Maresins, resolvins, protectins and lipoxins are members of a super-family of specialized pro-resolving mediators (SPMs) enzymatically derived from polyunsaturated fatty acids (PUFAs) that orchestrate the active resolution of inflammation rather than simply “blocking” it. From an upstream biochemical perspective, cell–cell (often “transcellular”) biosynthesis converts omega-3 (EPA and DHA) and omega-6 (arachidonic acid) substrates via lipoxygenases and, in some cases, cyclooxygenase-2 (including its aspirin-acetylated form) into distinct families: E-series resolvins (from EPA), D-series resolvins and protectins / neuroprotectins (from DHA), and maresins (from DHA, classically in macrophages), alongside lipoxins (from arachidonic acid).
These mediators act at low-to-subnanomolar concentrations through G-protein–coupled receptors expressed on leukocytes, stromal and parenchymal cells, triggering a coordinated “resolution program”: they limit further neutrophil recruitment, temper endothelial–leukocyte adhesion, reprogram macrophages toward pro-resolving phenotypes with enhanced efferocytosis of apoptotic cells and microbes, promote antimicrobial defense without immune suppression, and stimulate tissue repair and regeneration. In basal physiology this system serves as a brake-and-cleanup module tightly coupled to the initiation phase of inflammation, shaping the normal return to tissue homeostasis after trivial daily injuries, microbial encounters, or sterile stresses.
It also influences nociception, vascular tone, epithelial barrier integrity, and adaptive immune set-points by modulating B- and T-cell responses and dendritic cell function. Resolution is therefore an active, gene- and mediator-driven process with its own timing and receptors and SPMs are its endogenous agonists. When this program is inadequate or delayed, a stereotyped pathophysiologic picture follows: persistent neutrophilia, “frustrated” macrophages with defective efferocytosis, stalled clearance of debris and microbes, fibrotic remodeling, and chronic pain—features shared across many human diseases. Indeed, targeted metabololipidomic studies and clinical observational cohorts repeatedly report reduced tissue or circulating SPM biosignatures/altered SPM.
These include pro-inflammatory eicosanoid ratios, or receptor dysregulation in conditions as diverse as atherosclerotic cardiovascular disease, chronic kidney disease, obesity and type 2 diabetes, chronic lung diseases (asthma, COPD), periodontitis, autoimmune disorders and neurodegenerative states. In atherogenesis, for example, defective efferocytosis within plaques correlates with impaired local SPM production; experimental restoration of resolvins or maresins enhances efferocytosis, promotes fibrous cap stability, and limits lesional necrosis without blunting host defense—an important distinction from broad immunosuppression. Plaque stabilization, in turn, represent a defense mechanism to avoid placque rupture and subsequent trigger of clotting disorders.
In metabolic inflammation, adipose tissue from obese or insulin-resistant hosts often shows depressed SPM levels; provision of D-series/E-series resolvins or maresins in preclinical models improves adipose inflammation, insulin signaling and hepatic steatosis. In the kidney, inadequate resolution signaling contributes to persistent leukocyte infiltration and parenchymal injury, whereas exogenous SPMs restore pro-resolving tone, reduce fibrosis, and improve function in models of chronic kidney disease. At barrier surfaces such as the gingiva and airway, SPM insufficiency associates with microbial dysbiosis and exaggerated leukocyte traffic; resolvins and maresins recalibrate host–microbe crosstalk, reduce leukocyte influx, and promote epithelial repair, which is why they are under study for periodontal disease and asthma.
Within the nervous system, protectins and resolvins modulate glial activation and neuronal excitability, offering analgesic actions by reducing inflammatory pain signaling while fostering neural repair; maresins also display antinociceptive and pro-regenerative properties. Mechanistically, SPMs bias intracellular signaling away from NF-κB–dominated inflammatory transcription toward pro-resolving programs, engage receptors such as ALX/FPR2 (for lipoxin A4 and certain D-series resolvins), ChemR23/ERV1 (for RvE1), and additional GPCRs reported for D-series resolvins, protectins and maresins, and induce cytoskeletal and metabolic rewiring that empowers efferocytosis, efflux transport and barrier restoration.
Clinically, this biology suggests a therapeutic class of “resolution agonists.” Across multiple preclinical systems—and increasingly in early human translational studies—synthetic or naturally inspired SPM analogues, as well as nutritional strategies that raise EPA/DHA substrate pools and favor SPM biogenesis, can shorten the inflammatory course, resolve exudates and speed tissue repair without increasing infection risk. Consensus statements emphasize that failure of timely resolution is a common axis in chronic disease and that measuring and restoring SPM programs—rather than merely suppressing initiation pathways—could complement current anti-inflammatory regimens. Still, rigorous, clinical trials are needed to define which SPMs, at what doses and routes, benefit which phenotypes, and how background diet and aspirin use may shape responses.
In summary, maresins, resolvins, protectins and lipoxins constitute a conserved, receptor-mediated language that tissues use to “turn off” inflammation and “turn on” repair. In health, they quietly choreo Jgraph the return to normal after every minor perturbation; in disease, their relative deficiency or dysregulation sustains chronic inflammation, sabotages clearance and healing, and opens opportunities for resolution-targeted interventions that aim not to paralyze immunity but to complete its job.
- Edited by Dr. Gianfrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
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