Group X secretory phospholipase A2 enhances TLR4 signaling in macrophages

Preetha Shridas, William M. Bailey, Kayla R. Talbott, Rob C. Oslund, Michael H. Gelb, Nancy R. Webb

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Secretory phospholipase A2s (sPLA2) hydrolyze glycerophospholipids to liberate lysophospholipids and free fatty acids. Although group X (GX) sPLA2 is recognized as the most potent mammalian sPLA2 in vitro, its precise physiological function(s) remains unclear. We recently reported that GX sPLA2 suppresses activation of the liver X receptor in macrophages, resulting in reduced expression of liver X receptor-responsive genes including ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1), and a consequent decrease in cellular cholesterol efflux and increase in cellular cholesterol content (Shridas et al. 2010. Arterioscler. Thromb. Vasc. Biol. 30: 2014-2021). In this study, we provide evidence that GX sPLA2 modulates macrophage inflammatory responses by altering cellular cholesterol homeostasis. Transgenic expression or exogenous addition of GX sPLA2 resulted in a significantly higher induction of TNF-α, IL-6, and cyclooxygenase-2 in J774 macrophage-like cells in response to LPS. This effect required GX sPLA2 catalytic activity, and was abolished in macrophages that lack either TLR4 or MyD88. The hypersensitivity to LPS in cells overexpressing GX sPLA2 was reversed when cellular free cholesterol was normalized using cyclodextrin. Consistent with results from gain-of-function studies, peritoneal macrophages from GX sPLA2-deficient mice exhibited a significantly dampened response to LPS. Plasma concentrations of inflammatory cytokines were significantly lower in GX sPLA2-deficient mice compared with wild-type mice after LPS administration. Thus, GX sPLA2 amplifies signaling through TLR4 by a mechanism that is dependent on its catalytic activity. Our data indicate this effect is mediated through alterations in plasma membrane free cholesterol and lipid raft content.

Original languageEnglish
Pages (from-to)482-489
Number of pages8
JournalJournal of Immunology
Volume187
Issue number1
DOIs
StatePublished - Jul 1 2011

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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