Contribution of the inflammasome to inflammaging

Abstract

BackgroundInflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer’s disease and Parkinson’s disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins.ResultsOur findings indicate that the inflammasome proteins NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are elevated in the cytosol of cortical lysates in aged mice when compared to young. In addition, in the cytosolic fraction of hippocampal lysates in aged mice, we found an increase in NLRC4, caspase-1, caspase-11, ASC and IL-1β. Moreover, we found higher levels of ASC in the mitochondrial fraction of aged mice when compared to young, consistent with higher levels of the substrate of pyroptosis gasdermin-D (GSDM-D) and increased pyroptosome formation (ASC oligomerization). Importantly, in this study we obtained fibroblasts from a subject that donated his cells at three different ages (49, 52 and 64 years old (y/o)) and found that the protein levels of caspase-1 and ASC were higher at 64 than at 52 y/o. In addition, the 52 y/o cells were more susceptible to oxidative stress as determined by lactose dehydrogenase (LDH) release levels. However, this response was ameliorated by inhibition of the inflammasome with Ac-Tyr-Val-Ala-Asp-Chloromethylketone (Ac-YVAD-CMK). In addition, we found that the protein levels of ASC and IL-18 are elevated in the serum of subjects over the age of 45 y/o when compared to younger subjects, and that ASC was higher in Caucasians than Blacks and Hispanics, whereas IL-18 was higher in Caucasians than in blacks, regardless of age.ConclusionsTaken together, our data indicate that the inflammasome contributes to inflammaging and that the inflammasome-mediated cell death mechanism of pyroptosis contributes to cell demise in the aging brain.

Ic100: A Novel Anti-ASC Monoclonal Antibody Improves Functional Outcomes In An Animal Model Of Multiple Sclerosis

“…IC100 was quantified in brain, spinal cord, liver and spleen at 35 days post-induction (dpi) of EAE using a proprietary assay developed by InflamaCORE, LLC using Meso Scale Technology. Protein lysates were obtained as described in [29]. The assay was read using the QuickPlex SQ 120 instrument (Meso Scale Diagnostics, Maryland).…”

NLRP inflammasomes and induced skin inflammation, barrier recovery and extended skin hydration

“…Treatment of activated NHEKS with botanically‐derived blends of known anti‐inflammatory or antioxidant ingredients could potentially inhibit the expression of active Caspase‐1, thereby potentially retarding the inflammaging process as described by Mejias . Using 60 mJ cm −2 of UVB radiation and 5 mM ATP as the activators for active Caspase‐1 release in NHEKs, various extracellular treatments using naturally derived botanical blends were examined to see whether the ingredients could inhibit the expression of active Caspase‐1.…”

“…Essentially, it is suggested that, while it is essential for the body to respond to exogenous threats with inflammation, continuous or repeated upregulation of the inflammation response leads to accelerated ageing, including ageing of the skin. In the work reported by Mejias et al, they were able to examine fibroblasts isolated from the same individual at ages 49, 52 and 64 years. The studies demonstrated that: (i) ageing cells accumulate markers of inflammasome activation including ACS protein and active Caspase‐1 and (ii) that reduction of these markers via treatments with a known Caspase‐1 inhibitor, Ac‐YVAD‐CMK, after oxidative stress demonstrated that ‘inhibition of the inflammasome in the ageing process has the potential to treat the cellular damage associated with oxidative stress.’ This study directly links the skin’s ageing processes with inflammasome activation in human fibroblasts.…”

Update of inflammasome activation in microglia/macrophage in aging and aging‐related disease

“…Inflammasome, the efficient inflammation amplifier, was inclined to get activated in aged microglia/macrophage. Multiple components of inflammasome, including NLRC4, Caspse‐1, Caspase‐11, ASC, and IL‐1β, were found to be increased in hippocampus of aged mice . In particular, expression of NLRP3, the most studied sensor of inflammasome, was increased in senile microglia compared with their young counterparts .…”

“…Multiple components of inflammasome, including NLRC4, Caspse-1, Caspase-11, ASC, and IL-1β, were found to be increased in hippocampus of aged mice. 26 In particular, expression of NLRP3, the most studied sensor of inflammasome, was increased in senile microglia compared with their young counterparts. 27 Correspondingly, spontaneous activation of Caspase-1 was detected in aged brain.…”