The interaction of secreted phospholipase A2-IIA with the microbiota alters its lipidome and promotes inflammation

  • JCI Insight. 2022 Jan 25;7(2):e152638. doi: 10.1172/jci.insight.152638.
Etienne Doré  1  2 ,  Charles Joly-Beauparlant  3 ,  Satoshi Morozumi  4  5 ,  Alban Mathieu  3 ,  Tania Lévesque  1  2 ,  Isabelle Allaeys  1  2 ,  Anne-Claire Duchez  1 ,  Nathalie Cloutier  1 ,  Mickaël Leclercq  3 ,  Antoine Bodein  3 ,  Christine Payré  6 ,  Cyril Martin  7 ,  Agnes Petit-Paitel  6 ,  Michael H Gelb  8 ,  Manu Rangachari  9 ,  Makoto Murakami  10 ,  Laetitia Davidovic  6 ,  Nicolas Flamand  2  7 ,  Makoto Arita  4  5  11 ,  Gérard Lambeau  6 ,  Arnaud Droit  3 ,  Eric Boilard  1  2
Affiliations
  • 1. CHU de Québec-Université Laval Research Center, Department of Microbiology, Infectiology and Immunology, Quebec City, Quebec, Canada.
  • 2. ARThrite Research Center, University Laval, Quebec City, Quebec, Canada.
  • 3. CHU de Québec-Université Laval Research Center, Endocrinology and Nephrology Axis, Quebec City, Quebec, Canada.
  • 4. Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
  • 5. Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, Japan.
  • 6. Côte d'Azur University, The French National Centre for Scientific Research, Institute of Molecular and Cellular Pharmacology, UMR7275, Valbonne Sophia Antipolis, France.
  • 7. The Research Center of the University Institute of Cardiology and Pneumology of Quebec, Quebec City, Quebec, Canada.
  • 8. Department of Chemistry, University of Washington, Seattle, Washington, USA.
  • 9. CHU de Québec-Université Laval Research Center, Neurosciences Axis, Quebec City, Quebec, Canada.
  • 10. Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
  • 11. Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama-City University, Yokohama, Japan.
PMID: 35076027 DOI: 10.1172/jci.insight.152638
Abstract

Secreted Phospholipase A2-IIA (sPLA2-IIA) hydrolyzes Phospholipids to liberate lysophospholipids and Fatty Acids. Given its poor activity toward eukaryotic cell membranes, its role in the generation of proinflammatory lipid mediators is unclear. Conversely, sPLA2-IIA efficiently hydrolyzes Bacterial membranes. Here, we show that sPLA2-IIA affects the immune system by acting on the intestinal microbial flora. Using mice overexpressing transgene-driven human sPLA2-IIA, we found that the intestinal microbiota was critical for both induction of an immune phenotype and promotion of inflammatory Arthritis. The expression of sPLA2-IIA led to alterations of the intestinal microbiota composition, but housing in a more stringent pathogen-free facility revealed that its expression could affect the immune system in the absence of changes to the composition of this flora. In contrast, untargeted lipidomic analysis focusing on bacteria-derived lipid mediators revealed that sPLA2-IIA could profoundly alter the fecal lipidome. The data suggest that a singular protein, sPLA2-IIA, produces systemic effects on the immune system through its activity on the microbiota and its lipidome.

Keywords
Arthritis; Inflammation; Microbiology; Molecular pathology; Mouse models.
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