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.
Highlights
The mammalian digestive tract harbors trillions of microorganisms, collectively known as the microbiota [1]
The study was initiated by the serendipitous observation of spontaneous swelling in the neck of sPLA2-IIATGN mice housed in a specific pathogen– free (SPF) facility for an extended duration, by approximately 8 months of age
Given that young sPLA2-IIATGN mice are more susceptible to K/B×N serum–transferred arthritis [35, 86, 87] and that the microbiota can contribute to rheumatoid arthritis (RA) [88], we investigated the susceptibility to inflammatory arthritis of 12-week-old sPLA2-IIATGN mice either conventionally colonized or treated with antibiotics to deplete microbiota
Summary
The mammalian digestive tract harbors trillions of microorganisms, collectively known as the microbiota [1]. Cohabitation of the commensal microbiota with cells that populate the intestinal epithelium plays a central role in host metabolism and acts as an important barrier that prevents the implantation of pathogens [2,3,4]. Dysbiosis notably contributes to the advent or exacerbation of inflammation, such as in inflammatory bowel diseases [7, 8], but it can have systemic consequences that expand beyond the intestinal tract. Dysbiosis has been associated with a wide variety of diseases, including autoimmune, metabolic, and neurological disorders [9, 10]. It is still unclear whether dysbiosis is a cause or a consequence of these diseases [11]. It is critical to identify the factors that promote dysbiosis and to define their contribution to inflammatory processes
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