[The effect of the AIM2 inflammasome in noise-induced cognitive dysfunction in rats].

Objective: To explore the effect of the absent in melanoma 2 (AIM2) -mediated neuroinflammation in noise-induced cognitive dysfunction in rats. Methods: In April 2023, sixteen male Wistar rats were randomly divided into control group and noise group, with 8 rats in each group. The rats in the noise group were placed in 50 cm×50 cm×40 cm transparent boxes and exposed to 100 dB (A) white noise with a sound pressure level of 100 dB (A) (4 h/d for 30 d) . At the same time, rats in the control group were kept in similar boxes with environmental noise less than 60 dB (A) . After 30 days of noise exposure, the Morris water maze experiment was applied to test the learning and memory abilities of the rats; the pathological morphology of hippocampal tissues was observed by Hematoxylin-Eosin (HE) staining. Western blot was used to detect the protein expression levels of AIM2, cysteinyl aspartate specific proteinase-1 (caspase-1) , apoptosis-associated speck-like protein (ASC) , interleukin-1ß (IL-1ß) , IL-18, ionic calcium-binding articulation molecule-1 (Iba-1) , and glial fibrillary acidic protein (GFAP) . The expression of both Iba-1 and GFAP in hippocampal tissue was assessed by immunohistochemical staining. The co-localization of AIM2 with Iba-1 or GFAP was determined by immunofluorescence double staining. Results: Compared with the control group, the escape latency of rats in the noise group was increased by 16.29 s, 17.71 s, and 20.26 s on days 3, 4, and 5, respectively. On day 6, the noise-exposed rats spent shorter time in the target quadrant and had fewer times in crossing the platform[ (7.25±2.27) s and (1.13±0.64) times] than the control group[ (15.64±3.99) s and (4.25±2.12) times] (P<0.05) . After noise exposure, hippocampal neurons of rats displayed marked nuclear hyperchromatic and pyknosis phenomenon. The noise-exposed rats had higher numbers of both microglia and astrocytes (27.00±2.65 and 43.33±5.51) in the DG area of the hippocampus relative to the control group (14.67±3.06 and 20.00±4.58) (P<0.05) . Moreover, the glial cells in the noise group had larger cell cytosol with more and thicker branches. The protein expression levels of inflammatory cytokines Cleaved-IL-1ß and Cleaved-IL-18 in the hippocampus of rats in the noise group (1.55±0.19 and 1.74±0.12) were significantly higher than the control group (1.00±0.11 and 1.00±0.13) (P<0.05) . After noise exposure, the protein expression levels of AIM2, Cleaved-Caspase-1 and ASC (1.19±0.09, 1.34±0.07 and 1.14±0.01) were higher than the control group (1.00±0.07, 1.00±0.14 and 1.00±0.06) and differences between the two groups were statistically significant (P<0.05) . A significant increase in the number of cells co-localizing AIM2 with Iba-1 or GFAP in the noise group (28.67±4.04 and 40.67±5.13) compared with the control group (15.67±4.04 and 17.67±3.79) , and statistically significant differences were observed between the two groups (P<0.05) . Conclusion: Noise exposure may activate the AIM2 inflammasome in hippocampal glial cells of rats, releasing excessive inflammatory cytokines and causing neuroinflammation that damages neurons.

The cytosolic DNA sensor AIM2 promotes Helicobacter-induced gastric pathology via the inflammasome.

Helicobacter pylori (H. pylori) infection can trigger chronic gastric inflammation perpetuated by overactivation of the innate immune system, leading to a cascade of precancerous lesions culminating in gastric cancer. However, key regulators of innate immunity that promote H. pylori-induced gastric pathology remain ill-defined. The innate immune cytosolic DNA sensor absent in melanoma 2 (AIM2) contributes to the pathogenesis of numerous autoimmune and chronic inflammatory diseases, as well as cancers including gastric cancer. We therefore investigated whether AIM2 contributed to the pathogenesis of Helicobacter-induced gastric disease. Here, we reveal that AIM2 messenger RNA and protein expression levels are elevated in H. pylori-positive versus H. pylori-negative human gastric biopsies. Similarly, chronic Helicobacter felis infection in wild-type mice augmented Aim2 gene expression levels compared with uninfected controls. Notably, gastric inflammation and hyperplasia were less severe in H. felis-infected Aim2-/- versus wild-type mice, evidenced by reductions in gastric immune cell infiltrates, mucosal thickness and proinflammatory cytokine and chemokine release. In addition, H. felis-driven proliferation and apoptosis in both gastric epithelial and immune cells were largely attenuated in Aim2-/- stomachs. These observations in Aim2-/- mouse stomachs correlated with decreased levels of inflammasome activity (caspase-1 cleavage) and the mature inflammasome effector cytokine, interleukin-1ß. Taken together, this work uncovers a pathogenic role for the AIM2 inflammasome in Helicobacter-induced gastric disease, and furthers our understanding of the host immune response to a common pathogen and the complex and varying roles of AIM2 at different stages of cancerous and precancerous gastric disease.

AIM2 participates in house dust mite (HDM)-induced epithelial dysfunctions and ovalbumin (OVA)-induced allergic asthma in infant mice.

Objective: Allergen sensitization and high rates of concomitant allergic diseases are characteristic of severe pediatric asthma. The present study was aimed to explore the mechanism of allergic asthma via bioinformatics and experiment investigation.Methods: The GSE27011 dataset contained the expression profiles of normal and pediatric asthma white blood cells was downloaded for analyzing the different expression genes and function enrichment. The allergic asthma model in infant mice was established by ovalbumin (OVA) stimulation. The cellular model was established by house dust mite (HDM)-stimulation in human bronchial epithelial cells. The absent in melanoma 2 (AIM2) knockdown was achieved by intranasal lentivirus injection or cell infection. The bronchoalveolar lavage fluid (BALF) was collected for cell counting and ELISA assessment of cytokines. Lung tissues were collected for HE staining and immunohistochemical (IHC) staining. Real-time PCR and immunoblotting were used for the determination of key gene expressions in mouse and cell models.Results: upregulation of AIM2 gene expression was observed in pediatric asthma patients based on GSE27011 and OVA-induced infant mouse allergic asthma model. AIM2 knockdown ameliorated OVA caused elevation in airway hyper-responsiveness (AHR), elevation in cell quantities (eosinophils, neutrophils, lymphocytes), and levels of cytokines (IL-4, IL-13, TNF-α, and OVA-specific IgE) in BALF. Moreover, AIM2 knockdown relieved OVA-caused histopathological alterations in mouse lungs, up-regulation of AIM2 levels, and NOD1 and receptor-interacting protein 2 (RIP2) protein levels, as well as p65 phosphorylation. In the cell model, AIM2 knockdown partially ameliorated HDM-induced epithelial dysfunctions by promoting cell viability, down-regulating inflammatory cytokines levels, and decreasing the protein levels of AIM2, NOD1, RIP2, and phosphorylated p65.Conclusion: AIM2 participates in HDM-induced epithelial dysfunctions and OVA-induced allergic asthma progression. AIM2 could be a promising target for pediatric allergic asthma treatment regimens, which warrants further in vivo investigations.

Absent in melanoma 2 (AIM2) in rheumatoid arthritis: novel molecular insights and implications.

Absent in melanoma 2 (AIM2), a member of the Pyrin and HIN domain protein family, is a cytoplasmic receptor that recognizes double-stranded DNA. AIM2 exhibits limited expression under physiological conditions but is widely expressed in many human diseases, including autoimmune diseases, and plays an essential role in the immune response. Rheumatoid arthritis (RA) is an autoimmune disease that poses a severe threat to physical and mental health, and is caused by several genetic and metabolic factors. Multiple immune cells interact to form a complex inflammatory network that mediates inflammatory responses and bone destruction. Abnormal AIM2 expression in multiple immune cell populations (T cells, B cells, fibroblast-like synoviocytes, monocytes, and macrophages) may regulate multiple functional responses in RA through mechanisms such as pyroptosis, PANoptosis, and regulation of other molecules. In this review, we describe and summarize the functional regulation and impact of AIM2 expression in immune cells to improve our understanding of the complex pathological mechanisms. These insights may provide potential directions for the development of new clinical diagnostic strategies for RA.

Absent in Melanoma 2 (AIM2) Regulates the Stability of Regulatory T Cells.

Absent in melanoma 2 (AIM2) is a cytosolic dsDNA sensor that has been broadly studied for its role in inflammasome assembly. However, little is known about the function of AIM2 in adaptive immune cells. The purpose of this study was to investigate whether AIM2 has a cell-intrinsic role in CD4+ T cell differentiation or function. We found that AIM2 is expressed in both human and mouse CD4+ T cells and that its expression is affected by T cell receptor (TCR) activation. Naïve CD4+ T cells from AIM2-deficient (Aim2-/-) mice showed higher ability to maintain forkhead box P3 (FOXP3) expression in vitro, while their capacity to differentiate into T helper (Th)1, Th2 or Th17 cells remained unaltered. Transcriptional profiling by RNA sequencing showed that AIM2 might affect regulatory T cell (Treg) stability not by controlling the expression of Treg signature genes, but through the regulation of the cell's metabolism. In addition, in a T cell transfer model of colitis, Aim2-/--naïve T cells induced less severe body weight loss and displayed a higher ability to differentiate into FOXP3+ cells in vivo. In conclusion, we show that AIM2 function is not confined to innate immune cells but is also important in CD4+ T cells. Our data identify AIM2 as a regulator of FOXP3+ Treg cell differentiation and as a potential intervention target for restoring T cell homeostasis.

Downregulating expression of OPTN elevates neuroinflammation via AIM2 inflammasome- and RIPK1-activating mechanisms in APP/PS1 transgenic mice.

BACKGROUND: Neuroinflammation is thought to be a cause of Alzheimer's disease (AD), which is partly caused by inadequate mitophagy. As a receptor of mitophagy, we aimed to reveal the regulatory roles of optineurin (OPTN) on neuroinflammation in the pathogenesis of AD. METHODS: BV2 cells and APP/PS1 transgenic (Tg) mice were used as in vitro and in vivo experimental models to determine the regulatory roles of OPTN in neuroinflammation of AD. Sophisticated molecular technologies including quantitative (q) RT-PCR, western blot, enzyme linked immunosorbent assay (ELISA), co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were employed to reveal the inherent mechanisms. RESULTS: As a consequence, key roles of OPTN in regulating neuroinflammation were identified by depressing the activity of absent in melanoma 2 (AIM2) inflammasomes and receptor interacting serine/threonine kinase 1 (RIPK1)-mediated NF-κB inflammatory mechanisms. In detail, we found that expression of OPTN was downregulated, which resulted in activation of AIM2 inflammasomes due to a deficiency in mitophagy in APP/PS1 Tg mice. By ectopic expression, OPTN blocks the effects of Aß oligomer (Aßo) on activating AIM2 inflammasomes by inhibiting mRNA expression of AIM2 and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), leading to a reduction in the active form of caspase-1 and interleukin (IL)-1ß in microglial cells. Moreover, RIPK1 was also found to be negatively regulated by OPTN via ubiquitin protease hydrolysis, resulting in the synthesis of IL-1ß by activating the transcriptional activity of NF-κB in BV2 cells. As an E3 ligase, the UBAN domain of OPTN binds to the death domain (DD) of RIPK1 to facilitate its ubiquitination. Based on these observations, ectopically expressed OPTN in APP/PS1 Tg mice deactivated microglial cells and astrocytes via the AIM2 inflammasome and RIPK-dependent NF-κB pathways, leading to reduce neuroinflammation. CONCLUSIONS: These results suggest that OPTN can alleviate neuroinflammation through AIM2 and RIPK1 pathways, suggesting that OPTN deficiency may be a potential factor leading to the occurrence of AD.

Significance of expression of AIM2, IL-1ß, and IL-18 in plasma of patients with acute cerebral infarction. / æ€¥æ€§è„‘æ¢—æ­»æ‚£è€ è¡€æµ†ä¸­AIM2、IL-1ß和IL-18的表达及意义.

OBJECTIVES: Inflammation especially the overexpression of inflammasome and inflammatory cytokines, is one of the important reasons that affect the occurrence and development of acute cerebral infarction, including the initiation of cerebral infarction, the progress and recovery of post-infarction injury. This study aims to explore expressions of absent in melanoma 2 (AIM2), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) in plasma of patients with acute cerebral infarction and its significance. METHODS: A total of 85 patients with acute cerebral infarction were enrolled in the cerebral infarction group. They were assigned into mild, moderate, and severe groups according to the severity of neurological deficits. They were assigned into small, middle, and large cerebral infarction groups according to the area of cerebral infarction. They were assigned into a good prognosis group and a poor prognosis group according to the Modified Rankin Scale (mRS) score on the 90th day after the onset. A total of 85 healthy controls were selected as a control group. The levels of AIM2, IL-1ß, and IL-18 in plasma of the cerebral group and the control group were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The levels of plasma AIM2, IL-1ß, and IL-18 in the cerebral infarction group were significantly higher than those in the control group (all P<0.001). In the cerebral infarction group, the expression levels of plasma AIM2, IL-1ß, and IL-18 were as follows: The severe neurological deficitc group>the moderate group>the mild group, the large area of cerebral infarction group>the middle area group>the small area group, and the poor prognosis group> the good prognosis group (all P<0.05). The levels of plasma AIM2 were positively correlated with National Institute of Health Stroke Scale (NIHSS) score, the cerebral infarction area, and the mRS score (r=0.791, r=0.710, r=0.763, respectively, all P<0.001). The levels of plasma IL-1ß were positively correlated with the NIHSS score, the cerebral infarction area, and the mRS score (r=0.716, r=0.690, r=0.688, respectively, all P<0.001). The levels of plasma IL-18 were positively correlated with the NIHSS score, the cerebral infarction area, and the mRS score (r=0.714, r=0.638, r=0.653, respectively, all P<0.001). The level of plasma AIM2 was positively correlated with that of IL-1ß and IL-18 (r=0.828, r=0.751, both P<0.001). CONCLUSIONS: Expressions of AIM2, IL-1ß, and IL-18 are up-regulated in the plasma of patients with acute cerebral infarction, and they are closely related to the severity of neurological deficit, cerebral infarction area, and prognosis in patients with acute cerebral infarction, suggesting that AIM2, IL-1ß, and IL-18 may play an important role in the occurrence and development of acute cerebral infarction.

The Emerging Relevance of AIM2 in Liver Disease.

Absent in melanoma 2 (AIM2) is a cytosolic receptor that recognizes double-stranded DNA (dsDNA) and triggers the activation of the inflammasome cascade. Activation of the inflammasome results in the maturation of inflammatory cytokines, such as interleukin (IL)-1 ß and IL-18, and a form of cell death known as pyroptosis. Owing to the conserved nature of its ligand, AIM2 is important during immune recognition of multiple pathogens. Additionally, AIM2 is also capable of recognizing host DNA during cellular damage or stress, thereby contributing to sterile inflammatory diseases. Inflammation, either in response to pathogens or due to sterile cellular damage, is at the center of the most prevalent and life-threatening liver diseases. Therefore, during the last 15 years, the study of inflammasome activation in the liver has emerged as a new research area in hepatology. Here, we discuss the known functions of AIM2 in the pathogenesis of different hepatic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and hepatocellular carcinoma (HCC).

Overexpression of absent in melanoma 2 in oral squamous cell carcinoma contributes to tumor progression.

We had previously reported that in addition to p53 inactivation, overexpression of the DNA sensor protein-absent in melanoma 2 (AIM2)-contributes to tumorigenesis of oral squamous cell carcinoma (OSCC). Given that AIM2 is highly expressed in the OSCC tumors from patients with metastasis, we investigated whether AIM2 expression contributes to the progression of OSCC metastasis. In in vitro assays using OSCC cell lines, the high migration and invasion capacity of OSCC cells were dependent on the increased expression of AIM2, resulting in enhanced epithelial-mesenchymal transition (EMT), with EMT-related gene expression. Moreover, the in vivo short-term metastasis assay using orthotopic implantation into immunodeficient mice demonstrated that OSCC cells with high levels of AIM2 expression exhibited enhanced tumor growth in the tongue, resulting in decreased survival of the mice. Further, the cells overexpressing AIM2 dominantly invaded into the tumor lymphatic vessels, unlike OSCC cells with low AIM2 expression. Thus, the high expression of AIM2 in OSCC enhances progression of tumor growth.

Immune signalling by supramolecular assemblies.

Formation of supramolecular assemblies appears to be a general mechanism in immune signalling pathways. These supramolecular assemblies appear to form through a nucleated polymerization mechanism. This review examines selected immune signalling pathways that involve supramolecular assemblies, describes the concepts of protein polymerization, and discusses how those concepts of protein polymerization implicate new elegant ways for signal amplification, setting threshold and noise reduction in these pathways.

Quercetin inhibits the poly(dA:dT)-induced secretion of IL-18 via down-regulation of the expressions of AIM2 and pro-caspase-1 by inhibiting the JAK2/STAT1 pathway in IFN-γ-primed human keratinocytes.

Quercetin, a polyphenol, belongs to a class of flavonoids that exerts anti-inflammatory effects. Interleukin (IL)-18 is a member of the IL-1 family cytokine that regulates immune responses and is implicated in various inflammatory skin diseases. Absent in melanoma 2 (AIM2) is a cytosolic double-stranded (ds) DNA sensor that recognizes the dsDNA of a microbial or host origin. Binding of dsDNA to AIM2 simulates caspase-1-dependent inflammasome activity, which leads to the production of IL-1ß and IL-18. Increased levels of AIM2 have been observed in patients with inflammatory skin diseases. In the current study, we investigated the issue of whether or how Quercetin attenuates poly (dA:dT), a synthetic analog of microbial dsDNA, -induced IL-18 secretion in IFN-γ-primed human keratinocytes. Treatment with 5 and 10 µM of Quercetin inhibited the poly (dA:dT)-induced secretion of IL-18 after IFN-γ priming and before poly (dA:dT)-induced AIM2 activation. In addition, treatment with Quercetin at 10 µM, significantly inhibited the phosphorylation of JAK2 and STAT1, and the nuclear translocation of phosphorylated STAT1 in poly (dA:dT)-treated and IFN-γ-primed keratinocytes. These results suggest that treatment with Quercetin inhibits the poly (dA:dT)-induced secretion of IL-18 via down-regulation of the expressions of AIM2 and pro-caspase-1 by inhibiting the JAK2/STAT1 pathway in IFN-γ-primed keratinocytes.

Absent in melanoma 2 triggers a heightened inflammasome response in ascitic fluid macrophages of patients with cirrhosis.

BACKGROUND & AIMS: Inflammation is a common event in the pathogenesis of liver cirrhosis. The inflammasome pathway has acquired significant relevance in the pathogenesis of inflammation, but its role in the inflammatory response in patients with decompensated cirrhosis remains unexplored. METHODS: We performed a prospective study in which 44 patients with decompensated cirrhosis and 12 healthy volunteers were included. We isolated macrophages from blood and ascitic fluid and assessed the expression and activation of the inflammasome, its response to priming by bacterial products, and its association with the degree of liver disease. RESULTS: Macrophages from sterile ascitic fluids showed constitutive activation of caspase-1 and a marked increase in the expression of IL-1ß, IL-18, and absent in melanoma 2 (AIM2) when compared to blood macrophages. Pre-stimulation of blood-derived macrophages from cirrhotic patients with bacterial DNA increased the expression of AIM2 and induced a higher AIM2-mediated inflammasome response than priming with other bacterial products such as lipopolysaccharide. By contrast, activation of the AIM2 inflammasome did not require a priming signal in ascitic fluid-derived macrophages, demonstrating the preactivated state of the inflammasome in these cells. Last, higher IL-1ß and IL-18 production by ascitic fluid macrophages correlated with a more advanced Child-Pugh score. CONCLUSIONS: The inflammasome is highly activated in the ascitic fluid of cirrhotic patients, which may explain the exacerbated inflammatory response observed in these patients under non-infected conditions. Clinically, activation of the inflammasome is associated with a higher degree of liver disease.

Epigallocatechin-3-gallate attenuates the AIM2-induced secretion of IL-1ß in human epidermal keratinocytes.

The pro-inflammatory cytokine interleukin-1ß (IL-1ß) plays a central role in the pathogenesis of psoriasis. Keratinocytes are a major source of IL-1ß and express absent in melanoma 2 (AIM2). AIM2 recognizes a double-stranded DNA and initiates the IL-1ß-processing of inflammasome. The AIM2 inflammasome is a cytosolic multiprotein complex composed of AIM2, an apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and pro-caspase-1. Epigallocatechin-3-Gallate (EGCG), a major polyphenolic component of green tea, has anti-inflammatory properties. In the current study, we investigated the issue of whether or how EGCG suppresses AIM2 inflammasome in human epidermal keratinocytes, neonatal (HEKn). Treatment with EGCG, before or after IFN-γ priming, attenuated poly(dA:dT)-induced IL-1ß secretion in HEKn cells. Pre-treatment with EGCG reduced the level of IFN-γ-induced priming signal via the down-regulation of pro-IL-1ß and pro-capspase-1 in HEKn cells. Furthermore, treatment with EGCG attenuated poly(dA:dT)-induced ASC oligomerization and caspase-1 activation in IFN-γ-primed HEKn cells. These results suggest that EGCG attenuates AIM2-induced IL-1ß secretion by suppressing both IFN-γ-mediated priming and poly(dA:dT)-induced ASC oligomerization of inflammasomes in human epidermal keratinocytes.

Viral infection of the lung: host response and sequelae.

Because of its essential role in gas exchange and oxygen delivery, the lung has evolved a variety of strategies to control inflammation and maintain homeostasis. Invasion of the lung by pathogens (and in some instances exposure to certain noninfectious particulates) disrupts this equilibrium and triggers a cascade of events aimed at preventing or limiting colonization (and more importantly infection) by pathogenic microorganisms. In this review we focus on viral infection of the lung and summarize recent advances in our understanding of the triggering of innate and adaptive immune responses to viral respiratory tract infection, mechanisms of viral clearance, and the well-recognized consequences of acute viral infection complicating underlying lung diseases, such as asthma.

Importance of AIM2 as a serum marker for reflecting severity and predicting a poor outcome of human severe traumatic brain injury: A prospective longitudinal cohort study.

BACKGROUND: Absent in melanoma 2 (AIM2) participates in neuroinflammation. Here, the prognostic significance of serum AIM2 was explored in severe traumatic brain injury (sTBI). METHODS: A total of 135 sTBI patients and 80 healthy controls were recruited in this prospective cohort study. Serum C-reactive protein (CRP) and AIM2 levels were measured. Glasgow Coma Scale (GCS) and Rotterdam computed tomography (CT) classification were recorded as the severity indicators. Prognostic parameters were posttraumatic six-month extended Glasgow outcome scale (GOSE) scores and poor outcome (GOSE scores of 1-4). RESULTS: As opposed to controls, there were significantly elevated serum AIM2 levels after sTBI. Serum AIM2 levels were independently correlated with serum CRP levels, GCS scores, Rotterdam CT scores, GOSE scores and poor outcome. Also, serum AIM2 levels were efficiently predictive of poor outcome under the receiver operating characteristic (ROC) curve. Under the restricted cubic spline, serum AIM2 levels were linearly correlated with risk of poor outcome. Using subgroup analysis, serum AIM2 levels did not significantly interact with other indices, such as age, gender, alcohol drinking, cigarette smoking, etc. Also, combination model, in which serum AIM2, GCS scores and Rotterdam CT scores were merged, was outlined using nomogram and performed well under calibration curve, ROC curve and decision curve. CONCLUSIONS: Raised serum AIM2 levels after sTBI, in intimate correlation with systemic inflammation and trauma severity, are independently discriminative of posttraumatic six-month neurological outcome, substantializing serum AIM2 as an inflammatory prognostic biomarker of sTBI.

Usability of serum AIM2 as a predictive biomarker of stroke-associated pneumonia and poor prognosis after acute supratentorial intracerebral hemorrhage: A prospective longitudinal cohort study.

Background: Absent in melanoma 2 (AIM2) is implicated in inflammatory processes. We measured serum AIM2 with intent to unveil its predictive significance for stroke-associated pneumonia (SAP) and functional prognosis following acute intracerebral hemorrhage (ICH). Methods: In this prospective cohort study, serum AIM2 concentrations of 163 ICH patients were gauged upon admission and 57 of them also consented for measurements at days 1, 3, 5, 7, 10 and 14. Coupled with 57 individuals without health conditions, dynamic change of serum AIM2 levels were uncovered. National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume were identified as the dual indicators of severity. Poststroke six-month modified Rankin Scale (mRS) scores ranging from 3 to 6 indicated an unfavorable outcome. SAP was observed during the first seven days after ICH. Sequential univariate and multivariate analyses were performed to discern predictors of SAP and adverse prognosis. Results: The serum levels of AIM2 in patients exhibited a marked elevation upon admission, reaching peak levels on the third and fifth days, and remained notably elevated until day 14 compared to those of the control group. Serum AIM2 levels showed independent correlations with both NIHSS scores and the volume of hematoma. Additionally, AIM2 concentrations were independently associated with a poor prognosis and SAP at the six-month mark. Within the framework of restricted cubic spline analysis, serum AIM2 concentrations exhibited a linear correlation with the likelihood of developing SAP and experiencing a poor prognosis. In the context of receiver operating characteristic (ROC) curve analysis, serum AIM2 concentrations effectively differentiated risks of SAP and poor prognosis. By employing segmented analysis, serum AIM2 concentrations showed negligible interactions with several traditional variables, such as age, gender, smoking habits, alcohol consumption, and more. The integrated model incorporating serum AIM2, NIHSS scores, and the volume of hematoma was depicted by employing a nomogram and demonstrated strong predictive performance for poor prognosis or SAP across various evaluation metrics, including ROC curve analysis, calibration curve analysis, and decision curve analysis. Conclusion: Serum AIM2 levels show a marked increase shortly after intracerebral hemorrhage (ICH), which may accurately reflect stroke severity, and effectively predict SAP and poor neurological outcomes, and therefore serum AIM2 stands out as an encouraging predictive indicator for ICH.

Hepatocellular carcinoma and AIM2: Therapeutic potential through regulation of autophagy and macrophage polarization.

OBJECTIVE: Hepatocellular carcinoma (HCC) poses a significant challenge to global health. Its pathophysiology involves interconnected processes, including cell proliferation, autophagy, and macrophage polarization. However, the role of Absent in Melanoma 2 (AIM2) in HCC remains elusive. METHODS: The expression of AIM2 in Huh-7 and Hep3B cell lines was manipulated and cell proliferation, autophagy, apoptosis, and migration/invasion, together with the polarization of M2 macrophages, were evaluated. The markers of autophagy pathway, LC3B, Beclin-1, and P62, underwent examination through Western blot analysis. An autophagy inhibitor, 3-MA, was used to measured the role of autophagy in HCC. Finally, the effect of AIM2 overexpression on HCC was further evaluated using a subcutaneous tumor model in nude mice. RESULTS: Our results established that AIM2 overexpression inhibits HCC cell proliferation, migration, and invasion while promoting apoptosis and autophagy. Conversely, knockdown of AIM2 engendered opposite effects. AIM2 overexpression was correlated with reduced M2 macrophage polarization. The autophagy inhibitor substantiated AIM2's role in autophagy and identified its downstream impact on cell proliferation, migration, invasion, and macrophage polarization. In the in vivo model, overexpression of AIM2 led to the inhibition of HCC tumor growth. CONCLUSION: The findings underscore AIM2's crucial function in modulating major biological processes in HCC, pointing to its potential as a therapeutic target. This study inaugurally demonstrated that AIM2 activates autophagy and influences macrophage polarization, playing a role in liver cancer progression.

Activating MC4R Promotes Functional Recovery by Repressing Oxidative Stress-Mediated AIM2 Activation Post-spinal Cord Injury.

Spinal cord injury (SCI) is a destructive neurological trauma that induces permanent sensory and motor impairment as well as a deficit in autonomic physiological function. Melanocortin receptor 4 (MC4R) is a G protein-linked receptor that is extensively expressed in the neural system and contributes to inhibiting inflammation, regulating mitochondrial function, and inducing programmed cell death. However, the effect of MC4R in the modulation of oxidative stress and whether this mechanism is related to the role of absent in melanoma 2 (AIM2) in SCI are not confirmed yet. In the current study, we demonstrated that MC4R is significantly increased in the neurons of spinal cords after trauma and oxidative stimulation of cells. Further, activation of MC4R by RO27-3225 effectively improved functional recovery, inhibited AIM2 activation, maintained mitochondrial homeostasis, repressed oxidative stress, and prevented Drp1 translocation to the mitochondria. Meanwhile, treating Drp1 inhibitors would be beneficial in reducing AIM2 activation, and activating AIM2 could abolish the protective effect of MC4R on neuron homeostasis. In conclusion, we demonstrated that MC4R protects against neural injury through a novel process by inhibiting mitochondrial dysfunction, oxidative stress, as well as AIM2 activation, which may serve as an available candidate for SCI therapy.

Longitudinal change of serum AIM2 levels after aneurysmal subarachnoid hemorrhage and its prognostic significance: a two-center prospective cohort study.

Absent in melanoma 2 (AIM2) is implicated in neuroinflammation. Here, we explored the prognostic significance of serum AIM2 in human aneurysmal subarachnoid hemorrhage (aSAH). We conducted a consecutive enrollment of 127 patients, 56 of whom agreed with blood-drawings not only at admission but also at days 1, 2, 3, 5, 7 and 10 days after aSAH. Serum AIM2 levels of patients and 56 healthy controls were measured. Disease severity was assessed using the modified Fisher scale (mFisher) and World Federation of Neurological Surgeons Scale (WFNS). Neurological outcome at poststroke 90 days was evaluated via the modified Rankin Scale (mRS). Univariate analysis and multivariate analysis were sequentially done to ascertain relationship between serum AIM2 levels, severity, delayed cerebral ischemia (DCI) and 90-day poor prognosis (mRS scores of 3-6). Patients, in comparison to controls, had a significant elevation of serum AIM2 levels at admission and at days 1, 2, 3, 5, 7 and 10 days after aSAH, with the highest levels at days 1, 2, 3 and 5. AIM2 levels were independently correlated with WFNS scores and mFisher scores. Significantly higher serum AIM2 levels were detected in patients with a poor prognosis than in those with a good prognosis, as well as in patients with DCI than in those without DCI. Moreover, serum AIM2 levels independently predicted a poor prognosis and DCI, and were linearly correlated with their risks. Using subgroup analysis, there were no significant interactions between serum AIM2 levels and age, gender, hypertension and so on. There were substantially high predictive abilities of serum AIM2 for poor prognosis and DCI under the receiver operating characteristic curve. The combination models of DCI and poor prognosis, in which serum AIM2, WFNS scores and mFisher scores were incorporated, showed higher discriminatory efficiencies than anyone of the preceding three variables. Moreover, the models are delineated using the nomogram, and performed well under the calibration curve and decision curve. Serum AIM2 levels, with a substantial enhancement during early phase after aSAH, are closely related to bleeding severity, poor 90-day prognosis and DCI of patients, substantializing serum AIM2 as a potential prognostic biomarker of aSAH.

Clustering human dental pulp fibroblasts spontaneously activate NLRP3 and AIM2 inflammasomes and induce IL-1ß secretion.

Objectives: The objective of the present study was to investigate whether NOD-like receptor family pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes pathways were involved in an experimental model of fibroblast activation named nemosis, which was used to mimic circumstances without bacteria stimulation. Methods: Nemosis of human dental pulp fibroblast (DPFs) was induced by three-dimensional culture in U-shaped 96-well plates and investigated by scanning electron microscopy (SEM). DPFs monolayers were used as control. Annexin V-FITC/7-AAD apoptosis assay was performed on the DPFs spheroids by flowcytometry. Caspase-1 activity detection assay was conducted on the DPFs spheroids. Quantitative real-time polymerase chain reaction (qRT-PCR), cytokine measurements, Western blot and the effect of COX-2 inhibitor on spheroids was studied. Results: SEM study observed human dental pulp fibroblast clusters and cell membranes damage on the surface of DPFs spheroids. The percentages of necrotic cells from DPFs spheroids gradually increased as the incubation time increased. A statistically significant increase in caspase-1 activity was observed after DPFs spheroids formation. DPFs spheroids displayed significant amounts of NLRP3, AIM2 mRNA and protein expression, caspase-1 mRNA expression and cleaved Caspase-1 protein expression and high IL-1ß concentrations (P < 0.05) than DPFs monolayers. Specific COX-2 inhibitor (NS-398) decreased NLRP3 mRNA and protein expression, cleaved Caspase-1 protein expression, Caspase-1 activity and IL-1ß mRNA expression and IL-1ß concentrations (P < 0.05). However, Specific COX-2 inhibitor had no impact on AIM2 mRNA and protein expression, caspase-1 mRNA expression and pro-Caspase-1 protein expression. Conclusions: In conclusion, clustering human DPFs spontaneously activated NLRP3 and AIM2 inflammasomes and induced IL-1ß secretion which could be partially attenuated by COX-2 inhibitor. Thus, nemosis could become a powerful model for studying mechanisms underlying aseptic pulpitis.