Unpacking the lipid–immune axis in health and disease

The lipid-immune system relationship represents an important but overlooked axis of inflammation and host defense regulation. Radically different from an energy source or structural component, lipids influence immune cell regulation, signaling and inflammatory responses. This narrative review provides a broad overview of the role lipids play in immune regulation in both healthy and pathogenic states. We initiate the review by summarizing the role of a variety of lipid classes in immune cell biology, with an emphasis on explaining how lipid composition and metabolism influence both innate and adaptive immunity. Next, we analyze the role that lipid-based mediators eicosanoids, resolvins and ceramides play in regulating inflammatory and pro-resolving pathways. We observe dietary and circulatory lipids additionally direct the immune response and modulate the resolution of inflammatory processes. In diseases characterized by prolonged and persistent immune activation and low-grade inflammation, such as atherosclerosis, obesity, type 2 diabetes and autoimmune diseases, impaired lipid metabolism ultimately aids this persistent state of immune activation. Moreover, we also consider the emergent role of the lipid-immune interface in infectious disease, demonstrating ways in which pathogens can hijack or modify lipid metabolism to escape the host immune response. We cover the potential therapeutic implications of lipid-immune interactions, noting potential strategies using statins, omega-3 fatty acids, or specialized lipid mediators, all with the objective of modulating inflammation rather than broad immunosuppression. Finally, we also identify important knowledge gaps and will suggest avenues for future research, particularly the need for more integrated lipidomic and immunologic studies.