Phospholipid Regulation of Inflammatory Processes and Viral Infection

Abstract

Gas exchange between the external environment and erythrocyte hemoglobin takes place within the alveolar compartment of the lung, which contains an extracellular, phospholipid‐rich complex known as pulmonary surfactant. The major phospholipid classes of pulmonary surfactant consist of phosphatidylcholine (~70%), phosphatidylglycerol (PG) (~10%) and phosphatidylinositol (PI) (~2%). Dipalmitoyl‐phosphatidylcholine plays an essential role in reducing surface tension within the alveoli during respiration, but the roles played by phosphatidylglycerol (PG) and phosphatidylinositol (PI) remained enigmatic for decades. PG and PI are uniquely secreted by alveolar epithelial cells, and their concentrations in this extracellular compartment greatly exceed that of any other tissue. Unexpectedly, studies of the innate immune Toll‐like receptors (TLRs) have revealed that PG and PI are potent antagonists of the activation of multiple TLRs including TLRs 1,2,3,4 and 6. The lipids bind to the receptors and prevent their activation by cognate ligands, and consequently prevent downstream activation of inflammatory signaling pathways, and release of inflammatory mediators such as interleukins 6 and 8, interferon‐lambda, eicosanoids and TNF‐alpha. In addition to suppressing activation of TLRs, the lipids also inhibit infection by major respiratory viruses including respiratory syncytial virus (RSV) and influenza A virus (IAV). Both PG and PI prevent the viral infections in cultured cells, and in vivo in mice. PG also completely abrogates lethal challenge of mice with pandemic H1N1‐IAV. Additional studies with ferrets further demonstrate protection against pandemic H1N1‐IAV. The lipids act as decoy receptors for both RSV and IAV, and block virus attachment to epithelial cell surfaces. We have constructed a library of 25 analogs of POPG and PI, which vary in both the structure of the polar headgroup and their hydrophobic moieties. Some of these analogs exhibit improved pharmacological properties compared with PG and PI. These studies demonstrate regulation of innate immune processes by pulmonary surfactant phospholipids, and also reveal their potential use for suppressing inflammatory processes in the lung and inhibiting establishment and spread of respiratory viral infections.Support or Funding InformationSupported by NIH Grants HL 094629, U19‐AI 125357, GM 118819This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.