Peroxisomal Lipid Synthesis Regulates Inflammation by Sustaining Neutrophil Membrane Phospholipid Composition and Viability

Abstract

SUMMARY Fatty acid synthase (FAS) is altered in metabolic disorders and cancer. Conventional FAS null mice die in utero so effects of whole body inhibition of lipogenesis following development are unknown. Inducible global knockout of FAS (iFASKO) in mice was lethal due to a disrupted intestinal barrier and leukopenia. Conditional loss of FAS was associated with the selective suppression of granulopoiesis without disrupting granulocytic differentiation. Transplantation of iFASKO bone marrow into wild type mice followed by Cre induction resulted in selective neutrophil depletion but not death. Impaired lipogenesis increased ER stress and apoptosis in neutrophils by preferentially decreasing peroxisome-derived membrane phospholipids containing ether bonds. Inducible global knockout of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, also produced neutropenia. FAS knockdown in neutrophil-like HL-60 cells caused cell loss that was partially rescued by ether lipids. Inhibiting ether lipid synthesis selectively constrains neutrophil development, revealing an unrecognized pathway in immunometabolism.

PexRAP Inhibits PRDM16-Mediated Thermogenic Gene Expression

“…We recently reported that PexRAP expression was decreased in multiple tissues of tamoxifen-treated PexRAP-iKO mice, including liver, bone marrow, and white adipose tissue, but not in the brain. Adult PexRAP-iKO mice treated with tamoxifen survive but have leukopenia due to the nearly complete loss of neutrophils (Lodhi et al, 2015). …”

“…Generation of tamoxifen-inducible global PexRAP knockout (PexRAP-iKO) mice has been previously described (Lodhi et al, 2015). To induce knockout, ten to twelve week-old control (PexRAP lox/lox without Cre) and PexRAP-iKO (PexRAP lox/lox /Rosa-CreER) mice were treated daily with tamoxifen (50 μg/g body weight) for 5 consecutive days.…”

Mitochondria in the Regulation of Innate and Adaptive Immunity

“…Given the shared roles in ROS and lipid metabolism between the two organelles, we speculate that MAVS recruitment to mitochondrial and peroxisomal membranes could be related to lipid and/or ROS metabolism. Indeed peroxisomal lipid synthesis can regulate immune cells as highlighted by the recent finding that loss of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, results in neutropenia (Lodhi et al, 2015). …”

Peroxisomal Dysfunction in Age-Related Diseases

“…The gene encoding the enzyme that catalyzes the terminal peroxisomal step was recently identified, and the protein was named peroxisomal reductase activating peroxisome proliferator-activated receptor γ (PexRAP), based on its proposed function in adipocytes [14]. Ether lipids account for up to 20% of the total phospholipid content in humans and are particularly abundant in the brain, heart, and neutrophils [15]. Plasmalogens are important components of cellular membranes and may be involved in the organization of cholesterol-rich membrane regions known as detergent-resistant microdomains, which have been implicated in cellular signaling [16].…”