Abstract
Lysophosphatidic acid receptor 1 (LPA1) contributes to brain injury following transient focal cerebral ischemia. However, the mechanism remains unclear. Here, we investigated whether nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation might be an underlying mechanism involved in the pathogenesis of brain injury associated with LPA1 following ischemic challenge with transient middle cerebral artery occlusion (tMCAO). Suppressing LPA1 activity by its antagonist attenuated NLRP3 upregulation in the penumbra and ischemic core regions, particularly in ionized calcium-binding adapter molecule 1 (Iba1)-expressing cells like macrophages of mouse after tMCAO challenge. It also suppressed NLRP3 inflammasome activation, such as caspase-1 activation, interleukin 1β (IL-1β) maturation, and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) speck formation, in a post-ischemic brain. The role of LPA1 in NLRP3 inflammasome activation was confirmed in vitro using lipopolysaccharide-primed bone marrow-derived macrophages, followed by LPA exposure. Suppressing LPA1 activity by either pharmacological antagonism or genetic knockdown attenuated NLRP3 upregulation, caspase-1 activation, IL-1β maturation, and IL-1β secretion in these cells. Furthermore, nuclear factor-κB (NF-κB), extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 were found to be LPA1-dependent effector pathways in these cells. Collectively, results of the current study first demonstrate that LPA1 could contribute to ischemic brain injury by activating NLRP3 inflammasome with underlying effector mechanisms.
Highlights
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that possesses diverse physiological and pathological functions throughout the body by activating its specific six G protein-coupled receptors (LPA1–6) [1,2]
In case of cerebral ischemia that occurs by a sudden blockade of blood supply in the brain and causes severe brain damage, Lysophosphatidic acid receptor 1 (LPA1) has been identified as a pathogenic factor for brain injury after ischemic challenge
We further determined whether LPA1 could influence protein expression levels of NLRP3 in an injured brain after transient middle cerebral artery occlusion (tMCAO) challenge by immunohistochemical analysis
Summary
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that possesses diverse physiological and pathological functions throughout the body by activating its specific six G protein-coupled receptors (LPA1–6) [1,2]. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is a sensor for various pathogen- and host-derived factors [7] Upon activation, it forms a complex called NLRP3 inflammasome, leading to the production of proinflammatory cytokines, interleukin 1β (IL-1β) and IL-18 [8,9]. Considering increased amounts of LPA in human ischemic patients [19] and animal models of cerebral ischemia [5,20], LPA signaling may regulate NLRP3 inflammasome activation in injured brain following ischemic challenge. LPA1 may be responsible for NLRP3 inflammasome activation To test such possible role of LPA1, the current study determined whether suppressing LPA1 activity by its specific antagonist could ameliorate NLRP3 upregulation in an injured brain of mouse with tMCAO challenge through biochemical and immunohistochemical analyses. We determined which LPA1-dependent pathways were involved in NLRP3 inflammasome activation
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