Phospholipid signaling in innate immune cells

Abstract

Phospholipids comprise a large body of lipids that define cells and organelles by forming membrane structures. Importantly, their complex metabolism represents a highly controlled cellular signaling network that is essential for mounting an effective innate immune response. Phospholipids in innate cells are subject to dynamic regulation by enzymes, whose activities are highly responsive to activation status. Along with their metabolic products, they regulate multiple aspects of innate immune cell biology, including shape change, aggregation, blood clotting, and degranulation. Phospholipid hydrolysis provides substrates for cell-cell communication, enables regulation of hemostasis, immunity, thrombosis, and vascular inflammation, and is centrally important in cardiovascular disease and associated comorbidities. Phospholipids themselves are also recognized by innate-like T cells, which are considered essential for recognition of infection or cancer, as well as self-antigens. This Review describes the major phospholipid metabolic pathways present in innate immune cells and summarizes the formation and metabolism of phospholipids as well as their emerging roles in cell biology and disease.

Figure 1. Structures of the major PL classes.

(A) The five PL classes: phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and phosphatidylcholine (PC). (B) Ether and plasmalogen PLs. (C) Structures of common sn1 fatty acids in PLs. (D) Structures of common sn2 fatty acids in PLs.

Figure 2. PL cleavage and PL asymmetry in innate immune cells.

(A) Phospholipases PLA₁, PLA₂, PLC, and PLD hydrolyze PLs and are named by the site of hydrolysis, as shown. (B) Flippase and floppase enzymes maintain membrane symmetry on resting platelet membranes. Upon activation, calcium-dependent externalization of PE and PS provides a negatively charged surface that supports coagulation factor binding and facilitates prothrombin’s conversion to active thrombin. X and V, zymogen coagulation factors X and V; Xa/Va, a complex of activated factor X and factor V (prothrombinase complex).

Figure 3. PLC, PLD, and phosphoinositide pathways.

(A) PLC and PLD generate lipid intermediates that promote innate immunity. (B) PI is phosphorylated/dephosphorylated by a series of known enzymes, generating a complex array of transient lipid molecular species, which display potent bioactivity.