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The journal Science Bulletin has recently published a review of research on specialized pro-resolving lipid mediators (SPMs) and autoimmune disease. As discussed in this review, sustained leukocyte activation is central to many autoimmune diseases, and while both specific and nonspecific immunosuppressants relieve symptoms by supporting a healthy inflammatory response, a wide range of side effects underscores the need for better therapies. A growing understanding of the important differences between the natural inhibition and resolution of inflammation has sparked significant interest in the potential SPMs offer with autoimmune conditions.
Briefly, SPMs are compounds derived from omega-6 and omega-3 fatty acids, including resolvins, protectins, and maresins (metabolites of DHA/EPA), as well as lipoxins and aspirin-derived lipoxins (metabolites of arachidonic acid), requiring metabolic steps catalyzed by lipoxygenases, cyclooxygenase-2, and other enzymes. Much of the action of SPMs is mediated by G protein-coupled receptors found on immune cells (leukocytes, macrophages, neutrophils, etc.), though they do interact with other receptor types, such as the aryl hydrocarbon receptor, cannabinoid receptor 1, and transient receptor potential channels, with many downstream effects on both innate and adaptive immune responses. This includes helping to lower proinflammatory cytokine secretion by dendritic cells, enhancing macrophage phagocytosis and autophagy, as well as promoting polarization to the M2 macrophage anti-inflammatory phenotype, regulating B cell hyperactivation, modulating Th1/Th17 and Treg equilibrium, and much more, with the cumulative effect of restoring homeostasis by actively promoting the natural resolution of inflammation. This recognition that inflammation resolves via an active process rather than a passive one is the breakthrough understanding that makes SPMs so promising.
The review in Science Bulletin provides a detailed discussion of common autoimmune conditions, including rheumatoid arthritis, multiple sclerosis, type 1 diabetes mellitus, etc., as well as animal models and human studies investigating the role of SPMs in these conditions. To date, most human studies have not been intervention trials but rather assessments of the potential use of SPMs as biomarkers in autoimmune diseases. For example, a small study found significantly lower levels of Resolvin D1 (RvD1) in people with systemic lupus erythematosus (SLE), suggesting a possible threshold with 80% sensitivity and 63.3% specificity for identifying SLE. Lower levels of RvD1 have also been found among people with Hashimoto’s thyroiditis, with an inverse correlation with anti-thyroid peroxidase antibody (TPOAb) titers, with similar findings for Resolvin E1 (RVE1) and anti-thyroglobulin antibodies (TgAb). RvD1 levels were also found to be decreased among people with neuromyelitis optica spectrum disorders (NMOSD) and negatively correlated with aquaporin-4 (AQP4) antibody titers, while leukotriene B4 (LTB4) levels were increased in cerebrospinal fluid.
Preclinical and experimental models suggest SPMs may be novel therapies for various autoimmune conditions, though human clinical trials demonstrating efficacy, determining dosage and administration, optimal SPM combinations, etc., are still lacking. However, their role as immunomodulators (rather than immunosuppressants) that promote the resolution of pathological compromised inflammatory responses makes SPMs distinct from existing therapies.
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