AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 13; pp. 4050 - 4055
• Main Authors: Denes, Adam, Coutts, Graham, Lénárt, Nikolett, Cruickshank, Sheena M., Pelegrin, Pablo, Skinner, Joanne, Rothwell, Nancy, Allan, Stuart M., Brough, David
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 31.03.2015; National Acad Sciences
• Subjects: Animals; Apoptosis Regulatory Proteins - metabolism; Biological Sciences; brain; Brain - metabolism; Brain - pathology; Brain Injuries - metabolism; Brain Ischemia - pathology; Calcium-Binding Proteins - metabolism; CARD Signaling Adaptor Proteins; Carrier Proteins - metabolism; Cell Death; Cytokines; Cytokines - metabolism; dementia; DNA-Binding Proteins - metabolism; Gene Expression Regulation; hypoxia; Hypoxia - pathology; Infarction, Middle Cerebral Artery - pathology; inflammation; Inflammation - pathology; interleukin-1; Ischemia; Ischemia - pathology; Male; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Fluorescence; NLR Family, Pyrin Domain-Containing 3 Protein; people; Protein Structure, Tertiary; Stroke; Traumatic brain injury; brain injury; cell death; inflammation; cerebral ischemia; inflammasome
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1419090112

Significance Cerebral ischemia (CI; stroke, brain injury, vascular dementia, neonatal hypoxia, and many other conditions) affects people at all stages of life. Of the many diseases associated with CI, stroke alone causes up to 10% of deaths worldwide and is a leading cause of disability; yet treatment options are extremely limited, so this represents an area of massive unmet clinical need. Inflammation involving the cytokine interleukin-1 is a major contributor to cell death in the ischemic brain. Inflammation can be regulated by large protein complexes called inflammasomes. Here we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes, but not the NLRP3 (NLR family, pyrin domain containing 3) inflammasome, contribute to inflammation and injury in an ischemic brain and are thus potential therapeutic targets for these devastating diseases. Inflammation that contributes to acute cerebrovascular disease is driven by the proinflammatory cytokine interleukin-1 and is known to exacerbate resulting injury. The activity of interleukin-1 is regulated by multimolecular protein complexes called inflammasomes. There are multiple potential inflammasomes activated in diverse diseases, yet the nature of the inflammasomes involved in brain injury is currently unknown. Here, using a rodent model of stroke, we show that the NLRC4 (NLR family, CARD domain containing 4) and AIM2 (absent in melanoma 2) inflammasomes contribute to brain injury. We also show that acute ischemic brain injury is regulated by mechanisms that require ASC (apoptosis-associated speck-like protein containing a CARD), a common adaptor protein for several inflammasomes, and that the NLRP3 (NLR family, pyrin domain containing 3) inflammasome is not involved in this process. These discoveries identify the NLRC4 and AIM2 inflammasomes as potential therapeutic targets for stroke and provide new insights into how the inflammatory response is regulated after an acute injury to the brain.