Ayaka Ito

Immune cells undergo substantial metabolic rewiring during differentiation and activation to satisfy the energy demands of an appropriate immune response. Lipids serve as energy sources and function as essential components of cellular membranes and signaling molecules. Recent studies have revealed that reprogramming of lipid metabolism, including lipid uptake, de novo synthesis of cholesterol and fatty acids, and fatty acid oxidation, leads to dynamic alterations in the quantity and quality of intracellular lipids. These metabolic changes play crucial roles in shaping immune cell functions, promoting anti-inflammatory responses, and facilitating the resolution of inflammation. Conversely, dysregulation of lipid metabolism can result in immune cell dysfunction, contributing to the onset and progression of chronic inflammatory diseases such as autoimmune diseases and metabolic syndrome. Notably, cholesterol and fatty acid metabolism influence immune responses by modulating membrane lipid composition and downstream inflammatory signaling. Given these insights, targeting lipid metabolism has emerged as a promising therapeutic approach for restoring immune homeostasis and treating chronic inflammatory diseases.

Immune cells adapt their metabolism in response to their differentiation and activation status to meet the energy demands for an appropriate immune response. Recent studies have elucidated that during immune cell metabolic reprogramming, lipid metabolism, including lipid uptake, de novo lipid synthesis and fatty acid oxidation, undergoes significant alteration, resulting in dynamic changes in the quantity and quality of intracellular lipids. Given that lipids serve as an energy source and structural components of cellular membranes, they have important implications for physiological function. Myeloid cells, which are essential in bridging innate and adaptive immunity, are sensitive to these changes. Dysregulation of lipid metabolism in myeloid cells can result in immune dysfunction, chronic inflammation and impaired resolution of inflammation. Understanding the mechanism by which lipids regulate immune cell function might provide novel therapeutic insights into chronic inflammatory diseases, including metabolic diseases, autoimmune diseases and cancer. (143 words).

Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.

A growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood. Here, we show that macrophages rely on extracellular serine to suppress aberrant cytokine production. Depleting serine from the culture media reduced the cellular serine content in macrophages markedly, suggesting that macrophages depend largely on extracellular serine rather than cellular synthesis. Under serine deprivation, macrophages stimulated with lipopolysaccharide showed aberrant cytokine expression patterns, including a marked reduction of anti-inflammatory interleukin-10 expression and sustained expression of interleukine-6. Transcriptomic and metabolomics analyses revealed that serine deprivation causes mitochondrial dysfunction: reduction in the pyruvate content, the NADH/NAD+ ratio, the oxygen consumption rate, and the mitochondrial production of reactive oxygen species (ROS). We also found the role of mitochondrial ROS in appropriate cytokine production. Thus, our results indicate that cytokine production in macrophages is tightly regulated by the nutritional microenvironment.