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Introduction: Alzheimer's disease (AD) is an inflammatory neurodegenerative disease characterized by memory loss and cognitive impairment that worsens over time. AD is associated with many comorbidities, including cardiovascular disease that are associated with poorer outcomes. Comorbidities, especially heart disease and stroke, play a significant role in the demise of AD patients. Thus, it is important to understand how comorbidities are linked to AD. We have previously shown that extracellular vesicle (EV)-mediated inflammasome signaling plays an important role in the pathogenesis of brain injury and acute lung injury after traumatic brain injury. Methods: We analyzed the cortical, hippocampal, ventricular, and atrial protein lysates from APP/PS1 mice and their respective controls for inflammasome signaling activation. Additionally, we analyzed serum-derived EV for size, concentration, and content of inflammasome proteins as well as the EV marker CD63. Finally, we performed conditioned media experiments of EV from AD patients and healthy age-matched controls delivered to cardiovascular cells in culture to assess EV-induced inflammation. Results: We show a significant increase in Pyrin, NLRP1, caspase-1, and ASC in the brain cortex whereas caspase-8, ASC, and IL-1ß were significantly elevated in the heart ventricles of AD mice when compared to controls. We did not find significant differences in the size or concentration of EV between groups, but there was a significant increase of caspase-1 and IL-1ß in EV from AD mice compared to controls. In addition, conditioned media experiments of serum-derived EV from AD patients and age-matched controls delivered to cardiovascular cells in culture resulted in inflammasome activation, and significant increases in TNF-a and IL-2. Conclusion: These results indicate that EV-mediated inflammasome signaling in the heart may play a role in the development of cardiovascular diseases in AD patients. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) affects not only the brain but also peripheral organs like the heart and the lungs, which influences long-term outcomes. A heightened systemic inflammatory response is often induced after TBI, but the underlying pathomechanisms that contribute to co-morbidities remain poorly understood. Here, we investigated whether extracellular vehicles (EVs) containing inflammasome proteins are released after severe controlled cortical impact (CCI) in C57BL/6 mice and cause activation of inflammasomes in the heart that result in tissue damage. The atrium of injured mice at 3 days after TBI showed a significant increase in the levels of the inflammasome proteins AIM2, ASC, caspases-1, -8 and -11, whereas IL-1β was increased in the ventricles. Additionally, the injured cortex showed a significant increase in IL-1β, ASC, caspases-1, -8 and -11 and pyrin at 3 days after injury when compared to the sham. Serum-derived extracellular vesicles (EVs) from injured patients were characterized with nanoparticle tracking analysis and Ella Simple Plex and showed elevated levels of the inflammasome proteins caspase-1, ASC and IL-18. Mass spectrometry of serum-derived EVs from mice after TBI revealed a variety of complement- and cardiovascular-related signaling proteins. Moreover, adoptive transfer of serum-derived EVs from TBI patients resulted in inflammasome activation in cardiac cells in culture. Thus, TBI elicits inflammasome activation, primarily in the atrium, that is mediated, in part, by EVs that contain inflammasome- and complement-related signaling proteins that are released into serum and contribute to peripheral organ systemic inflammation, which increases inflammasome activation in the heart. [ABSTRACT FROM AUTHOR]

Traumatic Brain Injury (TBI) is a major cause of death and disability in the US and a recognized risk factor for the development of Alzheimer's disease (AD). The relationship between these conditions is not completely understood, but the conditions may share additive or synergistic pathological hallmarks that may serve as novel therapeutic targets. Heightened inflammasome signaling plays a critical role in the pathogenesis of central nervous system injury (CNS) and the release of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck from neurons and activated microglia contribute significantly to TBI and AD pathology. This study investigated whether inflammasome signaling after TBI was augmented in AD and whether this signaling pathway impacted biochemical and neuropathological outcomes and overall cognitive function. Five-month-old, 3xTg mice and respective wild type controls were randomized and underwent moderate controlled cortical impact (CCI) injury or served as sham/uninjured controls. Animals were sacrificed at 1 hour, 1 day, or 1 week after TBI to assess acute pathology or at 12 weeks after assessing cognitive function. The ipsilateral cerebral cortex was processed for inflammasome protein expression by immunoblotting. Mice were evaluated for behavior by open field (3 days), novel object recognition (2 weeks), and Morris water maze (6 weeks) testing after TBI. There was a statistically significant increase in the expression of inflammasome signaling proteins Caspase-1, Caspase-8, ASC, and interleukin (IL)-1β after TBI in both wild type and 3xTg animals. At 1-day post injury, significant increases in ASC and IL-1β protein expression were measured in AD TBI mice compared to WT TBI. Behavioral testing showed that injured AD mice had altered cognitive function when compared to injured WT mice. Elevated Aβ was seen in the ipsilateral cortex and hippocampus of sham and injured AD when compared to respective groups at 12 weeks post injury. Moreover, treatment of injured AD mice with IC100, an anti-ASC monoclonal antibody, inhibited the inflammasome, as evidenced by IL-1β reduction in the injured cortex at 1-week post injury. These findings show that the inflammasome response is heightened in mice genetically predisposed to AD and suggests that AD may exacerbate TBI pathology. Thus, dampening inflammasome signaling may offer a novel approach for the treatment of AD and TBI. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease that destroys memory and cognitive function. Inflammasome activation has been suggested to play a critical role in the neuroinflammatory response in AD progression, but the cell‐type expression of inflammasome proteins in the brain has not been fully characterized. In this study, we used samples from the hippocampus formation, the subiculum, and the entorhinal cortex brain from 17 donors with low‐level AD pathology and 17 intermediate AD donors to assess the expression of inflammasome proteins. We performed analysis of hippocampal thickness, β‐amyloid plaques, and hyperphosphorylated tau to ascertain the cellular pathological changes that occur between low and intermediate AD pathology. Next, we determined changes in the cells that express the inflammasome sensor proteins NOD‐like receptor proteins (NLRP) 1 and 3, and caspase‐1. In addition, we stained section with IC100, a humanized monoclonal antibody directed against the inflammasome adaptor protein apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), and a commercially available anti‐ASC antibody. Our results indicate that hippocampal cortical thickness did not significantly change between low and intermediate AD pathology, but there was an increase in pTau and β‐amyloid clusters in intermediate AD cases. NLRP3 was identified mainly in microglial populations, whereas NLRP1 was seen in neuronal cytoplasmic regions. There was a significant increase of ASC in neurons labeled by IC100, whereas microglia in the hippocampus and subiculum were labeled with the commercial anti‐ASC antibody. Caspase‐1 was present in the parenchyma in the CA regions where amyloid and pTau were identified. Together, our results indicate increased inflammasome protein expression in the early pathological stages of AD, that IC100 identifies neurons in early stages of AD and that ASC expression correlates with Aβ and pTau in postmortem AD brains. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder marked by the death of dopaminergic neurons in the midbrain, the accumulation of α-synuclein aggregates, and motor deficits. A major contributor to dopaminergic neuronal loss is neuroinflammation. The inflammasome is a multiprotein complex that perpetuates neuroinflammation in neurodegenerative disorders including PD. Increases in inflammasome proteins are associated with worsened pathology. Thus, the inhibition of inflammatory mediators has the potential to aid in PD treatment. Here, we investigated inflammasome signaling proteins as potential biomarkers of the inflammatory response in PD. Plasma from PD subjects and healthy age-matched controls were evaluated for levels of the inflammasome protein apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin (IL)-18. This was carried out using Simple Plex technology to identify changes in inflammasome proteins in the blood of PD subjects. The area under the curve (AUC) was obtained through calculation of the receiver operating characteristics (ROC) to obtain information on biomarker reliability and traits. Additionally, we completed a stepwise regression selected from the lowest Akaike information criterion (AIC) to assess how the inflammasome proteins caspase-1 and ASC contribute to IL-18 levels in people with PD. PD subjects demonstrated elevated caspase-1, ASC, and IL-18 levels when compared to controls; each of these proteins were found to be promising biomarkers of inflammation in PD. Furthermore, inflammasome proteins were determined to significantly contribute to and predict IL-18 levels in subjects with PD. Thus, we demonstrated that inflammasome proteins serve as reliable biomarkers of inflammation in PD and that inflammasome proteins provide significant contributions to IL-18 levels in PD. [ABSTRACT FROM AUTHOR]

Introduction: One of the main characteristics of COVID-19 is an exacerbated inflammatory response that results in cardiometabolic complications and dysfunction in the nervous system. Moreover, these complications may extend beyond the period of active SARS-CoV2 infection and even extend over a year. Thus, it is important to better understand the contribution of the inflammatory responses in COVID-19 patients, not just in the acute phase but also after the infection has subsided. Methods: We measured the protein levels of inflammasome signaling proteins using Simple Plex microfluidics technology in patients with an active SARS-CoV2 infection and in recovered patients to determine their potential use as biomarkers of COVID-19. We carried out statistical analyses to identify which proteins were increased in COVID-19 patients with active infection and in recovered patients. The receiver operating characteristics (ROC) were calculated for each analyte to determine their potential fit as biomarkers. Results: The inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-1b and IL-18 were elevated in the plasma of patients with active infection and remained elevated after the infection was resolved for approximately 2 months after. Levels of caspase-1 and ASC continued to increase long after patients had recovered from the infection. Furthermore, when measuring biomarkers of inflammation during active infection, analyses with area under the curve (AUC) values above 0.75 indicated that caspase-1, ASC, IL-1β and IL-18 are reliable biomarkers of the inflammatory response during active COVID-19 infection. Moreover, when measuring biomarkers of inflammation after recovery from active infection, caspase-1 and ASC presented AUC values above 0.9. Discussion: These findings indicate that inflammasome signaling proteins can be used to reliably monitor the inflammatory innate immune response in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases currently affect millions of people worldwide and continues to increase in the expanding elderly population. Neurodegenerative diseases usually involve cognitive decline and are among the top causes of death. Thus, there is a critical need for the development of treatments and preventive strategies for neurodegenerative diseases. One of the risk factors of neurodegeneration is inflammaging, a low level of chronic inflammation due to old age. We have previously shown that the inflammasome contributes to inflammaging in the central nervous system (CNS). The inflammasome is a multiprotein complex of the innate immune response consisting of a sensor protein, apoptosis speck-like protein containing a CARD (ASC), and caspase-1. Our lab has developed a humanized monoclonal antibody against ASC (anti-ASC). Here, we analyzed cortical lysates from young (3 months old), aged (18 months old), and aged anti-ASC treated mice for the expression of canonical and non-canonical inflammasome proteins. We show that the protein levels of NLRP1, ASC, caspase-1, and caspase-8 were elevated in the cortex of aged mice, and that anti-ASC decreased the expression of these proteins, consistent with lower levels of the pro-inflammatory cytokine interleukin (IL)-1β. Additionally, we show that these proteins form a novel NLRP1-caspase-8 non-canonical inflammasome comprised of NLRP1, caspase-8 and ASC. Moreover, these inflammasome proteins were present in neurons in young and aged mice. Together, these results indicate that a novel NLRP1-caspase-8 non-canonical inflammasome is present in the cortex of mice and that anti-ASC is a potential therapeutic to decrease inflammasome-mediated inflammaging in the CNS. [ABSTRACT FROM AUTHOR]

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1β and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1β in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Inflammasome activation in the innate immune response plays a role in the pathogenesis of psoriasis largely due to the increased levels of pro-inflammatory cytokines. However, the precise role of inflammasomes in psoriasis (Ps) and psoriatic arthritis (PsA) is largely undefined. To establish the reliability of inflammasome signaling proteins as diagnostics and predictive biomarkers of clinical severity in this disease population, serum from healthy donors and patients with Ps/PsA were analyzed for the protein expression of caspase-1, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), interleukin (IL)-1β and IL-18 levels to determine cut-off points, positive and negative predictive values, and receiver operator characteristic (ROC) curves. Our data revealed that ASC and IL-18 proteins were significantly higher in the Ps group when compared to healthy controls. The area under the curve (AUC) for ASC was 0.9224 with a cut-off point of 321.8 pg/ml, while IL-18 had an AUC of 0.7818 and a cut-off point of 232.1 pg/ml. In addition, levels of IL-18 had a statistically significant linear correlation with that of ASC with an adjusted R squared of 0.2566, indicating that approximately 25% of IL-18 levels could be explained by ASC levels in serum. Our findings indicate that ASC and IL-18 play a significant role in the inflammatory response associated with the pathology of Ps. These inflammasome proteins appear to be key biomarkers in determining diagnoses in this patient population. [ABSTRACT FROM AUTHOR]

Hyperoxia plays a key role in the development of bronchopulmonary dysplasia (BPD), a chronic lung disease of preterm infants. Infants with BPD often have brain injury that leads to long-term neurodevelopmental impairment, but the underlying mechanisms that control BPD-induced neurodevelopmental impairment remain unclear. Our previous studies have shown that hyperoxiainduced BPD in rodents is associated with lung inflammasome activation. Here, we tested the hypothesis that hyperoxia-induced lung and brain injury is mediated by inflammasome activation, and that inhibition of caspase-1, a key component of the inflammasome, attenuates hyperoxia-induced lung and brain injury in neonatal mice. C57/BL6 mouse pups were randomized to receive daily intraperitoneal injections of Ac-YVAD-CMK, an irreversible caspase-1 inhibitor, or placebo during exposure to room air or hyperoxia (85% O2) for 10 days. We found that hyperoxia activated the NLRP1 inflammasome, increased production of mature IL-1β, and upregulated expression of p30 gasdermin-D (GSDMD), the active form of GSDMD that is responsible for the programmed cell death mechanism of pyroptosis in both lung and brain tissue. Importantly, we show that inhibition of caspase-1 decreased IL-1β activation and p30 GSDMD expression, and improved alveolar and vascular development in hyperoxia-exposed lungs. Moreover, caspase-1 inhibition also promoted cell proliferation in the subgranular zone and subventricular zone of hyperoxia-exposed brains, resulting in lessened atrophy of these zones. Thus, the inflammasome plays a critical role in hyperoxia-induced neonatal lung and brain injury, and targeting this pathway may be beneficial for the prevention of lung and brain injury in preterm infants. [ABSTRACT FROM AUTHOR]

The inflammasome is a key contributor to the inflammatory innate immune response after stroke. We have previously shown that inflammasome proteins are released in extracellular vesicles (EV) after brain and spinal cord injury. In addition, we have shown that inflammasome proteins offer great promise as biomarkers of central nervous system (CNS) injury following brain trauma. In the present study, we used a Simple Plex Assay (Protein Simple), a novel multi-analyte automated microfluidic immunoassay platform, to analyze serum and serum-derived EV samples from stroke patients and control subjects for inflammasome protein levels of caspase-1, apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), Interleukins (IL)-1β, and (IL)-18. Receiver operator characteristic (ROC) curves with associated confidence intervals obtained from the analysis of serum samples revealed that the area under the curve (AUC) for ASC was 0.99 with a confidence interval between 0.9914 and 1.004, whereas the AUC for caspase-1, IL-1β, and IL-18 were 0.75, 0.61, and 0.67, respectively. Thus, these data indicate that ASC is a potential biomarker of stroke and highlight the role of the inflammasome in the inflammatory response after brain ischemia. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease that affects the brain and spinal cord. The inflammasome is a multiprotein complex that contributes to the innate immune response in animal models of MS as well as in patients with the disease. Important to the care of patients with MS is the need for biomarkers that can predict disease onset, disease exacerbation, as well as response to treatment. In this study, we analyzed serum samples from 32 patients with MS and 120 age-matched controls, and provide receiver operator characteristic (ROC) curves with associated confidence intervals following analyses of serum samples from patients with MS, most of which had the relapsing-remitting form of the disease, and from healthy unaffected donors, and determine the sensitivity and specificity of inflammasome proteins as biomarkers of MS. We report that caspase-1 (1.662 ± 0.6024 difference between means), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) (407.5 ± 35.79), and interleukin (IL)-18 (78.53 + 17.86) were elevated in the serum of MS patients when compared to controls. Interestingly, the levels of IL-1ß (-0.5961 ± 0.265) were lower in the MS cohort. Importantly, the area under the curve (AUC) for ASC and caspase-1 were 0.9448 and 0.848, respectively. Taken together, these data suggest that ASC and caspase-1 could be potential candidate biomarkers for MS onset. [ABSTRACT FROM AUTHOR]

The inflammatory response appears to play a critical role in clotting in which neutrophil extracellular traps (NETs) are the major drivers of thrombosis in acute ischemic stroke (AIS). The inflammasome is an innate immune complex involved in the activation of interleukin (IL)-18 and IL-1β through caspase-1, but whether the inflammasome plays a role in NETosis in AIS remains poorly understood. Here we assessed the levels of inflammasome signaling proteins in NETs and their association with clinical and procedural outcomes of mechanical thrombectomy for AIS. Electron microscopy and immunofluorescence indicate the presence of NETs in thrombi of patients with AIS. Moreover, the inflammasome signaling proteins caspase-1 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) were also present in clots associated with the marker of NETosis citrullinated histone 3H (CitH3). Analysis of protein levels by a simple plex assay show that caspase-1, ASC and interleukin (IL)-1β were significantly elevated in clots when compared to plasma of AIS patients and healthy controls, while IL-18 levels were lower. Moreover, multivariate analyses show that IL-1β levels in clots contribute to the number of passes to achieve complete recanalization, and that ASC, caspase-1 and IL-18 are significant contributors to time to recanalization. Thus, inflammasome proteins are elevated in NETs present in thrombi of patients with AIS that contribute to poor outcomes following stroke. [ABSTRACT FROM AUTHOR]

Approximately 30% of traumatic brain injured patients suffer from acute lung injury or acute respiratory distress syndrome. Our previous work revealed that extracellular vesicle (EV)-mediated inflammasome signaling plays a crucial role in the pathophysiology of traumatic brain injury (TBI)-induced lung injury. Here, serum-derived EVs from severe TBI patients were analyzed for particle size, concentration, origin, and levels of the inflammasome component, an apoptosis-associated speck-like protein containing a caspase-recruiting domain (ASC). Serum ASC levels were analyzed from EV obtained from patients that presented lung injury after TBI and compared them to EV obtained from patients that did not show any signs of lung injury. EVs were co-cultured with lung human microvascular endothelial cells (HMVEC-L) to evaluate inflammasome activation and endothelial cell pyroptosis. TBI patients had a significant increase in the number of serum-derived EVs and levels of ASC. Severe TBI patients with lung injury had a significantly higher level of ASC in serum and serum-derived EVs compared to individuals without lung injury. Only EVs isolated from head trauma patients with gunshot wounds were of neural origin. Delivery of serum-derived EVs to HMVEC-L activated the inflammasome and resulted in endothelial cell pyroptosis. Thus, serum-derived EVs and inflammasome proteins play a critical role in the pathogenesis of TBI-induced lung injury, supporting activation of an EV-mediated neural-respiratory inflammasome axis in TBI-induced lung injury. [ABSTRACT FROM AUTHOR]

Invasive neuroprosthetics rely on microelectrodes (MEs) to record or stimulate the activity of large neuron assemblies. However, MEs are subjected to tissue reactivity in the central nervous system (CNS) due to the foreign body response (FBR) that contribute to chronic neuroinflammation and ultimately result in ME failure. An endogenous, acute set of mechanisms responsible for the recognition and targeting of foreign objects, called the innate immune response, immediately follows the ME implant-induced trauma. Inflammasomes are multiprotein structures that play a critical role in the initiation of an innate immune response following CNS injuries. The activation of inflammasomes facilitates a range of innate immune response cascades and results in neuroinflammation and programmed cell death. Despite our current understanding of inflammasomes, their roles in the context of neural device implantation remain unknown. In this study, we implanted a non-functional Utah electrode array (UEA) into the rat somatosensory cortex and studied the inflammasome signaling and the corresponding downstream effects on inflammatory cytokine expression and the inflammasome-mediated cell death mechanism of pyroptosis. Our results not only demonstrate the continuous activation of inflammasomes and their contribution to neuroinflammation at the electrode-tissue interface but also reveal the therapeutic potential of targeting inflammasomes to attenuate the FBR in invasive neuroprosthetics. [ABSTRACT FROM AUTHOR]

Chronic corneal endothelial cell (CEC) loss results in corneal edema and vision loss in conditions such as pseudophakic bullous keratopathy (PBK), Fuchs' dystrophy, and corneal graft failure. Low CEC density has been associated with an elevation of intraocular pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interferon (INF)-γ. These cytokines are capable of triggering pyroptosis, a programmed cell death mechanism mediated by the inflammasome, prompting the activation of the pro-inflammatory cytokine interleukin (IL)-1β, the perpetuation of inflammation, and subsequent damage of corneal endothelial tissue. Therefore, the purpose of this study was to determine the deleterious contribution of the inflammasome and pyroptosis to CEC loss. CECs from human donor corneas were treated e x vivo with TNF-α and IFN-γ for 48 h. Levels of caspase-1 and IL-1β were then assayed by ELISA, and the expression of caspase-1 and gasdermin-D (GSDM-D) were confirmed by immunofluorescence. Endothelial cell damage was analyzed by a lactate dehydrogenase (LDH) release assay, and oxidative stress was determined by measuring the levels of reactive oxygen species (ROS) in the culture media. Inflammasome activation and oxidative stress were elevated in CECs following exposure to TNF-α and IFN-γ, which resulted in cell death by pyroptosis as determined by LDH release which was inhibited by the caspase-1 inhibitor Ac-YVAD-cmk. CEC death is induced by the pro-inflammatory cytokines TNF-α and IFN-γ, which contribute to inflammasome activation. Moreover, the inflammasome is a promising therapeutic target for the treatment of chronic CEC loss. • TNF-α and IFN-γ exacerbates inflammasome activation in corneal endothelial cells. • TNF-α and IFN-γ upregulates caspase-1 and GSDM-D in corneal endothelial cells. • Inflammation-mediated endothelial cell death is regulated by the inflammasome. • Inflammasome activation was in part the result of ROS formation. • Corneal endothelial pyroptosis is modulated by caspase-1 inhibition. [ABSTRACT FROM AUTHOR]

Objective: To study the mechanism leading to elevated semen cytokines in men with spinal cord injury (SCI) and to understand if inflammasome pathways are involved in this process. To investigate inflammasome components and end-product cytokines in semen of SCI and control subjects. Design: Prospective study. Setting: Major university medical center. Patient(s): Men with and without SCI (n = 28 per group). Intervention(s): None. Main Outcome Measure(s): Seminal plasma concentrations of caspase-1, interleukin (IL) 1β, and IL-18 were quantified by ELISA. Caspase-1 in sperm fractions and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) in seminal plasma and sperm fractions were identified by Western blot. Localization of proteins in sperm was accomplished by immunocytochemistry. Result(s): ASC, caspase-1, IL-1β, and IL-18 concentrations were elevated in the seminal plasma of SCI subjects compared with control subjects. ASC and caspase-1 were elevated in sperm cells of SCI subjects. Immunocytochemistry revealed that ASC was located in the acrosome, equatorial segment, and midpiece, and caspase-1 in the midpiece. Conclusion(s): This study provides the first evidence of ASC in human semen and demonstrates the involvement of inflammasome proteins in semen of men with SCI. These findings suggest an immunologic basis for abnormal semen quality in men with SCI. [ABSTRACT FROM AUTHOR]