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Specialized pro-resolving mediators

Specialized pro-resolving mediators (SPMs) are a superfamily of endogenous mediators that actively promote the resolution of by stimulating the clearance of apoptotic cells, neutrophils, and microbial debris while fostering regeneration. These mediators are biosynthesized from essential polyunsaturated fatty acids, primarily omega-3 fatty acids such as (EPA) and (DHA), as well as omega-6-derived lipoxins. First identified in the early 2000s through unbiased approaches, SPMs emerged from studies investigating the molecular mechanisms of , with key discoveries including E1 in 2002. The major families of SPMs encompass lipoxins, (E-series from EPA and D-series from DHA), protectins (e.g., protectin D1), maresins (macrophage mediators such as maresin 1), and cysteinyl-SPMs (e.g., from n-3 docosapentaenoic acid). Their production occurs via stereoselective enzymatic pathways involving lipoxygenases (e.g., 5-LOX, 15-LOX), (COX-2), and , often in inflammatory exudates or tissues at concentrations of 0.2–28 pg/mL in human serum. SPMs act primarily through G protein-coupled receptors (e.g., ALX/FPR2 for lipoxin A4 and resolvin D1, GPR18 for resolvin D2) on immune cells, where they limit pro-inflammatory cytokine production (e.g., TNF-α, IL-1β), enhance by macrophages, and promote phenotypic switching to pro-resolving macrophages. Beyond resolution, they exhibit antimicrobial properties, regulate adaptive immune responses by modulating T and functions (e.g., promoting regulatory T cells and reducing Th17 differentiation), and protect against organ injury in conditions like , , and autoimmune diseases. These actions distinguish SPMs from traditional drugs, as they do not suppress immune defenses, highlighting their potential in resolution pharmacology for treating chronic inflammation.

Overview

Definition and Characteristics

Specialized pro-resolving mediators (SPMs) are a class of endogenous mediators that actively orchestrate the phase of , promoting the clearance of cellular and apoptotic cells while countering pro-inflammatory signals without causing immunosuppression. These molecules are stereochemically distinct oxygenated products derived from essential polyunsaturated fatty acids (PUFAs), primarily omega-3 fatty acids such as (EPA), (DHA), and docosapentaenoic acid (DPA), as well as omega-6 (). Unlike classical eicosanoids, such as prostaglandins and leukotrienes, which amplify the inflammatory response, SPMs function as immunoresolvents that terminate and restore . Key characteristics of SPMs include their high potency at low concentrations, typically in the nanomolar to picomolar range, enabling stereospecific interactions with G-protein-coupled receptors to elicit targeted and pro-resolving actions. They enhance phagocytosis of apoptotic neutrophils and debris, limit further recruitment of polymorphonuclear leukocytes, and reduce the production of pro-inflammatory cytokines, thereby facilitating a non-suppressive return to physiological equilibrium. This distinguishes SPMs from immunosuppressive agents, as they actively promote resolution rather than merely suppressing immune activity. The major classes of SPMs encompass lipoxins, derived from ; resolvins, which include E-series from EPA and D-series from DHA; protectins, primarily from DHA; and maresins, also from DHA and DPA. These families share structural features involving specific hydroxylations and conjugations but differ in their biosynthetic origins and receptor affinities, contributing to their collective role in resolving acute .

Physiological Importance

Specialized pro-resolving mediators (SPMs) play a central role in immune surveillance by regulating leukocyte trafficking, enhancing of pathogens and apoptotic cells, and promoting without impairing host defense mechanisms, thereby preventing excessive during infections. In , SPMs such as resolvins and maresins accelerate tissue repair by stimulating polarization toward pro-resolving phenotypes and facilitating the clearance of debris, as demonstrated in models of injury and periodontitis where they reduce and enhance regeneration. For organ protection, SPMs confer through molecules like protectin D1 (neuroprotectin D1), which limits , reduces neuronal apoptosis, and promotes resolution in conditions such as retinal injury and by modulating microglial activity and production at nanomolar concentrations. Dysregulation of SPM biosynthesis and signaling contributes to chronic inflammatory diseases, including , where reduced levels of resolvins (e.g., RvD1) and maresins correlate with plaque instability, increased , and impaired in atherosclerotic lesions. In , lower circulating concentrations of SPMs like RvD1 and maresin 1 during active disease phases exacerbate joint inflammation, pain, and cartilage damage by failing to counterbalance pro-inflammatory cytokines such as TNF-α and IL-1β. Similarly, in neurodegenerative disorders, diminished SPM production, particularly of DHA-derived protectins and resolvins, promotes unresolved , amyloid-β accumulation, and microglial dysfunction, linking SPM deficits to progression in models. SPM pathways exhibit evolutionary conservation across species, from to mammals, where lipoxygenase-mediated supports tissue regeneration and , underscoring their fundamental role in maintaining . Dietary intake of omega-3 polyunsaturated fatty acids (PUFAs), such as (EPA) and (DHA), enhances SPM production by providing enzymatic precursors, with marine oil supplementation increasing plasma levels of resolvins, protectins, and maresins in a dose- and time-dependent manner in humans.

Historical Development

Discovery

The discovery of specialized pro-resolving mediators (SPMs) began in the 1980s with the identification of lipoxins, a class of eicosanoids derived from , by Charles N. Serhan and colleagues at . During studies on leukocyte interactions, Serhan's group isolated novel trihydroxytetraene compounds from human neutrophils and platelets, revealing their formation through transcellular biosynthesis pathways. In 1984, they demonstrated that lipoxins arise from sequential actions of 15-lipoxygenase in epithelial cells or monocytes and 5-lipoxygenase in neutrophils, producing compounds like lipoxin A4 (LXA4) and lipoxin B4 (LXB4) that actively dampen . By 1990, further work showed that platelets contribute via 12-lipoxygenase, converting leukotriene A4 from neutrophils into lipoxins during cell-cell interactions, highlighting a coordinated multicellular process essential for limiting excessive . Early investigations into self-limited inflammatory responses provided foundational evidence that is an active, biosynthetically driven rather than a passive dissipation of pro-inflammatory signals. Using murine models of acute and human cell systems, Serhan's team observed that inflammatory exudates naturally resolve within hours to days, with peak production of coinciding with and clearance of debris. These models demonstrated that disrupting pathways prolongs inflammation, underscoring the mediators' role in orchestrating timely without compromising host defense. In 2002, the scope of SPMs expanded with the identification of resolvins, novel bioactive lipids derived from omega-3 fatty acids (EPA) and (DHA), isolated from resolving inflammatory exudates in aspirin-treated murine models. Serhan and colleagues employed to profile exudates during the phase, uncovering EPA-derived E-series resolvins (e.g., E1) and DHA-derived aspirin-triggered resolvins (e.g., 17R-HDHA and its dihydroxy metabolites), formed via aspirin-triggered 15-lipoxygenase pathways that counter pro-inflammatory cytokines and reduce leukocyte infiltration by up to 80% at nanogram doses. These findings built on research, establishing resolvins as potent enhancers of . Initial efforts classified lipoxins and resolvins as distinct families of pro-resolving mediators, with "resolvins" specifically coined to reflect their stereoselective actions in actively promoting inflammation .

Key Milestones and Researchers

In the , research on specialized pro-resolving mediators (SPMs) expanded significantly with the identification of new families derived from omega-3 fatty acids. Maresins, a class of DHA-derived mediators produced by , were first characterized in 2009, with subsequent studies in the early elucidating their potent and tissue regenerative actions, such as stimulating and limiting influx. Protectins, including neuroprotectin D1, were further explored during this period for their roles in neural and ocular tissues, building on initial discoveries to confirm their stereoselective via pathways in resolving exudates. A major advancement came in 2013 with the discovery of n-3 docosapentaenoic acid (n-3 DPA)-derived SPMs, such as protectin D1n-3 DPA and D5n-3 DPA, which demonstrated stereoselective effects in models of ischemia-reperfusion injury by enhancing and reducing production. Charles N. Serhan, a pioneer in SPM research, led much of this progress from his laboratory at and , where he identified and structurally elucidated multiple SPM classes, including resolvins, protectins, and maresins, establishing their biosynthetic pathways and cellular targets. His work emphasized the active nature of inflammation resolution, introducing quantitative indices to measure SPM-driven processes like the clearance of apoptotic cells. Serhan's group collaborated internationally, notably with researchers like Jesmond Dalli at , to map SPM metabolomes in human tissues and validate their pro-resolving actions across species. These efforts culminated in the establishment of resolution pharmacology as a distinct field in 2015, focusing on SPMs as agonists for G-protein-coupled receptors to promote non-opioid analgesia and tissue repair without . The first patents on SPM compositions emerged in this era, with Serhan as a key inventor; for instance, a 2013 covered oils enriched in natural SPMs for applications, paving the way for therapeutic development. In the , research identified new SPM metabolites, including oxo-derivatives like electrophilic ω-3 PUFA oxidation products formed in macrophages during , which modulate signaling and enhance . Insights into SPM roles in revealed dysregulated biosynthesis in conditions like , where supplementation with SPM-enriched marine oils restored balance and reduced . Similarly, studies up to 2025 highlighted SPMs' analgesic effects in models, such as , where oral SPM administration decreased pain scores and improved by blocking sensitization and promoting .

Inflammation and Resolution

Inflammatory Response

The inflammatory response begins with the initiation phase, characterized by rapid vascular changes including and increased , which facilitate the exudation of plasma proteins and fluid into the affected tissue. These alterations are primarily triggered by the release of pro-inflammatory mediators such as , , and cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1), leading to the formation of an inflammatory . Concomitantly, leukocyte is orchestrated through a multi-step process involving rolling, adhesion, and transmigration of neutrophils and monocytes across the , driven by selectins, , and gradients that establish directional migration toward the site of injury or . Pro-inflammatory eicosanoids, including prostaglandins and leukotrienes derived from , further amplify this recruitment by promoting endothelial activation and enhancing expression. In the classical view, acute inflammation is an active, self-limiting process designed to contain and eliminate harmful stimuli while minimizing tissue damage, typically resolving within days through coordinated clearance mechanisms. Central to this orchestration is the activation of the pathway, a key that translocates to the nucleus upon stimulation by microbial products or cytokines, inducing the expression of pro-inflammatory genes encoding cytokines, , and adhesion molecules. Chemokine gradients, such as those formed by CXCL8 (IL-8), create a chemotactic field that guides leukocytes precisely to the inflammatory focus, ensuring an efficient but contained response. If the initiating stimulus persists or resolution fails, acute inflammation can transition to chronicity, marked by prolonged leukocyte infiltration, tissue remodeling, and , contributing to diseases such as or . This shift underscores the importance of timely counter-regulatory mechanisms, including those mediated by specialized pro-resolving mediators, to prevent pathological persistence.

Resolution Mechanisms

Specialized pro-resolving mediators (SPMs) actively orchestrate the termination of by promoting the clearance of cellular debris and apoptotic s while limiting further immune recruitment, thereby restoring without compromising host defense. These mediators, derived from fatty acids such as omega-3 polyunsaturated fatty acids, facilitate a programmed process that contrasts with passive dissipation of inflammatory signals. By enhancing non-inflammatory and modulating production, SPMs ensure efficient in various , preventing chronic . A primary mechanism of SPMs involves stimulating macrophage-mediated phagocytosis and efferocytosis, the uptake of apoptotic neutrophils and other , which clears inflammatory foci and promotes repair. For instance, SPMs increase the phagocytic capacity of macrophages, enabling the nonphlogistic removal of apoptotic cells to avoid secondary and prolonged . This process is crucial in models of acute , where SPM administration accelerates the phase by up to 50% compared to untreated controls. Additionally, SPMs reduce neutrophil influx into inflamed s by inhibiting and , thereby preventing excessive leukocyte accumulation that could exacerbate damage. SPMs also counter-regulate pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), by suppressing their production from immune cells like macrophages and dendritic cells. This inhibition occurs at the transcriptional and post-transcriptional levels, reducing systemic inflammatory signaling without broadly suppressing immune function. In experimental settings, SPMs have been shown to decrease TNF-α levels by 40-70% in response to challenges, facilitating a shift toward cytokine profiles, including increased IL-10. In tissue-specific contexts, SPMs support with properties that enhance bacterial clearance while avoiding , as demonstrated in models of and periodontal infections. This dual action allows SPMs to promote and epithelial integrity without increasing susceptibility to pathogens. For example, SPMs augment host defenses in infected tissues by stimulating microbial alongside , maintaining a balanced . SPMs integrate with broader immune networks through crosstalk with the and pathways, amplifying resolution signals. They modulate complement components like C5a to fine-tune leukocyte responses and interact with networks to promote activity, ensuring coordinated shutdown of . This interplay is evident in preclinical studies where SPMs enhance complement-dependent clearance while dampening excessive storms.

Biosynthesis

Precursor Fatty Acids

Specialized pro-resolving mediators (SPMs) are biosynthesized from specific polyunsaturated fatty acids (PUFAs) that serve as essential precursors, primarily essential fatty acids obtained through diet or endogenous metabolism. These precursors include both omega-6 and omega-3 PUFAs, which are incorporated into cellular membranes and released during inflammatory responses to generate SPMs. The major precursors are (AA, 20:4 n-6), an omega-6 PUFA that gives rise to lipoxins; (EPA, 20:5 n-3), an omega-3 PUFA serving as the substrate for E-series resolvins; and (DHA, 22:6 n-3), another omega-3 PUFA that is the primary precursor for D-series resolvins, protectins, and maresins. Additional SPMs are derived from docosapentaenoic acids, including n-3 DPA (22:5 n-3) and n-6 DPA (22:5 n-6), which contribute to specialized lipid mediators such as DPA-derived resolvins, protectins, and maresins, expanding the repertoire of pro-resolving signals beyond , , and . These precursor PUFAs are primarily sourced from the diet, with omega-3 fatty acids like and abundant in marine sources such as and fatty fish, providing direct for SPM production. In contrast, alpha-linolenic acid (, 18:3 n-3), found in plant-based foods like flaxseed and walnuts, undergoes endogenous to and via enzymatic and desaturation, though this process is inefficient, with conversion rates typically below 10% for and even lower for in humans. Within cells, these PUFAs are stored predominantly as esterified components of phospholipids, as a that can be mobilized by phospholipases during to supply free fatty acids for SPM biosynthesis. Modern Western diets often exhibit imbalances, with high intake of omega-6 PUFAs from oils promoting AA accumulation while omega-3 intake remains low, resulting in reduced availability of EPA, DHA, and DPA precursors that limits SPM production and may contribute to chronic .

Enzymatic Pathways

Specialized pro-resolving mediators (SPMs) are synthesized through multi-step enzymatic cascades primarily involving lipoxygenases (LOXs), , and enzymes, acting on precursor polyunsaturated fatty acids. The key enzymes include 5-lipoxygenase (5-LOX), which catalyzes the initial oxygenation at the 5-position, and 15-lipoxygenase (15-LOX), responsible for oxygenation at the 15-position of , while 12-LOX contributes to specific positional insertions in other pathways. plays a central role, particularly in its aspirin-acetylated form, which shifts the to generate 15R-hydroxy intermediates instead of the typical pro-inflammatory products. Cytochrome P450 monooxygenases further diversify the pathways by introducing hydroxyl groups at positions such as 18 or 20, enabling subsequent LOX actions. These enzymatic reactions often occur via transcellular biosynthesis, where intermediate metabolites are transferred between different types to complete SPM formation. For instance, neutrophils release 5-LOX-derived intermediates that are taken up by endothelial s or platelets expressing 15-LOX, facilitating cooperative synthesis during . This intercellular ensures efficient production in the inflammatory milieu, with aspirin enhancing the process by acetylating COX-2 in one , leading to variants that prime substrates for LOX in adjacent cells. Stereospecificity is a hallmark of these pathways, particularly in the formation of conjugated triene structures, as seen in lipoxin biosynthesis where 5-LOX acts on 15-LOX-generated hydroperoxy intermediates, followed by formation and to yield specific double-bond configurations. This precise is essential for the mediators' and is achieved through the enzymes' regiospecific and stereoselective oxygenation mechanisms. The pathways are tightly regulated by inflammatory signals, providing feedback to modulate enzyme expression and activity. Cytokines such as IL-4 and IL-13 upregulate 15-LOX-1 in macrophages, promoting SPM biosynthesis during the resolution phase, while interactions like 5-LOX with its activating protein (FLAP) can shift substrate channeling toward resolution pathways when inflammation subsides. This dynamic regulation ensures that SPM production aligns with the temporal needs of inflammation resolution.

Classes of SPMs

Lipoxins

Lipoxins represent the prototypical class of specialized pro-resolving mediators (SPMs) derived from the ω-6 polyunsaturated , playing a central role in actively terminating and promoting repair. These eicosanoids are characterized by their trihydroxytetraene structure, which enables stereospecific interactions with cellular receptors to dampen excessive immune responses without compromising host defense. Discovered in the late through studies of transcellular in leukocytes and platelets, lipoxins exemplify the shift from pro-inflammatory to pro-resolving during the resolution phase of . The primary lipoxins, and , possess distinct chemical structures that confer their bioactivity. LXA4 is 5S,6R,15S-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid, featuring hydroxyl groups at carbons 5, 6, and 15, along with conjugated double bonds at positions 7-8, 9-10, 11-12, and 13-14. LXB4, a , is 5S,14R,15S-trihydroxy-6E,8Z,10E,12E-eicosatetraenoic acid, with hydroxyls at carbons 5, 14, and 15 and double bonds configured at 6-7 (E), 8-9 (Z), 10-11 (E), and 12-13 (E). These structural features allow lipoxins to bind G-protein-coupled receptors such as ALX/FPR2 and GPR32, initiating downstream cascades. Biosynthesis of lipoxins occurs via enzyme-mediated pathways involving lipoxygenases (), primarily through transcellular interactions between leukocytes and other cells. The classical route employs sequential actions of 5-lipoxygenase (5-) in neutrophils and 15-lipoxygenase (15-) in endothelial cells or , converting to LXA4 and LXB4; this process is upregulated by cytokines like IL-4 and IL-13. An alternative pathway involves aspirin-acetylated (COX-2), which generates 15R-hydroperoxy intermediates that 5-LOX then transforms into aspirin-triggered lipoxins (AT-Ls), such as 15-epi-LXA4 (5S,6R,15R-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid). This aspirin-dependent mechanism shifts pro-inflammatory production toward pro-resolving lipoxins, enhancing their formation in vascular and mucosal sites. Lipoxins exert potent pro-resolving actions by modulating immune cell behavior, including the promotion of migration to sites of for non-phlogistic clearance of apoptotic cells and debris. Specifically, LXA4 stimulates monocyte-derived chemotaxis and at picomolar to nanomolar concentrations, facilitating without triggering further . Concurrently, lipoxins inhibit leukocyte and transmigration; for instance, LXA4 downregulates Mac-1 (CD11b/CD18) expression on neutrophils, reducing their adherence to endothelial cells and subsequent tissue infiltration by up to 50% in experimental models. Aspirin-triggered lipoxins (AT-Ls) mimic native lipoxins but exhibit enhanced metabolic stability due to the 15R , which resists rapid enzymatic degradation by 15-hydroxyprostaglandin . This stability allows AT-Ls to persist longer , amplifying their effects; stable analogs of 15-epi-LXA4, for example, inhibit recruitment and more effectively than native forms in aspirin-treated systems. Formation of AT-Ls is particularly prominent in aspirin-exposed endothelium-leukocyte interactions, providing a therapeutic link between low-dose aspirin use and resolution of .

Resolvins

Resolvins are a class of specialized pro-resolving mediators derived primarily from the omega-3 polyunsaturated fatty acids (EPA) and (DHA), with additional members from docosapentaenoic acid (DPA). They play a critical role in actively promoting the resolution of by limiting neutrophil infiltration, enhancing , and countering pro-inflammatory signals without . These lipid mediators are biosynthesized during the later phases of acute through enzymatic pathways involving lipoxygenases and other oxygenases, distinguishing them from pro-inflammatory eicosanoids. Resolvins are categorized into three main series based on their precursors. The E-series resolvins (RvE1, RvE2, and RvE3) are generated from EPA, while the D-series resolvins (RvD1 through RvD6) arise from DHA. Additionally, DPA-derived resolvins, such as RvD5n-3 DPA, contribute to pro-resolving actions in specific tissues like the vasculature and intestines. Structurally, resolvins feature a conjugated triene backbone with multiple hydroxyl groups, conferring stereospecific bioactivity; for example, RvD1 has the C22H32O5 and the 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid. These structures enable high-affinity interactions with G-protein-coupled receptors like ALX/FPR2 and GPR32. Biosynthesis of E-series resolvins from EPA typically involves initial oxygenation at the 18-position by enzymes or aspirin-acetylated (COX-2), followed by 5-lipoxygenase (5-LOX) action to form epoxy intermediates that are hydrolyzed by epoxide hydrolases to yield RvE1–RvE3. In contrast, D-series resolvins from DHA begin with 15-LOX or 17-LOX-mediated hydroperoxidation at the 17-position to produce 17-hydroperoxy-DHA, which is then epoxidized by 5-LOX and hydrolyzed to form RvD1–RvD6. For DPA-derived resolvins like RvD5n-3 DPA, pathways similarly utilize 15-LOX for initial oxygenation, leading to tissue-protective metabolites. These processes often occur transcellularly between leukocytes and endothelial cells during . Functionally, resolvins exhibit potent pro-resolving profiles, including blocking pain signals and enhancing bacterial clearance. For instance, RvD1 attenuates mechanical and inflammatory pain by inhibiting and TNF-α-mediated in the via ALX/FPR2 receptor signaling. Similarly, RvE1 promotes macrophage of bacteria such as , accelerating clearance in models of lung injury and . These actions underscore resolvins' role in restoring post-inflammation.

Protectins and Neuroprotectins

Protectins are a class of specialized pro-resolving mediators (SPMs) derived primarily from the (DHA), characterized by their dihydroxy-containing docosatriene structures and potent immunoresolvent actions. The term "protectin" is used generally for these mediators in peripheral tissues, while "neuroprotectin" specifically denotes their production and roles in neural contexts, such as the and , highlighting their tissue-specific neuroprotective properties. A prototypical example is protectin D1/neuroprotectin D1 (PD1/NPD1), which features a 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid structure, including chiral secondary alcohols and a conjugated E,E,Z-triene moiety essential for bioactivity. Biosynthesis of PD1/NPD1 begins with DHA oxygenation by 15-lipoxygenase (15-LOX) to form 17S-hydroperoxy-DHA (17S-HpDHA), which is then converted via an epoxide intermediate (16S,17S-epoxy-DHA) to the dihydroxy product through enzymatic hydrolysis. This pathway occurs in various human cells, including retinal pigment epithelial (RPE) cells and neutrophils, and is stereospecific, yielding the natural R/S configuration with high-affinity binding (Kd ≈ 31 pmol/mg protein in RPE cells). PD1/NPD1 limits oxidative stress by reducing reactive oxygen species and pro-inflammatory mediators, such as prostaglandins and leukotriene B4, while promoting cell survival signaling. In the retina, NPD1 protects photoreceptors from oxidative stress-induced apoptosis during renewal processes, inhibiting caspase-3 activation and upregulating anti-apoptotic proteins like Bcl-2 in RPE cells exposed to hydrogen peroxide and TNF-α (effective at 50 nM). It also safeguards neurons in ischemic conditions by counteracting inflammation and supporting homeostasis in brain tissues. Related protectins include those derived from n-3 docosapentaenoic acid (DPA), such as PD1 n-3 DPA (10R,17S-dihydroxy-docosa-7Z,11E,13E,15Z,19Z-pentaenoic acid), biosynthesized via a parallel 15-LOX pathway involving 16S,17S-epoxy-DPA as an intermediate. This mediator exhibits similar and potency (EC50 in the pico- to nanomolar range for phagocytosis enhancement). PD1 n-3 DPA resolves in models of epileptogenesis and ischemia, reducing expression (e.g., IL-1β and TNF-α), frequency by ~50%, and cognitive deficits while limiting oxidative damage in hippocampal neurons. These actions underscore the protectins' role in neural without broad overlap into peripheral mechanisms.

Maresins

Maresins are a class of specialized pro-resolving mediators (SPMs) primarily biosynthesized by from the (DHA), with additional derivatives from n-3 docosapentaenoic acid (n-3 DPA). They were discovered in 2009 through lipidomic analysis of self-resolving exudates in a model of , where they were identified as novel DHA-derived mediators produced by during the active resolution phase of . Named for their macrophage origin ("ma" from macrophage) and resolving actions ("resins"), maresins promote tissue repair and without immunosuppressive effects. The primary maresin, , has the structure 7,14-dihydroxydocosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid, featuring hydroxyl groups at positions 7 and 14 on the DHA backbone. , identified in macrophages, is 13R,14S-dihydroxy-4Z,7Z,9E,11E,16Z,19Z-docosahexaenoic acid, distinguished by its conjugated triene and epoxide-derived . From n-3 DPA, the analog n-3 DPA is 7,14-dihydroxy-8E,10E,12Z,16Z,19Z-docosapentaenoic acid, sharing a similar dihydroxy motif but with one fewer . Maresin biosynthesis begins with DHA or n-3 DPA serving as the in macrophages, where 12/15-lipoxygenase (), particularly the 14-LOX pathway, initiates to a 14S-hydroperoxy intermediate (14S-HpDHA or 14S-HpDPA). This hydroperoxy product then undergoes epoxidation at the 13,14-position to form an epoxy intermediate, followed by enzymatic —primarily by soluble epoxide (sEH)—yielding the dihydroxy maresins with specific . For MaR1 n-3 DPA, the pathway mirrors this, starting with 12-LOX-mediated peroxidation of n-3 DPA. This sequential enzymatic process ensures stereospecific production, with incorporation of oxygen from water during confirmed by . Maresins exert pro-resolving functions centered on tissue repair, notably accelerating by stimulating macrophage-mediated regeneration; for instance, MaR1 enhances tissue regrowth in models and improves muscle force recovery in volumetric muscle loss injuries. They limit by reducing deposition and inflammatory infiltration, as demonstrated in models where MaR1 treatment decreased fibrotic markers by up to 50% at early post-injury stages. Additionally, maresins promote , the of apoptotic cells by macrophages, with MaR1 enhancing uptake by 30-50% at nanomolar concentrations via activation of the LGR6 receptor, thereby preventing secondary and supporting . These actions collectively underscore maresins' role in macrophage-driven repair during .

Other Metabolites with SPM Activity

Beyond the canonical classes of specialized pro-resolving mediators (s), several emerging polyunsaturated fatty acid (PUFA) metabolites derived from docosapentaenoic acids (DPAs) and (DHA) exhibit SPM-like pro-resolving effects, including enhanced and suppression of excessive inflammation. n-3 DPA, an elongation product of (EPA), serves as a precursor for resolvins such as RvD5n-3 DPA, which is biosynthesized through sequential actions of 15-lipoxygenase (15-LOX) and other enzymes to yield a dihydroxylated at positions 10 and 17. Similarly, n-6 DPA metabolites, intermediates in metabolism, produce analogous pro-resolving dihydroxy and epoxy compounds that promote resolution in inflammatory contexts. These DPA-derived mediators are particularly noted for their roles in modulating function via receptors like GPR101. Cysteinyl-specialized pro-resolving mediators (cys-SPMs) represent another class derived primarily from DHA and n-3 DPA. These mediators are formed by enzymatic conjugation of to epoxy-intermediates in the and protectin biosynthetic pathways, yielding compounds such as cysteinyl- D1 (CTRD1) and cysteinyl-protectin D1 (CTPD1). Biosynthesis involves C4 synthase (LTC4S) for the transesterification step, followed by gamma-glutamyl transferase for , resulting in cysteine-conjugated dihydroxy structures. Cys-SPMs accelerate resolution of , enhance actions, and promote regeneration, acting through receptors like BLT1 and GPR32 to limit influx and stimulate . Oxidized keto forms, such as and , represent another group of auxiliary metabolites with SPM activity, formed through -mediated oxidation of hydroxylated PUFA intermediates. For instance, 17-oxo-DHA arises from 17-hydroxy-DHA via 15-hydroxyprostaglandin (15-PGDH) action in activated macrophages, resulting in an electrophilic α,β-unsaturated ketone that covalently modifies proteins like to activate Nrf2 signaling. These keto derivatives inhibit the production of pro-inflammatory eicosanoids, such as 5-HETE and LTB4, while promoting responses without impairing host defense. (DHEA), an endocannabinoid-like conjugate of DHA and produced by hydrolase (FAAH), further yields bioactive derivatives through (LOX) oxygenation, including 10,17-dihydroxy-DHEA, which signals via novel pathways to limit and support tissue repair. These metabolites display diverse pro-resolving activities, including anti-nociceptive effects by dampening neuronal and actions that enhance bacterial clearance without . For example, RvD5n-3 DPA reduces hypersensitivity in arthritis models by promoting macrophage and limiting release. Certain and isoprostane isomers, generated non-enzymatically or via COX-2, also contribute resolving properties; specifically, cyclopentenone isoprostanes derived from DHA exhibit effects by activating PPARγ and inhibiting , contrasting with their pro-inflammatory counterparts. Additionally, DHEA derivatives bolster peptide expression in epithelial cells during infections. Studies highlight the therapeutic relevance of these metabolites in . In autoimmune conditions like (RA), elevated plasma levels of RvD5n-3 DPA and related n-3 DPA products correlate with reduced synovial pathology and improved , suggesting their role in restoring immune .

Mechanisms of Action

Cellular and Molecular Targets

Specialized pro-resolving mediators (SPMs) primarily exert their effects through high-affinity interactions with G protein-coupled receptors (GPCRs) expressed on various immune and non-immune cells. Lipoxins, such as lipoxin A4 (LXA4), bind to the formyl peptide receptor 2 (FPR2, also known as ALX), while aspirin-triggered lipoxins like 15-epi-LXA4 also engage this receptor. D-series resolvins, including resolvin D1 (RvD1), act as agonists at both FPR2/ALX and G protein-coupled receptor 32 (GPR32). Resolvin E1 (RvE1), an E-series resolvin, selectively binds to chemokine-like receptor 1 (CMKLR1, also called ChemR23), and serves as a partial agonist and antagonist at the leukotriene B4 receptor 1 (BLT1). Resolvin D2 (RvD2) primarily targets GPR18 (also known as DRV2). These receptor interactions are stereoselective and occur with high specificity, enabling SPMs to promote resolution without suppressing immune function. Binding affinities for these GPCRs are typically in the nanomolar range, reflecting potent physiological activity. For instance, LXA4 exhibits a (Kd) of approximately 0.7 nM at FPR2/ALX, and 15-epi-LXA4 has a Kd of about 2.0 nM at the same receptor. RvD1 binds to both FPR2/ALX and GPR32 with a Kd of around 0.2 nM, while RvE1 interacts with ChemR23 at a Kd of approximately 11 nM and with BLT1 at an (Ki) of about 70 nM. These low nanomolar values for functional responses, such as calcium mobilization or β-arrestin recruitment, underscore the sensitivity of target cells to endogenous concentrations during . Protectin D1 (PD1, also known as neuroprotectin D1 or NPD1) binds to GPR37 on neutrophils with a Kd of about 25 nM. In addition to GPCRs, SPMs modulate non-receptor targets, including the γ (PPARγ). Protectins and maresins, such as PD1 and maresin 1, enhance PPARγ expression and activity in a dose-dependent manner, contributing to effects in macrophages and other cells. This modulation occurs independently of GPCR signaling and supports tissue repair processes. Tissue-specific expression influences SPM targeting; for example, protectins like NPD1 exhibit high-affinity binding sites in neuronal cells and retinal pigment epithelial cells, where they promote against . These localized interactions highlight the role of SPMs in organ-specific resolution, such as in the .

Signaling Pathways

Specialized pro-resolving mediators (SPMs) trigger intracellular signaling cascades that actively promote by suppressing pro-inflammatory pathways and enhancing protective cellular responses. These pathways ensure a timely switch from to , preventing chronic tissue damage. A primary mechanism involves the inhibition of (MAPK) signaling. For instance, A4 (LXA4) blocks ERK- and JNK-dependent pathways in macrophages and T cells, thereby reducing the production of pro-inflammatory cytokines like TNF-α. Similarly, resolvin D1 (RvD1) attenuates p38 MAPK activation in immune cells, limiting excessive inflammatory signaling. SPMs also elevate cyclic adenosine monophosphate (cAMP) levels through G-protein-coupled receptors (GPRs). By acting as positive allosteric modulators of the prostaglandin E2 receptor EP4, SPMs such as D-series resolvins and protectins enhance Gs-mediated cAMP formation in response to PGE2, which promotes anti-inflammatory macrophage polarization and phagocytosis. Another critical pathway is the suppression of nuclear factor-κB (NF-κB). RvD1 and LXA4 inhibit NF-κB nuclear translocation and DNA binding in activated immune cells, resulting in decreased expression of genes encoding pro-inflammatory mediators like IL-6 and COX-2. SPM signaling induces specific changes in gene expression to support resolution. They upregulate phagocytosis-related genes, such as Mer tyrosine kinase (MerTK), which facilitates efferocytosis of apoptotic cells by macrophages. Additionally, SPMs promote the expression of anti-apoptotic factors, enhancing cell survival and tissue repair during the resolution phase. SPMs engage in crosstalk with Toll-like receptor (TLR) signaling to mitigate excessive inflammation, including cytokine storms. RvD1 downregulates TLR4 expression via microRNA-146a in macrophages, thereby blunting downstream pro-inflammatory cytokine release and restoring immune balance. To ensure self-limitation and prevent over-, SPMs are subject to feedback loops involving enzymatic inactivation. For example, resolvin E1 (RvE1) induces its own metabolism through dehydrogenases and other enzymes during the late phase, rapidly reducing active levels and terminating signaling. This autocrine regulation maintains temporal control over inflammatory resolution.

Experimental Evidence

Genetic Manipulation Studies

Genetic manipulation studies have provided critical insights into the roles of specialized pro-resolving mediators (SPMs) in by altering key and receptors involved in their and signaling. In 5-lipoxygenase (5-LOX, encoded by ALOX5) knockout mice, the absence of this , which is essential for the initial oxygenation step in SPM production pathways including lipoxins and resolvins, results in significantly reduced levels of SPMs such as lipoxin A4 (LXA4) and resolvin D1 (RvD1). These mice exhibit exacerbated cardiac and impaired following , characterized by prolonged leukocyte infiltration and defective tissue repair, underscoring 5-LOX's necessity for timely SPM-mediated without affecting initial inflammatory responses. Knockout models of the formyl receptor 2 (FPR2, also known as ALX), the primary receptor for lipoxins and several other SPMs, demonstrate defective SPM signaling and prolonged . FPR2/ALX-deficient mice show increased and delayed clearance in models of acute , with persistent immune presence leading to exacerbated due to impaired pro-resolving actions of LXA4. Similarly, in zymosan-induced , Fpr2^{-/-} mice display reduced antimigratory responses to LXA4 and , resulting in heightened leukocyte accumulation and failure to initiate resolution phase in s. These findings confirm FPR2/ALX as a pivotal receptor for SPMs in limiting persistence and promoting . Overexpression studies using (LOX) transgenes highlight the protective effects of enhanced SPM production in models. Transgenic rabbits overexpressing 15-LOX, a key in lipoxin and protectin biosynthesis, exhibit elevated endogenous SPM levels during Porphyromonas gingivalis , leading to reduced neutrophil influx, diminished tissue destruction, and improved survival compared to wild-type controls. In analogous murine models with 12/15-LOX overexpression, increased SPM production, including LXA4, correlates with accelerated of inflammatory responses and against excessive in , demonstrating the therapeutic potential of augmenting LOX activity to boost SPMs in systemic inflammatory contexts akin to . Human genetic variants further link ALOX15 polymorphisms to altered SPM profiles in inflammatory diseases like . Promoter polymorphisms in ALOX15 (e.g., c.-5229G>A and c.-5204G>A) are associated with reduced activity, leading to lower production of 15-HETE, a precursor for lipoxins, and consequently diminished SPM levels in , a severe subtype characterized by heightened infiltration and poor resolution. These variants contribute to exacerbated airway by impairing the shift from pro-inflammatory leukotrienes to pro-resolving lipoxins, as evidenced by genetic association studies showing increased susceptibility to severity in carriers.

Animal Model Research

Animal model research has demonstrated the efficacy of specialized pro-resolving mediators (SPMs) in promoting the of across various preclinical disease models, particularly those involving acute and chronic inflammatory responses. In zymosan-induced models in mice, administration of SPMs such as resolvin D1 (RvD1), resolvin D2 (RvD2), and maresin 1 (MaR1) at low doses accelerates neutrophil clearance by approximately 45-60% and shortens the resolution interval by over 70%, thereby reducing scores and enhancing tissue . Similarly, in ischemia-reperfusion models, including cerebral and myocardial variants in rats and mice, SPMs like resolvin E1 (RvE1), neuroprotectin D1 (NPD1), and maresin 1 mitigate leukocyte infiltration, decrease pro-inflammatory expression (e.g., TNF-α and IL-1β), and improve organ function by limiting and blood-brain barrier disruption. In dextran sodium (DSS)- or trinitrobenzene sulfonic acid (TNBS)-induced models in mice, infusion of RvE1 or RvD1 reduces histologic scores by decreasing mononuclear and neutrophilic infiltration, crypt hyperplasia, and mucosal , while also lowering activity and pro-inflammatory (e.g., TNF-α, IL-12). Recent studies from 2023 onward have expanded SPM applications to cardiovascular and fibrotic conditions. In spontaneously hypertensive rat models, treatment with SPMs such as A4 (LXA4) and RvD1 at nanomolar concentrations enhances endothelium-dependent vascular relaxation via formyl peptide receptor-2 (FPR2) activation, counteracting and TNF-α-induced in resistance arteries. For , in - and nanomaterial-induced models in mice and rats, pulmonary delivery of SPM-based nanotherapeutics (e.g., resolvins encapsulated in fish-oilsomes) attenuates fibrosis progression by inhibiting and pathways in macrophages, reducing transforming growth factor-β (TGF-β)/Smad signaling in epithelial cells, and improving histological and functional outcomes at nanogram-per-milliliter doses. More recent investigations as of 2024 have shown that (MaR1) attenuates pain and joint pathology in mouse models of by reducing and promoting resolution of synovial . SPM efficacy in these models is achieved at nanomolar concentrations that mimic endogenous levels during active , reprogramming immune responses to enhance , antimicrobial activity, and tissue repair without . Dietary interventions further support SPM roles; in collagen-induced mouse models, omega-3 polyunsaturated (PUFA) supplementation elevates local production of SPMs like RvD1, reducing , cartilage degradation, and disease severity by modulating oxylipin profiles and pro-resolving pathways.

Clinical and Therapeutic Potential

Human Clinical Studies

Biomarker studies have identified reduced levels of specialized pro-resolving mediators (SPMs) in the plasma of patients with various inflammatory conditions. In (RA), circulating SPM concentrations, including resolvins and protectins, are lower compared to healthy controls, correlating with increased synovial inflammation and disease activity. Similarly, severe patients exhibit diminished SPM profiles, such as maresins, protectins, and resolvins, relative to mild cases or healthy individuals, with these reductions linked to impaired inflammation resolution and higher proinflammatory lipid mediators. In , gingival tissues and saliva from affected patients show decreased SPMs like resolvin D1 (RvD1) and maresin 1 (MaR1), which associate with heightened inflammation and microbial , improving post-therapy. Early interventional trials demonstrate that omega-3 supplementation elevates SPM levels in humans. In a double-blind, placebo-controlled crossover study of 22 healthy volunteers, enriched marine oil doses (3 g and 4.5 g) increased peripheral blood concentrations, including resolvins and protectins, in a time- and dose-dependent manner, peaking at 2-4 hours and enhancing up to 24 hours post-administration. Aspirin-triggered SPMs also show therapeutic links in ; in patients treated with omega-3 (Lovaza, 3.36 g EPA/DHA daily) for one year, absent aspirin-triggered D3 and B4 were restored, promoting macrophage-mediated clot by approximately 50%. Phase I and II data support the safety of SPM administration in acute conditions. In surgical contexts, SPM levels in correlate with reduced and tissue degradation; higher concentrations of MaR1 and RvD1 in human-derived samples decreased interleukin-6, matrix metalloproteinase-13, and breakdown markers in models of . Recent 2024-2025 findings highlight SPM profiling's prognostic value in autoimmunity cohorts. In rheumatic diseases including and systemic , altered SPM biosignatures predict disease progression and treatment response, with lower baseline levels indicating poorer resolution and higher relapse risk in longitudinal patient groups.

Emerging Therapeutic Applications

Specialized pro-resolving mediators (SPMs) hold promise as novel therapeutics in resolution pharmacology, a that targets the active of rather than mere suppression, offering advantages over traditional drugs by promoting tissue repair and limiting side effects. Recent preclinical and early clinical explorations highlight their potential in addressing unresolved inflammation in various diseases, with synthetic SPMs, precursors like omega-3 fatty acids, and modulators emerging as key delivery strategies to enhance . In management, SPMs such as resolvin D1 (RvD1), resolvin E1 (RvE1), and maresin 1 () demonstrate effects by modulating neuro-immune pathways, including inhibition of / channels and activation, at picogram to nanogram doses that outperform opioids and NSAIDs in animal models of neuropathic, inflammatory, and postoperative pain. For instance, RvD1 reduces mechanical in complete Freund's adjuvant-induced models, while stable analogs like 19-pf-RvE1 enhance potency in thermal assays. These findings position SPM-based s as a targeted approach for conditions where conventional therapies fail due to tolerance or side effects. SPMs also show therapeutic potential in pregnancy complications by supporting placental resolution and mitigating inflammatory dysregulation. In conditions like and fetal growth restriction, reduced levels of lipoxin A4 (LXA4) and RvD1 impair invasion and endothelial integrity, but supplementation with aspirin-triggered lipoxins or (DHA) precursors restores anti-inflammatory balance and improves vascular function in high-risk models. profiling in maternal has been proposed as a for predicting risks such as spontaneous , underscoring SPMs' role in personalized prenatal interventions. For pulmonary diseases, particularly interstitial lung diseases (ILDs), SPMs like LXA4 and RvD1 exhibit antifibrotic and pro-resolving actions by promoting polarization toward phenotypes and enhancing , thereby reducing storms and fibrosis progression in preclinical ILD models. In , aspirin-triggered LXA4 limits deposition, suggesting SPMs as adjuncts to current antifibrotics for better disease modification. In , SPMs contribute to protection by alleviating and inhibiting matrix metalloproteinase-13 (MMP13) activity, with RvD1 stimulating matrix production and reducing degradation in explant models. similarly suppresses interleukin-6 (IL-6) and type II cleavage in bovine osteochondral tissues, highlighting their role in preserving joint integrity. Therapeutic of SPMs relies on synthetic formulations, omega-3 , and modulators of biosynthetic enzymes like 15-lipoxygenase to overcome rapid , with and scaffold systems extending and targeting inflamed sites. This resolution approach enables low-dose administration that accelerates microbial clearance and tissue regeneration without . As of November 2025, ongoing clinical trials, such as NCT05774665 investigating omega-3-derived SPMs in , further explore their therapeutic potential. Innovations from 2023-2025 include the integration of SPMs into (PRP) for joint therapies, where higher MaR1 and RvD1 concentrations in PRP correlate with reduced IL-6, MMP13, and breakdown markers in human chondrocytes, potentially optimizing PRP efficacy for . Additionally, SPMs modulate B-cell responses in , with EPA/DHA supplementation suppressing B-cell differentiation and promoting regulatory B-cell IL-10 secretion in systemic models, thereby restoring and reducing renal . Despite these advances, challenges persist in SPM therapy, including chemical instability and short plasma half-lives that necessitate advanced delivery vehicles, as well as the need for SPM profiling in patient metabolomes to enable personalized dosing based on individual inflammatory signatures. Variability in SPM biosynthesis across patients further complicates , emphasizing the importance of biomarker-driven strategies for clinical translation.