Abstract
BackgroundMembers of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family of proteins are key modulators of innate immunity regulating inflammation. Our previous work has shown that among the members of this family, NLRP1/NALP1, present in neurons, plays a crucial role in inflammasome formation and the production of the inflammatory cytokines interleukin (IL) -1β and IL-18 after various types of central nervous system injury.ResultsWe investigated whether age-related cognitive decline may involve a heightened inflammatory response associated with activation of the NLRP1 inflammasome in the hippocampus. Young (3 months) and aged (18 months) male Fischer 344 rats were tested in a spatial acquisition task via Morris water maze. Following behavioral testing, hippocampal lysates were assayed for expression of NLRP1 inflammasome components and inflammatory cytokines. Hippocampal lysates from aged rats showed significantly higher levels of NLRP1 inflammasome constituents, caspase-1, caspase-11, the purinergic receptor P2X7, pannexin-1 and X-linked inhibitor of apoptosis (XIAP) than lysates from younger animals. Following treatment with probenecid, an inhibitor or pannexin-1, aged animals demonstrated reduction in inflammasome activation and improvement in spatial learning performance.ConclusionsOur behavioral findings are consistent with increases in IL-1β and IL-18 that have been previously shown to correlate with spatial learning deficits. Probenecid reduced activated caspase-1 and ameliorated spatial learning deficits in aged rats. Thus, aging processes stimulate activation of the NLRP1 inflammasome and secretion of IL-1β and IL-18 that may contribute to age-related cognitive decline in the growing elderly population. Moreover, probenecid may be potentially useful as a therapy to improve cognitive outcomes in the aging population.
Highlights
Members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family of proteins are key modulators of innate immunity regulating inflammation
Our recent work has shown that the Nucleotide-binding domain (NLRP1) inflammasome in neurons plays a crucial role in the innate central nervous system (CNS) immune response induced by injury [3,4,5,6], but whether the NLRP1 inflammasome contributes to inflammatory cytokine production and cognitive impairment due to aging remains largely undefined
Aging increases hippocampal expression of NLRP1 inflammasome components in the hippocampus The NLRP1 inflammasome in neurons constitutes a multiprotein complex consisting of caspase-1, caspase11, apoptosis-associated-speck-like protein containing a caspase recruitment domain (ASC), NLRP1, P2X7, pannexin-1 and X-linked inhibitor of apoptosis (XIAP) [4]
Summary
Members of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family of proteins are key modulators of innate immunity regulating inflammation. Our previous work has shown that among the members of this family, NLRP1/NALP1, present in neurons, plays a crucial role in inflammasome formation and the production of the inflammatory cytokines interleukin (IL) -1b and IL-18 after various types of central nervous system injury. A number of host-derived molecules that alert the innate immune system to cell injury and tissue damage activate the inflammasome [1] These molecules called “dangerassociated molecular patterns” include ATP [2] and high extracellular potassium [3]. Our recent work has shown that the NLRP1 inflammasome in neurons plays a crucial role in the innate CNS immune response induced by injury [3,4,5,6], but whether the NLRP1 inflammasome contributes to inflammatory cytokine production and cognitive impairment due to aging remains largely undefined
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