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Resolvin D2 (RvD2)

Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as from two isomers of docosapentaenoic acid (DPA), one omega-3 and one omega-6 fatty acid. As autacoids similar to hormones acting on local tissues, resolvins are under preliminary research for their involvement in promoting restoration of normal cellular function following the inflammation that occurs after tissue injury.[1][2] Resolvins belong to a class of polyunsaturated fatty acid (PUFA) metabolites termed specialized proresolving mediators (SPMs).[3][4]

Biochemistry and production

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Resolvins (Rvs) fall into several sub-classes based on the straight chain PUFA from which they are formed and derive their unique structure. The resolvins Ds (RvDs) are metabolites of the 22-carbon PUFA, DHA (i.e. 4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid); the resolvins Es (RvEs) are metabolites of the 20-carbon PUFA, EPA (i.e. 5Z,8Z,11Z,14Z,17Z-eicosapentaenoic acid); the resolvins Dn-6DPA (RvDsn-6DPA) are metabolites of the DPA isomer, osbond acid (i.e. 4Z,7Z,10Z,13Z,16Z-docosapentaenoic acid); the resolvins Dn-3DPA (RvDn-3DPA) are metabolites of the DPA isomer, clupanodonic acid (i.e. 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid); and the resolvins Ts (RvTs) are metabolites of clupanodonic acid, that possess a 17R hydroxyl residue, whereas all RvDsn-3DPA resolvins have a 17S hydroxyl residue. Certain isomers of RvDs are termed aspirin-triggered resolvin Ds (AT-RvDs) because their synthesis is initiated by a drug-modified COX-2 enzyme to form 17(R) hydroxyl rather than 17(S) hydroxyl residue of the RvEs; however, an unidentified as of 2023 cytochrome P450 enzyme(s) may also form this 17(R)-hydroxy intermediate and thereby contribute to the production of AT-RvEs. All of the cited resolvins except the RvDsn-6DPA are metabolites of omega-3 fatty acids.[3][4]

The following oxygenase enzymes may be responsible for metabolizing PUFA to resolvins: 15-lipoxygenase-1 (i.e. ALOX15), possibly 15-lipoxygenase-2 (i.e. ALOX15B), 5-lipoxygenase (i.e. ALOX5), cyclooxygenase-2 (i.e. COX-2), and certain cytochrome P450 monooxygenases.[3][5]

Resolvin Ds

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RvDs are poly-hydroxyl metabolites of DHA. To date, six RvDs, which vary in the number, position, and chirality of their hydroxyl residues as well as the position and cis–trans isomerism of their 6 double bonds, have been described. These are: RvD1 (7S,8R,17S-trihydroxy-DHA), RvD2 (7S,16R,17S-trihydroxy-DHA), RvD3 (4S,7R,17S-trihydroxy-DHA), RvD4 (4S,5,17S-trihydroxy-DHA; chirality at position 5 not yet determined as of 2023), RvD5 (7S,17S-dihydroxy-DHA), and RvD6 (4S,17S-dihydroxy-DHA). (The structures of these RvDs are further defined at Specialized pro-resolving mediators § DHA-derived resolvins). These metabolites are formed by a wide range of cells and tissues by the initial metabolism of DHA to 7S-hydroperoxy-DHA and 4S-hydroperoxy-DHA by a 15-lipoxygenase (either ALOX15 or possibly ALOX15B) followed by the further metabolism of the two intermediates by ALOX5 to their 17-hydroperoxy derivatives; these di-hydroperoxy products are further altered to the cited RvDs by these oxygenases or by non-enzymatic reactions and the conversion of their peroxy residues ubiquitous cellular peroxidases.[3][5]

Resolvin Es

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RvEs are di- or tri-hydroxyl metabolites of EPA. To date, four RvEs have been described: RvE1 (5S,12R,18R-trihydroxy-EPA), 18S-Rv1 (5S,12R,18S-trihydroxy-EPA), RvE2 (5S,18R-dihydroxy-EPA), and RvE3 (17R,18R/S-dihydroxy-EPA). (Structures of the RvEs are further defined at Specialized pro-resolving mediators § EPA-derived resolvins). Resolvins Es are formed in manner similar to AT resolvins Ts. COX-2 modified in activity by aspirin or atorvastatin or, alternatively, a microbial or possibly mammalian cytochrome P450 monoxygenase metabolizes EPA to its 18R-hydroperoxy derivative; this intermediate is then further metabolized by ALOX5 to a 5,6 epoxide which is hydrolyzed enzymatically or non-enzymatically to RvE1 and 18S-RvE1 or reduced to RvE2; alternatively the 18R-hydroperoxide is converted to the 17R,18S vicinal diol product, RvE3.[3][5]

T series resolvins

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Human platelets pretreated with aspirin or atorvastatin metabolize the omega-3 DPA, clupanodonic acid (DPAn-3) by aspirin-treated or atorvastatin-treated COX-2 to a 13S-hydroperoxy intermediate (aspirin and atorvastatin change the activity of COX-2 from a cyclooxygenase to a hydroxyperoxidase-forming enzyme. The intermediate is then passed to nearby human neutrophils which metabolize it, probably by ALOX5 enzyme activity, to four poly-hydroxyl metabolites: RvT1 (7S,13R,20S-trihydroxy-8E,10Z,14E,16Z,18E-DPA), RvT2 (7S,12R,13S-trihydroxy-8Z,10E,14E,16Z,19Z-DPA), RvT3 (7S,8R,13S-trihydroxy-9E,11E,14E,16Z,19Z-DPA), and RvT4 (7S,13R-dihydroxy-8E,10Z,14E,16Z,19Z-DPA).[6] Subsequent studies found that these four RvTs are also formed by mixtures of human neutrophils and vascular endothelium cells and, additionally, are detected in the infected tissues of rodents and humans.[7][8]

Putative mechanisms

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Following tissue injury, the inflammatory response is a protective process to promote restoration of the tissue to homeostasis.[2] Resolution of inflammation involves various specialized lipid mediators, including resolvins.[1][2] Resolvins are under laboratory research for their potential to act through G protein-coupled receptors (GPRs): 1) RvD1 and AT-RvD1 act through the formyl peptide receptor 2, which is also activated by certain lipoxins and is therefore often termed the ALX/FPR2 receptor; 2) RvD1, AT-RVD1, RvD3, AT-RvD3, and RvD5 act through the GPR32 receptor which is now also termed the RVD1 receptor; 3) RvD2 acts through the GPR18 receptor also now termed the RvD2 receptor; and 4) RvE1 and the 18(S) analog of RvE1 are full activators while RvE2 is a partial activator of the CMKLR1 receptor. All of these receptors activate their parent cells through standard GPR-mobilized pathways.[4][9] RvE1, 18(S)-RvE1, and RvE2 inhibit the leukotriene B4 receptor 1 which is the receptor for inflammation-promoting PUFA metabolites such as LTB4 and the R stereoisomer of 12-HETE; by inhibiting the action of these pro-inflammatory mediators.[5][9]

References

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Resolvin

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Resolvins are a class of (SPMs) derived from omega-3 polyunsaturated fatty acids, primarily (EPA) and (DHA), that actively orchestrate the resolution of acute by counterregulating pro-inflammatory signals, reducing recruitment, and enhancing —the clearance of apoptotic cells and debris by macrophages. These bioactive lipids, first identified in the early 2000s, represent a in understanding as an actively regulated process rather than a passive dissipation, with resolvins exhibiting potent stereoselective actions at picomolar to nanomolar concentrations to promote tissue repair and without . Discovered through lipidomic analyses of resolving inflammatory exudates in murine models, resolvins were coined by N. Serhan and colleagues in to denote their endogenous generation during the resolution phase of , highlighting their role in downregulating leukocytic infiltration and preparing tissues for . Biosynthesis occurs via enzymatic pathways involving lipoxygenases (LOX) and cyclooxygenases (COX); for instance, E-series resolvins (e.g., RvE1) arise from EPA through sequential actions of aspirin-acetylated COX-2 and 5-LOX, while D-series resolvins (e.g., RvD1) are produced from DHA via 15-LOX or aspirin-acetylated COX-2, yielding distinct epimers like aspirin-triggered resolvin D1 (AT-RvD1). These mediators exert their effects through specific G-protein-coupled receptors, such as ChemR23 for RvE1 and GPR32 or ALX/FPR2 for RvD1, which modulate production and immune cell functions. Beyond acute inflammation, resolvins have emerged as key regulators in chronic inflammatory conditions, including periodontitis, , and autoimmune diseases, where their dysregulation correlates with persistence and severity. Recent studies underscore their therapeutic potential, with synthetic resolvins or omega-3 supplementation showing promise in enhancing resolution pathways, reducing organ damage in , and alleviating in , including Phase 1 clinical trials for resolvin-based therapies in as of 2025, thereby positioning them as candidates for novel anti-inflammatory interventions.

History and Discovery

Initial Identification

The initial identification of resolvin occurred in 2000 through lipidomic analyses of inflammatory exudates and cellular interactions, revealing endogenous mediators derived from omega-3 polyunsaturated fatty acids that actively promote the resolution of inflammation. In 2000, Serhan and colleagues reported metabolites from (EPA) in aspirin-treated human endothelial cells and polymorphonuclear leukocytes (PMNs), including 18R-hydroxyeicosapentaenoic acid (18R-HEPE), which PMNs then convert via 5-lipoxygenase (5-LOX) into bioactive trihydroxy products, such as 5,12,18R-trihydroxyeicosapentaenoic acid (5,12,18R-triHEPE). These studies demonstrated that aspirin acetylates (COX-2), shifting EPA metabolism toward these products. Early functional assays showed these mediators potently blocked PMN transendothelial migration with IC50 values of 5–50 nM, highlighting their potential without suppressing immune cell function. Subsequent stereochemical assignment in 2005 confirmed the structure of resolvin E1 (RvE1) as 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (5S,12R,18R-trihydroxy-EPE), establishing its conjugated triene and hydroxyl configurations essential for bioactivity. This E-series pathway exemplified initial biosynthetic circuits involving omega-3 fatty acids like EPA and lipoxygenases such as 5-LOX and 15-LOX, where transcellular cooperation between cell types generates these mediators during aspirin-triggered resolution programs. The term "resolvins" was coined in 2002, with E-series formally named in subsequent work around 2004–2005. In 2002, the same group identified D-series resolvins, beginning with resolvin D1 (RvD1) from (DHA) in exudates from a murine zymosan-induced model, a self-resolving paradigm. mediator profiling revealed DHA conversion to 17R-hydroxydocosahexaenoic acid (17R-HDHA) via aspirin-acetylated COX-2, followed by PMN 5-LOX-mediated transformations yielding trihydroxy products that counter pro-inflammatory signals like B4. RvD1 was structurally defined as 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-, featuring a distinct conjugated triene system. , picomolar concentrations of RvD1 reduced infiltration by 40–80% in , promoting and microbial clearance while limiting excessive . These pioneering discoveries positioned resolvins as key members of the broader class of (SPMs), which orchestrate the active termination of . Early murine models, including air pouches and , provided foundational evidence of their stereoselective actions in dampening recruitment and enhancing resolution, setting the stage for further mechanistic exploration.

Key Developments

Following the initial identification of E-series resolvin precursors in 2000, the coining of "resolvins" with D-series in 2002, and naming of RvE1 in 2004–2005, researchers in Charles Serhan's laboratory expanded the resolvin family through lipid mediator of inflammatory exudates, identifying additional D-series resolvins (RvD2 through RvD6) in 2006 and 2007 using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate their structures and biosynthetic pathways from (DHA). Similarly, E-series resolvins RvE2 and RvE3 were identified in the mid-2000s via targeted in tissues and cells, confirming their derivation from (EPA) and roles in limiting infiltration during self-limited . In the , the discovery of T-series resolvins (RvT1 through RvT4) emerged from studies on n-3 docosapentaenoic acid (n-3 DPA) , with RvT1 characterized as 7S,14R,21R-trihydroxy-4Z,8E,10E,12Z,16Z,19Z-docosahexaenoic acid in 2014 using LC-MS/MS profiling of mouse exudates and human macrophages. These mediators were shown to enhance macrophage phagocytosis and reduce , broadening the scope of DHA-derived pro-resolving signals beyond traditional D-series. The concept of specialized pro-resolving mediators (SPMs) evolved under Serhan's group from 2008 to 2018, integrating resolvins with lipoxins and protectins into a unified framework for active resolution, as detailed in seminal reviews highlighting their stereoselective actions in temporal leukocyte trafficking and tissue repair. Key publications during this period, including a 2015 Reviews article, emphasized SPMs' endogenous regulation of resolution biology, shifting paradigms from passive dampening to programmed mediator networks. Advances in resolvin and accelerated functional validation, with the first complete stereoselective synthesis of RvD1 achieved in 2013 and refined analogs developed by 2015 to enable studies on bacterial clearance and without reliance on natural extraction. These synthetic approaches confirmed the bioactive 17R configuration's potency in human cell assays, facilitating high-fidelity pharmacological probes. From 2020 onward, human metabolomics studies using LC-MS/MS have confirmed the temporal production of resolvins during inflammation resolution, correlating with reduced pro-inflammatory eicosanoids.

Biosynthesis

Precursors and Sources

Resolvins are derived from specific omega-3 polyunsaturated fatty acids (PUFAs) as their primary precursors. The E-series resolvins originate from eicosapentaenoic acid (EPA, 20:5 n-3), while the D-series resolvins are biosynthesized from docosahexaenoic acid (DHA, 22:6 n-3). In addition, the T-series resolvins stem from n-3 docosapentaenoic acid (n-3 DPA, 22:5 n-3), an intermediate in the omega-3 PUFA metabolic pathway. Endogenously, these precursors are synthesized in humans through desaturation and elongation of alpha-linolenic acid (ALA, 18:3 n-3), primarily in tissues such as the liver, , and immune cells, where they accumulate in phospholipids and circulate in plasma. These omega-3 PUFAs are incorporated into cell membranes of resident cells and infiltrating leukocytes, serving as substrates for resolvin production during inflammatory responses. Dietary intake provides the main exogenous sources of EPA, DHA, and n-3 DPA, with fatty fish like and being rich in EPA and DHA, alongside supplements and algal oils as concentrated options. serve as a primary vegan source, as they are the origin of these PUFAs in the marine . Plant-based ALA from sources like flaxseeds and walnuts can contribute indirectly, but human conversion efficiency to EPA and DHA is low, estimated at 5-10% for EPA and less than 5% for DHA. Production of these is upregulated during acute , with increased release from infiltrating leukocytes and activated resident cells to support timely resolvin formation. In typical human plasma, DHA concentrations average around 100 μM under standard Western diets, while omega-3 deficiency leads to depleted levels of these PUFAs, impairing subsequent resolvin . These precursors are enzymatically transformed into resolvins to actively resolve .

Enzymatic Pathways

Resolvins are biosynthesized through multi-step enzymatic cascades involving sequential oxygenation of omega-3 polyunsaturated fatty acids by lipoxygenases (LOX), with additional roles for (CYP450) and aspirin-acetylated (COX-2), culminating in reduction and cyclization steps that generate bioactive trihydroxy products. These pathways often proceed via hydroperoxy intermediates that are further transformed into , followed by and reductase actions to yield the final resolvins, ensuring stereospecific configurations essential for their pro-resolving activities. Transcellular cooperation is a hallmark, where initial oxygenation occurs in one cell type (e.g., endothelial cells or neutrophils providing hydroperoxides), and downstream conversions are completed in others (e.g., macrophages via and reductase). In the E-series pathway, (EPA) undergoes initial oxygenation at the 18-position by CYP450 epoxygenases or aspirin-acetylated COX-2 to form 18R-hydroperoxy-EPA (18R-HpEPE), which is reduced to 18R-hydroxy-EPA (18R-HEPE). This intermediate is then acted upon by 5-LOX to introduce a 5S-hydroperoxy group, yielding 5S,18R-diH(p)EPE, which undergoes further conversion by 12/13-LOX to produce resolvin E1 (RvE1) or resolvin E2 (RvE2) through formation and . The aspirin-triggered variant shifts the to 18R series via acetylated COX-2, promoting distinct epimeric products with enhanced stability during inflammation. The D-series pathway begins with docosahexaenoic acid (DHA) oxygenated by 15-LOX at the 17-position to 17S-hydroperoxy-DHA (17S-HpDHA), reduced to 17S-hydroxy-DHA (17S-HDHA). Subsequent 5-LOX action introduces a 7S-hydroperoxy moiety, forming 7S,17S-diH(p)DHA, which is transformed into an epoxide intermediate and hydrolyzed to resolvin D1 (RvD1) or other D-series members like RvD2. An aspirin-modified route via acetylated COX-2 generates the 17R epimer series, leading to aspirin-triggered RvD1 (AT-RvD1) with altered stereospecificity at the 17-position. For T-series resolvins (13-series), n-3 docosapentaenoic acid (n-3 DPA) is initially oxygenated by cyclooxygenase-2 (COX-2) at the 13-position to form 13R-hydroperoxy-DPA (13R-HpDPA), which is reduced to 13R-hydroxy-DPA (13R-HDPA). This intermediate is then further metabolized by 5-LOX to introduce additional hydroxyl groups, followed by epoxide intermediates and stereospecific hydrolysis to yield RvT1 (7S,13R-trihydroxy-4Z,9E,11E,13R,14E,16Z,19Z-docosapentaenoic acid), RvT2, RvT3, and RvT4. Native COX-2 produces the standard T-series, while aspirin-acetylated COX-2 generates epimeric forms. Parallel pathways from n-3 DPA via 15-LOX or 12-LOX produce other specialized pro-resolving mediators, such as RvD1n-3DPA or maresin-like products, but not the core T-series members. These pathways are regulated by inflammatory signals, such as TNF-α, which upregulate 5-LOX expression and activity in macrophages, facilitating the timely production of resolvins during the transition to resolution. is preserved throughout by the chiral selectivity of LOX enzymes, ensuring the conjugated triene and hydroxyl arrangements critical for resolvin function.

Classification

E-series Resolvins

The E-series resolvins are a class of (SPMs) derived from the omega-3 fatty acid (EPA). They play a key role in actively resolving by regulating immune cell responses and mediator production. The primary members include resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid), resolvin E2 (RvE2; 5S,18R-dihydroxy-6Z,8Z,10E,14Z,16E-eicosapentaenoic acid), resolvin E3 (RvE3; 17R,18S-dihydroxy-5Z,8Z,11Z,13E,15E-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Biosynthesis of E-series resolvins occurs primarily through transcellular interactions between vascular endothelial cells and immune cells, such as neutrophils and macrophages. For RvE1 and RvE2, the pathway is often aspirin-dependent, where aspirin-acetylated (COX-2) in endothelial cells converts EPA to 18R-hydroxyeicosapentaenoic acid (18R-HEPE), which is then acted upon by 5-lipoxygenase (5-LOX) in neutrophils to yield the conjugated triene-containing RvE1 or the dihydroxy RvE2. RvE3 arises from 18S-HEPE via (CYP450) epoxygenases or alternative lipoxygenases, while RvE4 is generated through sequential actions of 15-LOX and 5-LOX on EPA, often under hypoxic conditions in leukocytes. An alternative microbial CYP450 pathway can also produce these mediators in certain contexts. These resolvins exhibit physicochemical properties that confer stability and bioactivity, including conjugated triene or double-bond systems in their structures, which provide characteristic UV absorbance (e.g., 270 nm for RvE1) and resistance to rapid degradation. They demonstrate nanomolar potency in bioassays, with values around 10-100 nM for limiting infiltration and promoting efferocytosis. Distinct features of E-series resolvins include their potent inhibition of pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α) and chemokines such as leukotriene B4 (LTB4), which reduces and endothelial . RvE1, in particular, promotes in dendritic cells, facilitating immune resolution without . Endogenous concentrations of E-series resolvins in human inflammatory fluids are typically in the picomolar range during resolution.

D-series Resolvins

D-series resolvins are biosynthesized from the omega-3 fatty acid (DHA), contributing to the active resolution of by limiting infiltration and promoting tissue repair. The family includes six main members: resolvin D1 (RvD1; 7S,8R,17S-trihydroxy-4Z,9E,11E,13Z,15E,19Z-DHA), resolvin D2 (RvD2; 7S,16R,17S-trihydroxy-4Z,8E,10Z,12E,14E,19Z-DHA), resolvin D3 (RvD3; 4S,11R,17S-trihydroxy-5Z,7E,9E,13Z,15E,19Z-DHA), resolvin D4 (RvD4; 4S,17S-dihydroxy-5Z,7E,9E,11Z,13E,15Z,19Z-DHA), resolvin D5 (RvD5; 5S,14R,17S-trihydroxy-6Z,8E,10Z,12E,14E,16Z,19Z-DHA), and resolvin D6 (RvD6; 4S,7S,16R,17S-tetrahydroxy-5E,8Z,10Z,12E,14E,19Z-DHA). These molecules feature tri- or tetra-hydroxylated structures with specific double-bond configurations that enable their interactions with cellular receptors and membranes. E- and D-series include native and aspirin-triggered (AT) epimers differing in at key positions, both contributing to resolution. Biosynthesis of D-series resolvins proceeds through sequential enzymatic conversions of DHA, primarily involving lipoxygenases in transcellular pathways during . Key intermediates include 17-hydroperoxy-DHA (17S-HpDHA) via the 17S pathway or 17R-HpDHA via the aspirin-triggered pathway, followed by further oxygenation and formation to yield the final resolvins. shares enzymes such as 15-lipoxygenase (15-LOX) with other DHA-derived mediators. Due to the high enrichment of DHA in neural tissues, D-series resolvins are produced in elevated yields in the and , supporting neuroprotective functions. The physicochemical properties of D-series resolvins are defined by their extended polyene chains, which facilitate incorporation into lipid bilayers and modulate for efficient cellular signaling. is essential for bioactivity; for instance, the native 17S configuration in RvD1 confers potent resolving actions, whereas certain synthetic or epimeric isomers lacking this specificity exhibit reduced or no activity. D-series resolvins distinctly enhance by macrophages and neutrophils, accelerating the clearance of apoptotic cells and debris without provoking further . They also regulate excessive production in models of , mitigating cytokine storms and improving survival outcomes. Endogenous concentrations of D-series resolvins in inflamed human tissues are typically in the picomolar range during resolution. To address their rapid , synthetic analogs of D-series resolvins, such as stabilized RvD1 mimetics, have been developed to enhance and prolong therapeutic efficacy.

T-series Resolvins

The T-series resolvins, also known as 13-series resolvins, are a family of derived from n-3 docosapentaenoic acid (n-3 DPA). The primary members include RvT1 (also denoted as RvD5n-3 DPA; 7S,14R,21R-trihydroxy-4Z,8E,10E,12Z,16Z,19Z-DPA), RvT2 (7S,17S-dihydroxy-DPA), RvT3 (10R,17S-dihydroxy-DPA), and RvT4 (8R,17S-dihydroxy-DPA). These molecules feature hydroxyl groups at specific chiral centers and conjugated double-bond systems characteristic of resolvin families, enabling their bioactive roles in resolution. Biosynthesis of T-series resolvins begins with the conversion of n-3 DPA to 13R-hydroxy-DPA via endothelial cyclooxygenase-2 (COX-2), followed by further oxygenation involving 12/15-lipoxygenase (LOX) activity to yield the trihydroxy and dihydroxy products. These mediators are prominently produced in platelets and vascular endothelium during inflammatory responses, though they occur at lower abundance compared to D- and E-series resolvins due to the relatively modest dietary intake of n-3 DPA. Physicochemically, T-series resolvins possess a 22-carbon backbone from n-3 DPA, with conjugated triene or moieties that confer UV similar to other resolvins, alongside enhanced circulatory stability attributed to their longer chain length and patterns. This structural profile supports their persistence in biological fluids, facilitating targeted vascular actions. Distinct from other series, T-series resolvins exhibit dual and properties, notably inhibiting platelet aggregation and modulating leukocyte-platelet interactions to limit thrombotic inflammation. These features underscore their specialized role in vascular protection, building on pathways akin to D-series resolvins but with greater emphasis on thromboregulation. T-series resolvins have been detected at picomolar concentrations in cardiovascular tissues during in studies as of 2025, with levels elevated by dietary n-3 DPA sources such as seal oil supplementation.

Mechanisms of Action

Receptor Interactions

Resolvins exert their pro-resolving actions primarily through interactions with specific G-protein-coupled receptors (GPCRs), enabling stereoselective binding and activation of pathways. In the D-series, resolvin D1 (RvD1) binds to two key receptors: GPR32 (also known as DRV1) and ALX/FPR2, the latter of which is shared with A4. Resolvin D2 (RvD2) specifically interacts with GPR18 (DRV2). For the E-series, resolvin E1 (RvE1) primarily engages ChemR23 (also termed CMKLR1), with lower-affinity binding to BLT1, the receptor. Binding affinities for these interactions fall within the nanomolar range, underscoring their potency. For instance, RvD1 exhibits high-affinity binding to human phagocytes with a (Kd) of approximately 0.17 nM, while RvD2 binds GPR18 with a Kd of about 10 nM. These interactions demonstrate strict , as only the native resolvin stereoisomers activate the receptors effectively, whereas isomers or antagonists fail to elicit responses. Receptors for resolvins are distributed across various cell types involved in , including leukocytes such as neutrophils, monocytes, and macrophages; endothelial cells; and neurons. GPR32, for example, is expressed on macrophages, T cells, and endothelial cells, facilitating localized resolution signals. This distribution allows resolvins to modulate immune responses at sites of . Resolvin-receptor binding often involves biased , particularly at FPR2, where resolvins preferentially activate pro-resolving signaling cascades over pro-inflammatory ones, promoting resolution without suppressing host defense. Resolvins also engage in receptor cross-talk by competing with pro-inflammatory ligands for binding sites. At FPR2, RvD1 and other resolvins displace formyl-methionyl-leucyl-phenylalanine (fMLF), a bacterial that drives , thereby dampening excessive leukocyte activation. For T-series resolvins (RvT1–RvT3), emerging evidence indicates interactions with GPR32 and FPR2, similar to D-series mediators, though further is ongoing.

Downstream Signaling

Upon binding to their cognate receptors, resolvins initiate downstream signaling primarily through Gi/o-coupled G-protein activation, which inhibits adenylyl cyclase and reduces cyclic AMP (cAMP) levels, thereby dampening pro-inflammatory responses in leukocytes. This Gi-mediated pathway also facilitates β-arrestin recruitment, promoting biased signaling that favors anti-inflammatory outcomes, such as enhanced efferocytosis and reduced neutrophil activation. Key intracellular cascades modulated by resolvins include the (MAPK)/extracellular signal-regulated kinase (ERK) pathway, where resolvins like RvD1 inhibit ERK1/2, p38, and JNK , thereby limiting pro-inflammatory release. In parallel, activation of the (PI3K)/Akt pathway by RvD1 and RvE1 promotes of apoptotic cells and debris, supporting tissue repair without excessive inflammation. Additionally, resolvins suppress nuclear factor-kappa B () translocation and activity, reducing production of such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in macrophages and neutrophils. Series-specific signaling highlights distinct mechanisms; for instance, RvE1 antagonizes leukotriene B4 (LTB4) signaling by directly competing at the BLT1 receptor, in addition to its actions through ChemR23 (also known as CMKLR1), thereby inhibiting LTB4-induced neutrophil chemotaxis and pro-inflammatory amplification. Conversely, RvD1 enhances IL-10 production via activation of signal transducer and activator of transcription 3 (STAT3), fostering an anti-inflammatory milieu that promotes resolution. The temporal dynamics of resolvin signaling exhibit rapid effects within minutes, such as promoting leukocyte through PI3K/Akt-dependent pathways, which facilitates the clearance of inflammatory cells. Sustained signaling over hours leads to changes, including upregulation of on macrophages to enhance of apoptotic neutrophils. Resolvins integrate with other (SPMs), exhibiting synergy with lipoxins at shared receptors like ALX/FPR2, where co-activation amplifies anti-inflammatory and pro-resolving programs in overlapping cellular contexts.

Physiological Roles

Inflammation Resolution

Resolvins actively terminate acute inflammatory responses by modulating key immune cell functions, thereby promoting the resolution phase without compromising host defense. These , derived from omega-3 fatty acids, limit excessive leukocyte infiltration and facilitate the clearance of inflammatory debris, restoring tissue . In , resolvins reduce recruitment by blocking pro-inflammatory signals such as IL-1β and TNF-α, with resolvin E1 (RvE1) inhibiting TNF-α-induced polymorphonuclear leukocyte (PMN) infiltration by 50-70% in murine models. They also promote neutrophil and , enhancing and subsequent clearance by macrophages. Additionally, resolvins like resolvin D1 (RvD1) facilitate reverse transmigration, allowing neutrophils to exit inflamed tissues and return to the circulation or lymphatics, reducing local accumulation. For macrophages, resolvins enhance , the of apoptotic cells, with RvD1 increasing uptake of apoptotic PMNs by macrophages. This process is complemented by a phenotypic switch from pro-inflammatory M1 macrophages to resolving macrophages, as seen with RvD2 dampening M1 responses in inflammatory exudates. Resolvins modulate lymphocytes by inducing tolerance in s and promoting regulatory T cells (Tregs). RvE1 inhibits migration and maturation, attenuating adaptive immune activation and fostering tolerance. RvD1 enhances Treg percentages and expression, suppressing effector T-cell responses. These actions occur temporally, with resolvin production peaking 4-24 hours post-inflammation onset, aligning with the resolution phase to restore without . In vivo evidence from murine models demonstrates robust efficacy, where RvD1 infusion reduces PMN infiltration by 50-80% in peritonitis and air pouch assays, accelerating resolution.

Tissue Repair and Protection

Resolvins play a crucial role in epithelial repair by promoting the migration and proliferation of keratinocytes, facilitating efficient wound closure without excessive vascularization. In skin injury models, topical application of D-series resolvins such as RvD1 and RvD2 accelerates re-epithelialization, reducing the time to 50% wound closure by approximately one day in mice. These effects are mediated through receptor-dependent pathways, including ALX/FPR2 for RvD1 and GPR18 for RvD2, which enhance keratinocyte migration via activation of the PI3K-AKT-mTOR-S6 signaling axis without significantly altering proliferation rates. In organ protection, resolvins confer during by limiting tissue damage in the penumbra region. Administration of RvD1 in mouse models of transient occlusion significantly reduces infarct volume at three days post-reperfusion, promoting microglial of neutrophils and energy to support neuronal . Similarly, RvD1 combined with neuroprotectin D1 (NPD1) enhances penumbral , decreasing infarct size and improving neurological outcomes in ischemic . For cardioprotection, resolvin E1 (RvE1) limits myocardial in rat models by reducing infarct size in a dose-dependent manner—from 30.7% in controls to 9.0% at 0.3 mg/kg—while decreasing leukocyte infiltration by up to 90% through PI3K/Akt/eNOS activation and inhibition of . RvD1 also attenuates ischemia-reperfusion damage in the heart by suppressing inflammatory cascades and preserving cardiomyocyte viability. Resolvins exhibit anti-fibrotic effects by suppressing transforming growth factor-β (TGF-β) signaling in myofibroblasts and resolving organ in preclinical models. In carbon tetrachloride-induced liver , RvD1 inhibits activation via the AKT/ pathway, reducing and downstream TGF-β1/Smad3-mediated expression of pro-fibrotic genes such as I, α-smooth muscle (α-SMA), and growth factor (). This leads to decreased deposition and progression. In the obstructed , both RvE1 and RvD1 inhibit interstitial by limiting proliferation and TGF-β-driven matrix accumulation. RvE1 further mitigates metabolic and physical liver in rats by promoting resolution of fibrotic lesions and modulating inflammatory pathways such as . In pulmonary models, aspirin-triggered RvD1 (AT-RvD1) exerts pleiotropic anti-fibrotic actions, decreasing α-SMA expression in myofibroblasts and alleviating bleomycin-induced lung . During microbial challenges, resolvins balance host defense by limiting excessive while preserving bacterial clearance. In experimental induced by cecal ligation and puncture, RvD1 enhances phagocytic bacterial clearance in mice, reduces infiltration, and suppresses pro-inflammatory cytokines via inhibition, thereby improving survival without impairing immune function. RvD2 similarly promotes resolution in and infections by enhancing and phagocytosis of while curtailing polymorphonuclear leukocyte accumulation. These actions ensure effective microbial elimination alongside controlled , as demonstrated in models of systemic bacterial where resolvins boost apoptotic cell and debris clearance. Regarding long-term outcomes, resolvins prevent chronic scarring by facilitating complete tissue remodeling and resolution of fibrotic processes. In 2020s studies, including RvD1 have shown potential in post-viral lung repair, inhibiting the transition from acute to in models relevant to sequelae, such as by regulating function and reducing persistent deposition in the s. This supports prevention of scarring in respiratory tissues following severe infections.

Therapeutic Potential

Preclinical Evidence

Preclinical studies have demonstrated the efficacy of resolvins in various animal models of , highlighting their role in promoting resolution without . In dextran sulfate sodium (DSS)-induced models in mice, administration of resolvin E1 (RvE1) significantly ameliorated disease severity by reducing weight loss, colonic shortening, and histological damage scores, with significant improvements in disease activity index scores (P<0.01) compared to untreated controls. Similarly, resolvin D1 (RvD1) attenuated arthritis in collagen-induced arthritis (CIA) mice by protecting joint cartilage and reducing paw swelling and inflammatory infiltration, significantly reducing clinical arthritis scores and protecting against cartilage degradation. In infectious disease models, resolvins enhance host defense and survival. For instance, RvE1 treatment in mice with Escherichia coli peritonitis increased survival rates to 70% at 6 hours post-infection compared to near-complete mortality in untreated groups, while also promoting neutrophil apoptosis and reducing lung inflammation. Resolvins also exhibit antiviral effects; in influenza A virus-infected mice, RvD1 and related mediators reprogrammed macrophages toward an M2 pro-resolving phenotype, decreasing viral load and inflammatory cytokine production such as IL-6 by over 50%. Neurodegenerative models further support resolvins' protective effects. In AppNL-G-F knock-in mice modeling , intranasal delivery of RvD1 alongside other resolvins improved memory performance in novel tasks and reduced microglial activation, though plaque burden remained unchanged. In cardiovascular contexts, T-series resolvins (RvTs) limited in hyperlipidemic mice by reducing and burden by 40-60%, enhancing clot resolution. Additionally, RvE1 reduced atherosclerotic plaque formation in cholesterol-fed rabbits by 30-50%, decreasing intima/media ratio and inflammatory cell infiltration in aortic tissues. Recent advancements from 2020 to 2025 have focused on improving resolvin delivery and synergies. Nanocarrier formulations, such as RvD1-loaded liposomes, enhanced with sustained release over 11 days and prolonged joint retention up to 14 days in mice, resulting in sixfold lower damage scores compared to free RvD1. Synergistic effects with omega-3 diets in high-fat diet-induced models showed that dietary supplementation increased endogenous resolvin levels, reducing hypothalamic and body weight gain by 20-30% more effectively than diet alone.

Clinical Applications

Resolvins and their analogs have shown promise in early-phase human clinical s for treating inflammatory conditions, particularly in and . A Phase II clinical evaluated RX-10045, a synthetic analog of resolvin E1 (RvE1), as topical for , demonstrating improvements in ocular symptoms such as discomfort compared to . Similarly, DHA-derived omega-3 formulations in have been tested in randomized s, leading to enhanced tear film stability and reduced in patients with dry eye, with symptom scores improving by up to 20-30% in responsive cohorts. For periodontitis, observational studies have measured elevated resolvin levels in gingival crevicular fluid, but therapeutic applications remain limited to topical analogs; a small of a stable resolvin/ analog applied locally reduced gingival and probing depths by approximately 1 mm in mild cases, suggesting potential for adjunctive . In systemic applications, pilot trials have explored resolvins indirectly through omega-3 enriched interventions that boost (SPMs). A Phase II pilot study of lipid-intensive therapy using emulsions in patients reported no significant difference in SOFA scores overall, but subgroups with early administration showed modest reductions in (ΔSOFA -2 points) and improved profiles conducive to SPM production. For COVID-19, multiple 2023 randomized trials investigated omega-3 supplementation as an adjunct, finding that high-dose EPA/DHA (2-4 g/day) increased plasma SPM levels and reduced ICU stays by 1-3 days in moderate-severe cases, with lower rates of (odds ratio 0.65). These effects were attributed to enhanced resolvin , correlating with decreased inflammatory cytokines like IL-6. In 2024-2025, Pharmaceuticals advanced TP-317, an oral Resolvin E1 analog, through Phase 1a trials demonstrating , favorable , and target engagement via the LTB4-BLT1 pathway, with a Phase 1b study planned for in 2025. Challenges in clinical translation include the short of resolvins (minutes to hours ), which has been addressed by liposomal encapsulation to improve stability and ; liposomal RvD1 formulations maintained activity for over 48 hours in early pharmacokinetic studies and showed tolerability in small cohorts for localized delivery. Plasma biomarkers for SPMs, such as resolvin D1 and E1 levels measured via LC-MS/MS, have been validated in and inflammatory cohorts, with levels below 1 nM indicating resolution deficits and guiding patient stratification. As of November 2025, no resolvins or direct analogs have received FDA approval for therapeutic use, though aspirin indirectly promotes their production by acetylating COX-2 to yield aspirin-triggered resolvins, as evidenced in cardiovascular trials where low-dose aspirin (81 mg) elevated AT-RvD1 by 20-50%. Future directions emphasize personalized approaches, such as 15-LOX variants to predict resolvin production efficiency, enabling tailored omega-3 dosing in responsive individuals. Dietary interventions, including 2-3 g/day EPA/DHA supplementation, have clinically increased endogenous resolvin levels by 2-5 fold in plasma, supporting resolution in chronic without synthetic drugs.

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