Lysophosphatidic acid receptor 1 (LPA1) plays critical roles in microglial activation and brain damage after transient focal cerebral ischemia

Abstract

Background Lysophosphatidic acid receptor 1 (LPA 1 ) is in the spotlight because its synthetic antagonist has been under clinical trials for lung fibrosis and psoriasis. Targeting LPA 1 might also be a therapeutic strategy for cerebral ischemia because LPA 1 triggers microglial activation, a core pathogenesis in cerebral ischemia. Here, we addressed this possibility using a mouse model of transient middle cerebral artery occlusion (tMCAO). Methods To address the role of LPA 1 in the ischemic brain damage, we used AM095, a selective LPA 1 antagonist, as a pharmacological tool and lentivirus bearing a specific LPA 1 shRNA as a genetic tool. Brain injury after tMCAO challenge was accessed by determining brain infarction and neurological deficit score. Role of LPA 1 in tMCAO-induced microglial activation was ascertained by immunohistochemical analysis. Proinflammatory responses in the ischemic brain were determined by qRT-PCR and immunohistochemical analyses, which were validated in vitro using mouse primary microglia. Activation of MAPKs and PI3K/Akt was determined by Western blot analysis. Results AM095 administration immediately after reperfusion attenuated brain damage such as brain infarction and neurological deficit at 1 day after tMCAO, which was reaffirmed by LPA 1 shRNA lentivirus. AM095 administration also attenuated brain infarction and neurological deficit at 3 days after tMCAO. LPA 1 antagonism attenuated microglial activation; it reduced numbers and soma size of activated microglia, reversed their morphology into less toxic one, and reduced microglial proliferation. Additionally, LPA 1 antagonism reduced mRNA expression levels of proinflammatory cytokines and suppressed NF-κB activation, demonstrating its regulatory role of proinflammatory responses in the ischemic brain. Particularly, these LPA 1 -driven proinflammatory responses appeared to occur in activated microglia because NF-κB activation occurred mainly in activated microglia in the ischemic brain. Regulatory role of LPA 1 in proinflammatory responses of microglia was further supported by in vitro findings using lipopolysaccharide-stimulated cultured microglia, showing that suppressing LPA 1 activity reduced mRNA expression levels of proinflammatory cytokines. In the ischemic brain, LPA 1 influenced PI3K/Akt and MAPKs; suppressing LPA 1 activity decreased MAPK activation and increased Akt phosphorylation. Conclusion This study demonstrates that LPA 1 is a new etiological factor for cerebral ischemia, strongly indicatin...

Inhibition of lysophosphatidic acid receptor 1-3 deteriorates experimental autoimmune encephalomyelitis by inducing oxidative stress

“…It also reduced microglial proliferation, in correspondence with reduced mRNA expression levels of proin ammatory cytokines and suppressed NF-κB activation in the ischemic brain. Particularly, these LPAR1-drived proin ammatory responses have appeared in activated microglia because NF-κB activation occurs mainly in activated microglia (45).…”

BMS-986020, a Specific LPA1 Antagonist, Provides Neuroprotection against Ischemic Stroke in Mice

“…To determine effects of BMS administration on neurogenesis and angiogenesis, BrdU/DCX-and BrdU/CD31-double immunofluorescence assays were performed as described previously [12,29]. In brief, BrdU (50 mg/kg in PBS, i.p., Sigma-Aldrich, St. Louis, MO, USA) was administered to mice at 13 and 14 days after tMCAO challenge for four times at 12 h interval.…”

“…It is also under another phase I clinical trial for psoriasis (ClinicalTrials.gov Identifier: NCT02763969). Considering the role of LPA 1 in diverse experimental models, BMS might also be an effective therapeutic to treat other types of LPA 1 -associated diseases including cancer, lung injury, systemic sclerosis, neuropathic pain, spinal cord injury, hydrocephalus, hypoxia, neuropsychiatric disorders, and traumatic brain injury [12][13][14][15][16][17][18]. Besides these disease types, ischemic stroke could also be a promising target disease for therapeutic application of BMS.…”

“…For stroke survivors, long-term functional disability after the stroke has been a major problem [21,22]. LPA 1 can contribute to acute brain injuries in mice challenged with ischemic stroke by regulating neuroinflammatory responses, such as activation of microglia and upregulation of pro-inflammatory cytokines in post-ischemic brains [12]. LPA 1 can also contribute to neuropathic pain in mice after ischemic challenge [18,23].…”

Inhibition of LPA5 Activity Provides Long-Term Neuroprotection in Mice with Brain Ischemic Stroke

“…Lysophosphatidic acid (LPA) affects six G protein-coupled receptors (LPA 1 -LPA 6 ) and influences various biological functions ( Choi and Chun, 2013 ). Among these receptors, LPA 1 ( Gaire et al ., 2019 ) and LPA 5 ( Sapkota et al ., 2020 ) have been identified as pathogenic factors in acute ischemic injury. In particular, the latter is upregulated in injured brain after acute ischemic stroke and suppressing its activity can successfully attenuate acute brain injuries (i.e., brain injuries at 1 or 3 days after ischemic challenge) by reducing inflammatory responses in the injured brain ( Sapkota et al ., 2020 ).…”