The abnormal immune system response that causes multiple sclerosis (MS) by attacking and damaging the central nervous system can be triggered by the lack of a specific fatty acid in fat tissue, according to a new Yale study.
The finding suggests that dietary change might help treat some people with the autoimmune disease.
The study was published Jan. 19 in The Journal of Clinical Investigation.
Fat tissue in patients diagnosed with MS lack normal levels of oleic acid, a monounsaturated fatty acid found at high levels in, for instance, cooking oils, meats (beef, chicken, and pork), cheese, nuts, sunflower seeds, eggs, pasta, milk, olives, and avocados, according to the study.
This lack of oleic acids leads to a loss of the metabolic sensors that activate T cells, that mediate the immune system’s response to infectious disease, the Yale team found.
Without the suppressing effects of these regulatory T cells, the immune system can attack healthy central nervous system cells and cause the vision loss, pain, lack of coordination and other debilitating symptoms of MS.
“We’ve known for a while that both genetics and the environment play a role in the development of MS,” said senior author David Hafler, William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology and chair of the Department of Neurology.
“This paper suggests that one of environmental factors involved is diet.”
He stressed, however, that more study is necessary to determine whether eating a diet high in oleic acid can help some MS patients.
Metabolic signatures of T cells are intricately linked to their differentiation and activation status. Metabolic pathways facilitate cellular functions, therefore linking metabolic remodeling to the development, activation, differentiation, and survival of T cells.
Upon activation, quiescent, naive T cells become rapidly dividing effector T cells (Teffs) and switch their metabolic program from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, known as the Warburg effect, in order to meet the increase in demand for cellular energy and biomass (1, 2).
However, despite having similar developmental origins, Tregs rely predominantly on a fatty acid β-oxidation–driven (FAO-driven) OXPHOS metabolic program to maintain their suppressive phenotype, which is further promoted by the expression of FOXP3 (3–5). Forced expression of FOXP3 in T cells suppresses glycolysis-related genes, while inducing lipid and oxidative metabolism–related genes that are required for maximum suppression (4).
Cytokines that promote Treg differentiation, such as TGF-β (6), activate AMPK (7) and promote FAO to skew naive T cells to a Treg phenotype (3, 8). Furthermore, Treg differentiation and suppression are reduced by inhibiting FAO (3), highlighting the importance of FAO-driven OXPHOS in the initiation and maintenance of the Treg phenotype.
The suppressive function of Tregs is critical for controlling immune responses and preventing autoimmunity. We have previously identified functional Treg defects in patients with autoimmune disease (9). However, a second critical function for Tregs is the regulation of tissue homeostasis that can have a secondary impact on organismal biology.
In mice and humans, Tregs infiltrate tissues not only during inflammatory conditions or injury, but also during homeostasis (10–12), and reside within tumors (13, 14). Resident Tregs adapt to perform tissue-specific functions in order to regulate inflammation and perform homeostatic functions, such as wound repair and maintenance of metabolic indices (10, 12, 15).
Specifically, in visceral adipose tissue (VAT), VAT-resident Tregs possess unique epigenetic and transcriptional profiles that allow Tregs to survive in lipotoxic environments and enable the utilization of FAO as metabolic fuel (10, 16). Despite these findings, the signals that act to balance canonical Treg function and Treg adaptations of tissue-specific signals remain unknown.
Dissecting the signals that act to either promote or inhibit Treg adaptation in tissues is essential to our understanding of tissue Treg biology. An example are the signals that prevent loss of FOXP3 or promote the generation of Th-like Tregs (9, 17–21). While both local antigens and the cytokine milieu play a role in tissue adaptation (22), we hypothesized that environmental cues, such as lipids, may be critical, considering their role in shaping the Treg metabolic/functional axis.
Here, we identify oleic acid as the most prevalent long-chain free fatty acid (FFA) in human adipose tissue and dissect its involvement in the maintenance of Treg function Oleic acid amplifies Treg FAO-driven OXPHOS metabolism, creating a positive feedback mechanism that induces the expression of FOXP3 and enhances the phosphorylation of STAT5 (p-STAT5), which act to stabilize the Treg lineage and increase suppressive function (23–27).
We compared the transcriptomic program induced by oleic acid with that of proinflammatory arachidonic acid (28, 29) and derived a computational transcriptome signature to quantify the similarity of the Treg RNA profile to either state. We found that Tregs sorted from peripheral blood and adipose tissue of healthy donors transcriptomically resembled the Tregs treated in vitro with oleic acid, whereas Tregs obtained from patients with relapsing-remitting multiple sclerosis (MS) more closely resembled the arachidonic acid–treated Treg profile.
A similar trend was observed when we compared patients with MS in the treated and untreated groups. Finally, we found that oleic acid concentrations were reduced in the fat tissue of patients with MS and that exposure of dysfunctional MS Tregs to oleic acid partially restored their suppressive function, highlighting the importance of fatty acids in regulating inflammatory signaling in tissues.
reference link : https://www.jci.org/articles/view/138519
Original Research: Open access.
“Oleic acid restores suppressive defects in tissue-resident FOXP3 Tregs from patients with multiple sclerosis” by Saige L. Pompura et al. JCI
