Lysophospholipid metabolism facilitates Toll-like receptor 4 membrane translocation to regulate the inflammatory response

Simon K. Jackson^*^,1, Wondwossen Abate^*, Joan Parton, Simon Jones and John L. Harwood

^* Centre for Research in Biomedicine, University of the West of England, Bristol, United Kingdom;
Department of Medical Microbiology, School of Medicine, and
School of Biosciences, Cardiff University, Cardiff, United Kingdom; and
School of Chemistry, University of Sheffield, Sheffield, United Kingdom

¹Correspondence: Centre for Research in Biomedicine, University of the West of England, Bristol, BS16 1QY, UK. E-mail: simon.jackson{at}uwe.ac.uk

ABSTRACT

Sepsis, an overwhelming inflammatory response to infection,is a major cause of morbidity and mortality worldwide and hasno specific therapy. Phospholipid metabolites, such as lysophospholipids,have been shown to regulate inflammatory responses in sepsis,although their mechanism of action is not well understood. Thephospholipid-metabolizing enzymes, lysophospholipid acyltransferases,control membrane phospholipid composition, function, and theinflammatory responses of innate immune cells. Here, we showthat lysophosphatidylcholine acyltransferase (LPCAT) regulatesinflammatory responses to LPS and other microbial stimuli. Specificinhibition of LPCAT down-regulated inflammatory cytokine productionin monocytes and epithelial cells by preventing translocationof TLR4 into membrane lipid raft domains. Our observations demonstratea new regulatory mechanism that facilitates the innate immuneresponses to microbial molecular patterns and provide a basisfor the anti-inflammatory activity observed in many phospholipidmetabolites. This provides the possibility of the developmentof new classes of anti-inflammatory and antisepsis agents.

Key Words: lipopolysaccharide • lysophosphatidylcholine acyltransferase • sepsis