NLRP3 Deficiency Ameliorates Neurovascular Damage in Experimental Ischemic Stroke

Abstract

Although the innate immune response to induce postischemic inflammation is considered as an essential step in the progression of cerebral ischemia injury, the role of innate immunity mediator NLRP3 in the pathogenesis of ischemic stroke is unknown. In this study, focal ischemia was induced by middle cerebral artery occlusion in NLRP3(-/-), NOX2(-/-), or wild-type (WT) mice. By magnetic resonance imaging (MRI), Evans blue permeability, and electron microscopic analyses, we found that NLRP3 deficiency ameliorated cerebral injury in mice after ischemic stroke by reducing infarcts and blood-brain barrier (BBB) damage. We further showed that the contribution of NLRP3 to neurovascular damage was associated with an autocrine/paracrine pattern of NLRP3-mediated interleukin-1β (IL-1β) release as evidenced by increased brain microvessel endothelial cell permeability and microglia-mediated neurotoxicity. Finally, we found that NOX2 deficiency improved outcomes after ischemic stroke by mediating NLRP3 signaling. This study for the first time shows the contribution of NLRP3 to neurovascular damage and provides direct evidence that NLRP3 as an important target molecule links NOX2-mediated oxidative stress to neurovascular damage in ischemic stroke. Pharmacological targeting of NLRP3-mediated inflammatory response at multiple levels may help design a new approach to develop therapeutic strategies for prevention of deterioration of cerebral function and for the treatment of stroke.

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

“…In the introduction we describe studies suggesting that NLRP3 inflammasomes contribute to ischemic brain injury (8,9), but that also NLRP1 inflammasomes are implicated in several models of brain injury (6,10,11), as are AIM2 inflammasomes (12). Here, using mice deficient in specific inflammasome components, we have shown that ischemic brain injury is profoundly influenced by multiple inflammasomes and, importantly, here was independent of the canonical sensor of sterile inflammation, the NLRP3 inflammasome.…”

“…Of these inflammasomes identified to date, the best characterized, and most strongly associated with sterile inflammation, is formed by NLRP3 (7). Indeed, there are now several studies suggesting that NLRP3 inflammasomes contribute to ischemic brain injury (8,9). However, the picture is more complicated.…”

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

“…1 Caspase-1 activation and interleukin-1 (IL-1) release have a central role in many disorders with an inflammatory component, 2 which comprises different diseases of the central nervous system (CNS) such as multiple sclerosis, Alzheimer disease, meningitis, or stroke. [3][4][5][6][7][8] The potential molecular signals, which activate the inflammasomes in the CNS, have already been delineated in detail before. 8,9 Thus, this overview aims at a more global, system biologic view of the potential role of the inflammasomes in CNS diseases and accounts for recent discoveries in related research fields.…”

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

“…During ischemic brain injury, a variety of processes such as ROS production, acidosis, K + efflux, etc., mediate the activation of the NLRP3 inflammasome and such altered physiological conditions also trigger the NLRP1 inflammasome (reviewed in [78]). NLRP3 was shown to mediate ischemic brain injury in a mouse model [79], which was later not confirmed [80]. Mice deficient in AIM2, NLRC4, or ASC had decreased infarct size and improved neurological scores and reduced activation of microglia and leukocyte recruitment, while the outcome of NLRP3 deficient mice was comparable to wild-type controls [80] in experimentally induced brain ischemia.…”