Dietary Regulation of Immunity

Abstract

Integrated immunometabolic responses link dietary intake, energy utilization, and storage to immune regulation of tissue function and is therefore essential for the maintenance and restoration of homeostasis. Adipose-resident leukocytes have non-traditional immunological functions that regulate organismal metabolism by controlling insulin action, lipolysis, and mitochondrial respiration to control the usage of substrates for production of heat versus ATP. Energetically expensive vital functions such as immunological responses might have thus evolved to respond accordingly to dietary surplus and deficit of macronutrient intake. Here, we review the interaction of dietary intake of macronutrients and their metabolism with the immune system. We discuss immunometabolic checkpoints that promote healthspan and highlight how dietary fate and regulation of glucose, fat, and protein metabolism might affect immunity.

Figure 1

Negative Energy Balance Drives Integrated Immunometabolic Responses to Counterbalance Homeostatic Processes to Promote Longevity Lower Disease Burden Negative energy balance is achieved when energy consumed is less than energy expended. This drives neuroendocrine hormone effectors such as ghrelin, FGF21, and GDF15, and the usage of alternative metabolic fuels such as fatty acids and ketone bodies. These signals get integrated by organs such as the brain, liver, adipose tissue, gut, and skeletal muscle with the immune system to promote metabolic reprogramming that prioritizes fatty acid oxidation over glycolysis. These changes adjust the balance of normal physiological processes such as regulation of body temperature, growth, reproduction, and immune response in a way that promotes longevity and health.

Figure 2

Obesity and Aging Lead to Distinct Changes in the Immune Profile of Adipose Tissue to Drive Inflammation and Pathology Healthy, lean adipose tissue is associated with anti-inflammatory immune subsets, such as CD206-expressing macrophage subsets (ATMs, NAMs, and PVMs), IL-4-expressing eosinophils, IL-10-expressing iNKT cells, B cells, Treg cells, and IL-5-expressing ILC2s. Energy imbalance leads to a disruption of immune and metabolic homeostasis, leading to an infiltration of inflammatory immune cells such as IL-6- and TNF-α-producing LAMs, elastase-producing neutrophils, IgG2C-producing B cells, degranulating mast cells, IFN-γ-producing CD4 T cells, IL-17-producing γδ T cells, and cytotoxic CD8 T cells. Accumulation of danger-associated molecular patterns (DAMPs) such as free fatty acids (FAs), oxidized LDL (oxLDL), cholesterol crystals, and islet amyloid polypeptides (IAPP) in obesity further drives the activation of NLRP3 inflammasomes. These changes in immune-mediated inflammation drive pathologies such as insulin resistance, type II diabetes, cardiovascular disease, and cancer while weakening immune defense against pathogens, leading to higher risk for premature death. Unlike obesity, which is characterized by an accumulation CLSs, where immune cells such as T cells and CD9⁺ macrophages associated with increased lipid processing and inflammation accumulate to deal with dying adipocytes, aging causes a reduction of adipose tissue macrophages that increase GDF3 and catecholamine degradation enzymes such as MAOA and COMT to promote lipolysis resistance. Aging also leads to an increase of FALCs, where B cells and T cells accumulate and contribute to dysregulated adipose homeostasis such as reduced insulin signaling and thermogenesis. Although γδ T cells increase with obesity, iNKT cells and Treg cells increase with age and decrease with obesity, and although no marked changes in eosinophils are reported in aged adipose, obesity is associated with significant decreases in eosinophil populations. These differences in immune profiles and immune lymphoid structures during aging and obesity suggest that distinct mechanisms contribute to the tissue dysfunction and pathologies associated with each condition.

Figure 3

Protein and Essential Amino Acid Restriction Induces the Transsulfuration Pathway and the Integrated Stress Response to Regulate Immune Response Induction of the transsulfuration pathway leads to production of byproducts such as hydrogen sulfide, which can reduce NLRP3 inflammasome-mediated inflammation and promote and maintain regulatory T cell differentiation. Low amino acid availability leads to the interaction of amino acid sensors such as Sestrin 2 and SAMTOR with GATOR2 and GATOR1, respectively, to restrict mTORC1 activation. Furthermore, sensing of uncharged amino acids by GCN2 and lack of glutathione by PERK further inhibits mTORC1 and leads to the activation of eIF2α, stress response genes, and autophagy, inhibiting NLRP3 inflammasome-mediated inflammation and Th17 responses.