the proliferation of resident stem cells or progenitor cells to facilitate tissue regeneration. These findings highlight the importance of inflammation during tissue repair and regeneration; however, the precise role of immune cells in tissue regeneration remains unclear. In this review, we summarize the current knowledge on the contribution of specific immune cell types to tissue repair and regeneration. We also discuss how inflammation affects the final outcome of tissue regeneration.

Supplementary Methods, Figures 1-5 from CIIA Is a Novel Regulator of Detachment-Induced Cell Death

The NLRP3 inflammasome is activated by mitochondrial damage and contributes to kidney fibrosis. However, it is unknown whether PGC-1α, a key mitochondrial biogenesis regulator, modulates NLRP3 inflammasome in kidney injury. Primary renal tubular epithelial cells (RTECs) were isolated from C57BL/6 mice. The NLRP3 inflammasome, mitochondrial dynamics and morphology, oxidative stress, and cell injury markers were examined in RTECs treated by TGF-β1 with or without Ppargc1a plasmid, PGC-1α activator (metformin), and siPGC-1α. In vivo, adenine-fed and unilateral ureteral obstruction (UUO) mice were treated with metformin. In vitro, TGF-β1 treatment to RTECs suppressed the expressions of PGC-1α and mitochondrial dynamic-related genes. The NLRP3 inflammasome was also activated and the expression of fibrotic and cell injury markers was increased. PGC-1α induction with the plasmid and metformin improved mitochondrial dynamics and morphology and attenuated the NLRP3 inflammasome and cell injury. The opposite changes were observed by siPGC-1α. The oxidative stress levels, which are inducers of the NLRP3 inflammasome, were increased and the expression of TNFAIP3, a negative regulator of NLRP3 inflammasome regulated by PGC-1α, was decreased by TGF-β1 and siPGC-1α. However, PGC-1α restoration reversed these alterations. In vivo, adenine-fed and UUO mice models showed suppression of PGC-1α and TNFAIP3 and dysregulated mitochondrial dynamics. Moreover, the activation of oxidative stress and NLRP3 inflammasome, and kidney fibrosis were increased in these mice. However, these changes were significantly reversed by metformin. This study demonstrated that kidney injury was ameliorated by PGC-1α-induced inactivation of the NLRP3 inflammasome via modulation of mitochondrial viability and dynamics.