Peroxisomes Regulate Cellular Free Fatty Acids to Modulate Mast Cell TLR2, TLR4, and IgE-Mediated Activation

Abstract

Mast cells are specialized, tissue resident, immune effector cells able to respond to a wide range of stimuli. MCs are involved in the regulation of a variety of physiological functions, including vasodilation, angiogenesis and pathogen elimination. In addition, MCs recruit and regulate the functions of many immune cells such as dendritic cells, macrophages, T cells, B cells and eosinophils through their selective production of multiple cytokines and chemokines. MCs generate and release multi-potent molecules, such as histamine, proteases, prostanoids, leukotrienes, heparin, and many cytokines, chemokines, and growth factors through both degranulation dependent and independent pathways. Recent studies suggested that metabolic shifts dictate the activation and granule content secretion by MCs, however the metabolic signaling promoting these events is at its infancy. Lipid metabolism is recognized as a pivotal immunometabolic regulator during immune cell activation. Peroxisomes are organelles found across all eukaryotes, with a pivotal role in lipid metabolism and the detoxification of reactive oxygen species. Peroxisomes are one of the emerging axes in immunometabolism. Here we identified the peroxisome as an essential player in MCs activation. We determined that lack of functional peroxisomes in murine MCs causes a significant reduction of interleukin-6, Tumor necrosis factor and InterleukinL-13 following immunoglobulin IgE-mediated and Toll like receptor 2 and 4 activation compared to the Wild type (WT) BMMCs. We linked these defects in cytokine release to defects in free fatty acids homeostasis. In conclusion, our study identified the importance of peroxisomal fatty acids homeostasis in regulating mast cell-mediated immune functions.

Activity-dependent FosB gene expression negatively regulates mast cell functions

“…Notably, lipid metabolism is a prominent category, highlighted by genes involved in very-low-density lipoprotein (VLDL) particle receptor binding (GO:0030229), stearoyl-CoA 9-desaturase activity (GO:0004768), and acyl-CoA desaturase activity (GO:0016215). This finding is intriguing because lipid metabolism is crucial in mast cell functions, including the synthesis of lipid mediators, modulation of membrane fluidity, and regulation of signaling pathways associated with FcER and TLR activation 85–87 . In addition, inflammatory pathways also emerge as a significant category, with genes related to cytokine receptor activity (GO:0004896), chemokine receptor binding (GO:0042379), IL-6 receptor binding (GO:0005138), and platelet-derived growth factor receptor binding (PDGF, GO:0005161) being enriched.…”

Chlorogenic acid improves food allergy through the AMPK/ACC/CPT‐1 pathway

“…shown that metabolism is of great significance to the immune homeostasis of allergic diseases, such as intestinal flora metabolism (Luu et al, 2020), fatty acid metabolism (Trinchese et al, 2015), and glucose metabolism (Vanherwegen et al, 2019). Similarly, it was reported that cellular fatty acid in mast cells increased after IgE-mediated stimulation, while lack of fatty acid turnover from peroxisomes functions at rest and during IgE-mediated activation (Meghnem et al, 2022). Metabolic reconstitution is expected to become a new way to treat FA, while better meeting the demands of different allergic patients.…”

The peroxisome: an update on mysteries 3.0

“…In Drosophila and murine macrophages lacking Pex2 , and thus functional peroxisomes, the total amount and cellular distribution of glycerophospholipids (whose levels are regulated by peroxisomal β-oxidation) was altered during immune activation in response to pro-inflammatory stimuli, which in turn reduced cytokine secretion (Nath et al 2022 ). Similarly, mast cells (immune effectors) from Pex2 -knockout mice also displayed lower cytokine release when challenged with immunogenic stimuli compared to controls, as a result of free fatty acids accumulating rather than being degraded in peroxisomes (Meghnem et al 2022 ). Overall, this suggests that peroxisomal β-oxidation is necessary for the normal inflammatory signalling cascades required for immune cell activation in response to extracellular stimuli.…”