Lipid News

Phospholipids and innate immunity

Valerie  B. O’Donnell
By Valerie B. O’Donnell
Nov. 1, 2019

The innate immune system is an ancient evolutionary arm of defense that responds to acute trauma by generating a barrier that prevents pathogen invasion and arrests bleeding. It also patrols healthy epithelial tissues, monitoring and responding to foreign antigens and supporting development of adaptive immunity.

Phospholipid bilayerThis representation of a phospholipid bilayer shows integral membrane proteins protruding throughout.

Healthy functioning of the innate immune system relies on communication among diverse cell types, both from the bloodstream and based in stromal tissues such as epithelia and fibroblasts. Here, phospholipid signaling takes center stage in diverse ways, many of which we are only beginning to understand.

Phospholipids, or PLs, provide the membranes that hold our cells together. Researchers increasingly appreciate how these unique and diverse lipids also play essential roles in communicating within the immune system and how this is required for human health and disease. Indeed, PLs and their metabolic products are central players in vascular inflammation, hemostasis, immunity, cancer, infection and cardiovascular disease.

Here is some of what we know about PL biology in mammals so far:

Prostaglandin and eicosanoid precursors: Researchers long have known that PL hydrolysis provides polyunsaturated fatty acid substrates for generation of eicosanoids and prostaglandins by cyclooxygenases and lipoxygenases. This involves large families of phospholipases expressed in a cell-specific manner. Prostaglandins signal by activating well-characterized G protein-coupled receptors, or GPCRs, after they are secreted from immune and stromal cells during inflammation.

Phosphoinositides: The phosphorylation of inositol headgroups of phosphatidylinositol at up to three sites leads to a multitude of PL products that are potently bioactive and highly transient. These lipids form short-lived membrane anchors for kinases that regulate GPCRs, apoptosis and endocytosis.

Platelet activating factor: This extremely transient lipid contains a choline headgroup, and an alkyl bond at sn1. According to IUPAC nomenclature, it is a plasmanylcholine, with an acetyl group at sn2. The chain at sn1 is generally a 16:0 ether, but variants of other length also show bioactivity towards platelets.

Phospholipase C and phospholipase D: Families of enzymes called PLCs cleave PLs to form diacylglycerol and release the phosphorylated headgroup. Diacylglycerols are potent activators of the protein kinase C pathway, while the PL headgroup mobilizes calcium. PLD metabolizes phosphatidylcholine to form phosphatidic acid, an intracellular molecule that regulates proteins involved in Ras and Rac1 signaling.

Enzymatically oxidized PL: Researchers long have known that PLs oxidize in atherosclerosis and inflammation via nonenzymatic processes. Now, they are finding that a cell-specific group of related lipids, generated by enzymatic oxidation, is formed in innate immune cells in the bloodstream. These lipids allow the interaction of coagulation factors with cell membranes, an event required for blood clotting. A deficiency of enzymatically oxidized PLs, or eoxPLs, leads to too much bleeding, and studies suggest eoxPLs are involved in vascular inflammatory diseases such as aneurysms. In some situations, eoxPLs and their nonenzymatically generated analogs may be regulators of ferroptosis, an iron-dependent cell-death process relevant for cancer and organ failure.

Phospholipid innate immune recognition: Both self- and pathogen-derived PLs can act as ligands for a family of MHC class I-like antigen-presenting molecules called CD1. Lipid reactive T cells such as natural killer T cells then recognize the lipid-CD1 complexes. This type of antigen recognition shows significant molecular diversity in terms of PL species implicated, and a role is emerging for CD1-lipid presentation in human allergies, including to dust mites, pollen and bee sting.

Our lab recently published a review covering these aspects of PL signaling in the innate immune system in the Journal of Clinical Investigation.

(Terminology in the section of this article on platelet activating factor was corrected by the author on Nov. 14, 2019.)

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Valerie  B. O’Donnell
Valerie B. O’Donnell

Valerie B. O’Donnell is co-director of the Systems Immunity Research Institute at Cardiff University, U.K.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Rare genetic mutation in Amish population linked to ‘bad’ cholesterol levels
Journal News

Rare genetic mutation in Amish population linked to ‘bad’ cholesterol levels

May 28, 2024

The affected SORT1 gene encodes for a protein that might influence LDL levels, though study results have been contradictory.

Snaking toward a universal antivenom
News

Snaking toward a universal antivenom

May 26, 2024

Scientists at Scripps Research have discovered antibodies that protect against a host of lethal snake venoms.

Cell’s 'garbage disposal' may have another role
News

Cell’s 'garbage disposal' may have another role

May 25, 2024

Researchers at Johns Hopkins University have determined that the proteasome could be helping neurons near skin sense the environment.

Clues from bird flu’s ground zero on dairy farms in the Texas panhandle
News

Clues from bird flu’s ground zero on dairy farms in the Texas panhandle

May 25, 2024

Dairy farmers and veterinarians in northern Texas furiously investigated a mysterious illness among cattle before the government got involved.

Universal tool for tracking cell-to-cell interactions
News

Universal tool for tracking cell-to-cell interactions

May 19, 2024

A team of researchers has developed LIPSTIC, which can lay the groundwork for a dynamic map tracking physical interactions between different cells — the elusive cellular interactome.

Weedy rice gets competitive boost from its wild neighbors
News

Weedy rice gets competitive boost from its wild neighbors

May 18, 2024

Rice feeds the world. But researchers have found that a look-alike weed has many ways of getting ahead.