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Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity

ABSTRACT: The peritoneal cavity (PerC) is an important site for immune responses to infection and cancer metastasis. Yet few ligand-receptor axes are known to preferentially govern immune cell accumulation in this compartment. GPR34 is a lysophosphatidylserine (lysoPS)-responsive receptor that frequently harbors gain-of-function mutations in mucosa-associated B cell lymphoma. Here, we set out to test the impact of a GPR34 knock-in (KI) allele in the B-lineage. We report that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB). These KI cells migrate robustly to lysoPS ex vivo, and the KI allele synergizes with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies reveal that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB are specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the lysoPS-generating PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A. These findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum.

ORGANISM(S): Mus musculus

PROVIDER: GSE274652 | GEO | 2024/10/03

REPOSITORIES: GEO

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Project description:Hereditary elliptocytosis is a red blood cell (RBC) disease mainly caused by mutations in spectrin, leading to cytoskeletal destabilization. Although patients with heterozygous mutation in α-spectrin (SPTA1) are asymptomatic, morphological changes and hemolysis are observed upon reduced functional α-spectrin production. The molecular mechanism is unknown. We analyzed the consequences of a α-spectrin mutation in a patient almost exclusively expressing the Pro260 variant of SPTA1 (pEl). pEl RBCs showed decreased size and circularity and increased fragility. The pEl RBC proteome was globally preserved but spectrin density at the cell edges rised and the two membrane anchorage complexes were less segregated. Hence, the pEl membrane was strongly impaired. First, the lipidome was modified, showing decreased phosphatidylserine vs increased lysophosphatidylserine species. Second, although membrane transversal asymmetry was preserved, curvature at the RBC edges and rigidity were increased. Third, sphingomyelin-enriched domains were altered in abundance, membrane:cytoskeleton anchorage and cholesterol content were targeted by the plasmatic acid sphingomyelinase (aSMase). Fourth, membrane calcium exchanges through the mechanosensitive channel PIEZO1 and the efflux pump PMCA were impaired, leading to increased intracellular calcium and ROS, lipid peroxidation and methemoglobin. Mecanistically, increased curvature through lysophosphatidylserine membrane insertion in healthy RBCs abrogated calcium influx. Cholesterol depletion of sphingomyelin-enriched domains by methyl-beta-cyclodextrin in pEl RBCs worsened calcium accumulation whereas aSMase inhibition by amitriptyline did the opposite. Those data indicated that α-spectrin tetramerization defect, lysophosphatidylserine, cholesterol domain depletion and aSMase cooperate to alter membrane properties and calcium exchanges, leading to calcium accumulation and oxidative stress. It could help develop novel therapies

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Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity

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