NLRP3 Inflammasome Activation Is Involved in LPA1-Mediated Brain Injury after Transient Focal Cerebral Ischemia.

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.

• Authors: Chi-Ho Lee, Arjun Sapkota, Bhakta Prasad Gaire, Ji Woong Choi
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 22 (Nov 14 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33202644 (Publication Type: Journal Article)

Chemical References

• IL1B protein, mouse
• Interleukin-1beta
• Lysophospholipids
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Receptors, Lysophosphatidic Acid
• lysophosphatidic acid receptor 1, mouse
• Extracellular Signal-Regulated MAP Kinases
• Casp1 protein, mouse
• Caspase 1
• lysophosphatidic acid

Topics

• Animals
• Brain Injuries (etiology, metabolism, pathology)
• Caspase 1 (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Interleukin-1beta (metabolism)
• Ischemic Attack, Transient (complications, metabolism, pathology)
• Lysophospholipids (metabolism)
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Inbred ICR
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Receptors, Lysophosphatidic Acid (metabolism)