Upregulation of IL-1 Receptor Antagonist by Aspirin in Glial Cells via Peroxisome Proliferator-Activated Receptor-Alpha1

Abstract

Background: Neuroinflammation is a recognized aspect of Alzheimer’s disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood. Objective: Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain. Methods: We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of AD, were treated with aspirin orally via gavage. Results: Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARβ –/–), but not PPARα –/–, mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARβ –/–, but not in PPARα –/– mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα –/– mice. Conclusion: Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation.

Regression of Lung Cancer in Mice by Intranasal Administration of SARS-CoV-2 Spike S1

“…Western Blotting was conducted as described before [ 23 , 24 ]. Briefly, cells were harvested and lysed with lysis buffer containing 150 mM NaCl, 50 mM Tris (pH 8.0), 1% Triton-X, 0.1% SDS, 0.5% Na-Deoxycholate, and protease and phosphatase inhibitor cocktail to extract the total protein.…”

Interleukin 1 receptor antagonist and neurodegenerative diseases: the future treatment strategy

“…The IL-1 family holds an additional member termed IL-1 receptor antagonist (IL-1Ra) which is encoded by the IL1RN gene. It serves as the single example of a naturally occurring antagonist molecule that competes with both IL-1α and IL-1β, thus decreasing inflammatory signalling and inhibiting them from further prompting the expression of other pro-inflammatory molecules (Chakrabarti et al, 2021;Sims et al, 1988). Based on the ability of IL-1Ra to inhibit neuronal loss could be an invaluable effective therapeutic agent for neurodegenerative diseases.…”

“…The utmost powerful and selective inhibitor of IL-1 actions is its antagonist, IL-1Ra. This antagonist is known to compete with both IL-1α and IL-1β, thereby decreasing inflammatory signalling transduction and inhibiting them from prompting pro-inflammatory molecules expression (Chakrabarti et al, 2021). Moreover, it was IL-1Ra that first demonstrated clear resistance towards neuronal injury, which typically occurs due to cerebral ischaemia, provoked by cerebral occlusion, and against damage caused in rodents by intracerebral administration of excitotoxins like N-methyl-Daspartate (NMDA) (Relton & Rothwell, 1992).…”

Amelioration of experimental autoimmune encephalomyelitis by gemfibrozil in mice via PPARβ/δ: implications for multiple sclerosis

“…It has been shown that gemfibrozil is capable of suppressing the expression of different proinflammatory molecules in astrocytes and microglia ( Pahan et al, 2002 ; Xu et al, 2005 ; Jana et al, 2007 ; Jana and Pahan, 2012 ). Usually, proinflammatory signaling pathways are kept in check by different anti-inflammatory molecules like SOCS3 and IL-1Ra in many cell types including brain cells ( Gabay et al, 2010 ; Ghosh et al, 2017 ; Chakrabarti et al, 2021 ). It has been reported that low-dose gemfibrozil treatment can upregulate the level of both SOCS3 ( Ghosh and Pahan, 2012 ) and IL-1Ra ( Corbett et al, 2012 ) in brain cells.…”