Specialized pro-resolving lipid mediators (SPM), such as resolvin D1 (RvD1), attenuate inflammation and improve vascular remodeling in small animal vascular injury models. We describe the translational development of thin-film sustained-release devices with Benzo-RvD1 (Benzo), a synthetic analog of RvD1. An ovine bypass graft model was used to evaluate perivascular delivery. Lab-scale devices were translated toward clinical devices through a development effort with a medical device contract manufacturing organization (CMO). Pre-clinical devices were applied to ovine carotid artery bypass grafts with saphenous vein. Either a 25

Following a meal, our gut microbiome and human cells collaborate via metaorganismal metabolic circuits to produce diverse nutrient metabolites that systemically circulate to influence health and disease. Although there are now several examples of bacterial fiber-, amino acid-, and micronutrient-derived metabolites impacting cardiometabolic disease, very little is known in regards to how diet-microbe-host interactions impact lipid homeostasis. Here we address this by defining dietary fatty acid substrate availability in germ-free versus conventionally-raised mice coupled to deep multi-omic metabolic phenotyping. Our data demonstrate that the effects of dietary saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA) on the host lipidome, transcriptome, proteome and metabolome are uniquely impacted by resident microbiota. Also, the hepatic levels of both pro-inflammatory and pro-resolving lipid mediators are strongly influenced by dietary fatty acid-microbe interactions. This study presents a unique resource to the nutrition and metabolism research community to advance our understanding of metaorganismal lipid metabolism. GRAPHICAL ABSTRACT

BACKGROUND:Diet-induced white adipose tissue inflammation is associated with insulin resistance and metabolic perturbations. Conversely, exercise protects against the development of diet-induced chronic inflammation and insulin resistance independent of weight loss; however, the mechanisms remain largely unknown. We have recently shown that through adrenergic stimulation of macrophages, exercise promotes resolution of acute peritoneal inflammation by enhancing the biosynthesis of specialized proresolving lipid mediators. In this study, we sought to determine whether exercise stimulates proresolving pathways in adipose tissue and whether this response is modified by diet. Specifically, we hypothesized that exercise stimulates proresolving pathways by adrenergic signaling, which is inhibited by high-fat diet, priming the development of chronic inflammation in the adipose tissue. METHODS:To explore the dietary dependence of the proresolving effects of exercise, mice were fed either a control or high-fat diet for 2 weeks before, and throughout, a 4-week period of daily treadmill running. Glucose handling, body weight and composition, lipemia, and exercise performance were evaluated at the end of the feeding and exercise interventions. Likewise, changes in catecholamines and their biosynthetic enzymes were measured along with adipose tissue specialized proresolving lipid mediator levels and macrophage phenotype and abundance. RESULTS:When compared with sedentary controls, macrophages isolated from mice exposed to 4 weeks of exercise display elevated expression of the specialized proresolving lipid mediator biosynthetic enzyme Alox15, while adipose tissue specialized proresolving lipid mediator levels and anti-inflammatory CD301+ M2 macrophages increased. These changes were dependent upon diet as 6 weeks of feeding with high-fat diet abrogated the proresolving effect of exercise when compared with control diet-fed animals. Interestingly, exercise-induced epinephrine production was inhibited by high-fat diet, which diminished the expression of the epinephrine biosynthetic enzyme PNMT (phenylethanolamine N-methyltransferase) in adrenal glands. CONCLUSIONS:Taken together, these results suggest that a diet high in fat diminishes the proresolving effects of exercise in the adipose tissue via decreasing the biosynthesis of catecholamines.

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.

Nucleotide-binding Oligomerization Domain-Containing Protein 2 (NOD2) is a cytosolic peptidoglycan receptor important for immune defense and homeostasis. Binding muramyl dipeptide (MDP) allows NOD2 to promote the activation of Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2 or RIP2) which transduces downstream signals leading to Nuclear Factor Kappa B (NF-kB) and MAPK activation and pro-inflammatory cytokine release. Due to the known dysregulation of NOD2 signaling in various inflammatory diseases, there has been a lot of interest in pharmacological targeting of this pathway through inhibition of RIP2. Using an MDP peritonitis model, we find that activation of NOD2 also leads to the production of both pro-inflammatory as well as pro-resolution lipid mediators, suggesting an underappreciated arm of NOD2/RIP2 signaling and a potential role for NOD2 and RIP2 in resolution biology. Mechanistically, we demonstrate that RIP2 promoted the phosphorylation and enzymatic activation of Arachidonate 5-Lipoxygenase (5LO), an enzyme important for lipid mediator production. The consequences of disrupting the interaction between RIP2 and XIAP and of pharmacologic inhibition of RIP2, on 5LO activation was also assessed. This work will uncover mechanisms unique to either NF-kB activation, or this novel arm of 5LO activation. Additionally, this could guide the development of therapies for targeting one or both signaling arms, with important consequences for drug efficacy. This work was supported through NSF CAREER 2338587 awarded to J.T.T-A. Immune Response Regulation: Molecular Mechanisms (IRM)

In response to organ injury in adults, macrophages often promote scarring, yet during early life, they are required for tissue regeneration. To elucidate the mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborn versus adult hearts. Single-cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the thromboxane A2 receptor, whose activation induced a metabolic shift that supported cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.

CONTEXT:Activation of brown adipose tissue (BAT) thermogenesis improves insulin sensitivity and is beneficial in obesity. Emerging evidence indicates that BAT activation increases lipid mediators that play autocrine and endocrine roles to regulate metabolism and inflammation. OBJECTIVE:The goal of the study was to determine the relationship between 2 distinct approaches of BAT activation (cold exposure and mirabegron treatment) with lipid mediators in humans. METHODS:Healthy female subjects (n = 14) were treated with the β3-adrenergic receptor agonist mirabegron (100 mg) daily for 28 days. A subset of female subjects (n = 8) was additionally exposed to cold temperatures (14-16 °C) for 2 hours using a cooling vest prior to initiating mirabegron treatment. A panel of lipid mediators was assessed in plasma using targeted liquid chromatography-tandem mass spectrometry, and their relationship to anthropometric and metabolic parameters was determined. RESULTS:Activation of BAT with cold exposure acutely increased levels of lipoxygenase and cyclooxygenase products, including 12-hydroxyeicosapentaenoic acid, 12-hydroxyeicosatetraenoic acid (HETE), 5-HETE, 14-hydroxydocosahexaenoic acid (HDHA), an isomer of maresin 2 (MaR2), 17-HDHA, protectin D1 (PD1), and prostaglandin E2. Mirabegron treatment similarly increased these products acutely, although levels of some mediators were blunted after chronic mirabegron treatment. Selected lipid mediators, including an MaR2 isomer, 17-HDHA, 5-HETE, and 15-HETE, positively correlated with nonesterified fatty acids and negatively correlated with the respiratory quotient, while PD1, 15-HETE, and 5-HETE positively correlated with adiponectin. CONCLUSION:These results indicate that selected lipid mediators may serve as biomarkers of BAT activation.

Acute vascular injury provokes an inflammatory response, resulting in neointimal hyperplasia (NIH) and downstream pathologies. The resolution of inflammation is an active process in which specialized proresolving lipid mediators (SPM) and their receptors play a central role. We sought to examine the acute phase response of SPM and their receptors in both circulating blood and the arterial wall in a rat angioplasty model. We found that the ratio of proresolving to pro-inflammatory lipid mediators (LM) in plasma decreased sharply 1 day after vascular injury, then increased slightly by day 7, while that in arteries remained depressed. Granulocyte expression of SPM receptors ALX/FPR2 and DRV2/GPR18, and a leukotriene B4 receptor BLT1 increased postinjury, while ERV1/ChemR23 expression was reduced early and then recovered by day 7. Importantly, we show unique arterial expression patterns of SPM receptors in the acute setting, with generally low levels through day 7 that contrasted sharply with that of the pro-inflammatory CCR2 receptor. Overall, these data document acute, time-dependent changes of LM biosynthesis and SPM receptor expression in plasma, leukocytes, and artery walls following acute vascular injury. A biochemical imbalance between inflammation and resolution LM pathways appears persistent 7 days after angioplasty in this model. These findings may help guide therapeutic approaches to accelerate vascular healing and improve the outcomes of vascular interventions for patients with advanced atherosclerosis.

Chronic inflammation is a major driver of atherosclerotic cardiovascular disease, and therapeutics that target inflammation reduce clinical cardiac events beyond levels seen with conventional strategies targeting cholesterol alone. Recent findings suggest innate immune cells maintain ‘memory’ of prior exposure to inflammatory stimuli, a phenomenon known as ‘trained immunity’. In response to inflammatory stimuli, macrophages undergo metabolic and epigenetic rewiring that primes them to mount an augmented response upon a second exposure. Oxidized low-density lipoproteins (oxLDL) have recently been shown to be potent triggers of trained immunity. While trained immunity has been shown to promote inflammation, little is known about how immune training impacts efferocytosis. Therefore, we hypothesize that trained immunity in macrophages promotes inflammation by impairing efferocytosis. We treated murine bone marrow progenitors with oxLDL for 24 hours, then washed and differentiated them into macrophages (BMDMs). Upon assessing efferocytosis, trained BMDMs were able to ingest a first apoptotic cell (AC) better than untrained BMDMs yet had an impaired ability to take up additional ACs, reflecting a defect in continual efferocytosis. Using an in vivo approach, we transplanted donor bone marrow from Ldlr -/- mice fed a chow or Western diet into naïve C57BL/6 recipients. After recovery, we elicited peritoneal macrophages to assess efferocytosis and found that recipients receiving marrow from Western diet fed Ldlr -/- mice not only displayed impaired efferocytosis, but also significantly upregulated PGE 2 production, suggesting impaired resolution. To determine whether PGE 2 is a mediator of trained immunity, we primed bone marrow progenitors with PGE 2 and differentiated them into BMDMs. We found that macrophages primed with PGE 2 elaborated higher levels of inflammatory cytokines in response to LPS stimulation than controls. Overall, these findings demonstrate that oxLDL/Western diet-training impinges on the resolution program by impairing efferocytosis and are durable effects that demonstrate heritability. Future directions include determining the impact of these findings on the development of atherosclerosis.

Severe tissue loss resulting from extremity trauma, such as volumetric muscle loss (VML), poses significant clinical challenges for both general and military populations. VML disrupts the endogenous tissue repair mechanisms, resulting in acute and unresolved chronic inflammation and immune cell presence, impaired muscle healing, scar tissue formation, persistent pain, and permanent functional deficits. The aberrant healing response is preceded by acute inflammation and immune cell infiltration which does not resolve. We analyzed the biosynthesis of inflammatory and specialized pro-resolving lipid mediators (SPMs) after VML injury in two different models; muscle with critical-sized defects had a decreased capacity to biosynthesize SPMs, leading to dysregulated and persistent inflammation. We developed a modular poly(ethylene glycol)-maleimide hydrogel platform to locally release a stable isomer of Resolvin D1 (AT-RvD1) and promote endogenous pathways of inflammation resolution in the two muscle models. The local delivery of AT-RvD1 enhanced muscle regeneration, improved muscle function, and reduced pain sensitivity after VML by promoting molecular and cellular resolution of inflammation. These findings provide new insights into the pathogenesis of VML and establish a pro-resolving hydrogel therapeutic as a promising strategy for promoting functional muscle regeneration after traumatic injury.

Alveolar macrophages (AMs) act as gatekeepers of the lung's immune responses, serving essential roles in recognizing and eliminating pathogens. The transcription factor (TF) early growth response 2 (EGR2) has been recently described as required for mature AMs in mice; however, its mechanisms of action have not been explored. Here, we identified EGR2 as an epigenomic regulator and likely direct proximal transcriptional activator in AMs using epigenomic approaches (RNA sequencing, ATAC sequencing, and CUT&RUN). The predicted direct proximal targets of EGR2 included a subset of AM identity genes and ones related to pathogen recognition, phagosome maturation, and adhesion, such as Clec7a, , Atp6v0d2, , Itgb2, , Rhoc, , and Tmsb10. . We provided evidence that EGR2 deficiency led to impaired zymosan internalization and reduced the capacity to respond to Aspergillus fumigatus. . Mechanistically, the lack of EGR2 altered the transcriptional response, secreted cytokines (i.e., CXCL11), and inflammation-resolving lipid mediators (i.e., RvE1) of AMs during in vivo zymosan-induced inflammation, which manifested in impaired resolution. Our findings demonstrated that EGR2 is a key proximal transcriptional activator and epigenomic bookmark in AMs responsible for select, distinct components of cell identity and a protective transcriptional and epigenomic program against fungi.

Dysregulated inflammation-resolution programs are associated with atherosclerosis progression. Resolvins, in part, mediate inflammation-resolution programs. Indeed, Resolvin D2 (RvD2) activates GPR18, a G-protein-coupled receptor, and limits plaque progression, though the cellular targets of RvD2 remain unknown. Here, we developed a humanized GPR18 floxed ("fl/fl") and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow-derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. To understand the functions of RvD2-GPR18 in atherosclerosis, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr-/- recipients. For these experiments, we treated each genotype with either Vehicle/PBS or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis, increased cleaved caspase-3+ cells and decreased percentage of Arginase-1+ -Mac2+ cells without a change in overall Mac2+ plaque macrophages, compared with fl/fl➔Ldlr-/- transplanted mice. RvD2 treatment decreased plaque necrosis, the percent of cleaved caspase-3+ cells and increased the percent of Arginase-1+ -Mac2+ cells in fl/fl➔Ldlr-/- mice, but not in the mKO➔Ldlr-/- transplanted mice. These results suggest that GPR18 plays a causal role in limiting atherosclerosis progression and that RvD2's ability to limit plaque necrosis is in part dependent on myeloid GRP18.

Aging is associated with non-resolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a pro-resolving ligand that acts through the G-protein coupled receptor (GPCR) called GRP18. Using an unbiased screen, we report increased Gpr18 expression in macrophages from old mice and in livers from elderly humans that is associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, monocyte-derived macrophages and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly upon the bone marrow to increase monocyte-macrophage progenitors. Using a transplantation assay we further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice, and transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, our study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.

Diet-induced adipose tissue (AT) inflammation is associated with obesity and the development of systemic insulin resistance. Our lab has shown that specialized proresolving mediators (SPMs), which are induced by exercise (Exe), restore insulin sensitivity and promote resolution of adipose tissue resolution. In this study, we sought to determine if exercise-enhanced production of SPMs extends to adipose tissue and has dietary dependence. Compared with sedentary controls (Sed), mice exposed to 4 wk of Exe display elevated AT expression of SPM biosynthetic enzyme Alox15 (Sed 1.12±0.18 vs. Exe 1.68±0.13 relative expression, n =5-7), SPM levels (Sed vs. Exe; RvD1 156.7±12.02 vs. 223.0±24.71; 17 R -RvD1 354.0±35.86 vs. 534.4±98.92; RvD4 31.31±6.93 vs. 123.1±30.69; and 17 R -RvD3 2.92±1.08 vs. 8.20±1.70 pg/g, n =5-7), and proresolving M2 macrophages (F4/80 + CD301 + ; Sed 17.5±3.2 vs. Exe 40.9±4.5 %F4/80 + , n =4-6). These changes were dependent upon diet as 6-weeks of high fat diet (60% kcal from fat; HFD) feeding abrogated the proresolving effect of exercise when compared with low fat diet fed (10% kcal from fat; LFD) controls—despite performing the same amount of exercise. Interestingly, exercise-induced epinephrine (Epi) production (LFD Sed 147.2±24.4 vs Exe 312.5±60.9 ng/mL) was inhibited by HFD (Sed 121.1±22.7 vs. Exe 140.0±16.8 ng/mL). HFD feeding resulted in diminished expression of the Epi biosynthetic enzyme phenylethanolamine N-methyltransferase (PNMT) in adrenal glands (protein expression: LFD 1.0±0.25 vs. HFD 0.36±0.15, n =4). Moreover, Sed HFD fed animals treated with Epi (0.1 mg/kg i.p. daily) for 1 wk display increased abundance of proresolving adipose tissue macrophages (F4/80 + CD301 + ; Sed 17.8±0.6 vs. Exe 25.2±3.1 %F4/80 + , n =6-7). These results suggest that the resolution promoting effect of exercise in adipose tissue is controlled by high fat diet consumption and adrenergic stimulation.

Non-resolving inflammation is an underpinning of cardiovascular diseases including atherosclerosis. The resolution of inflammation is an active and highly coordinated process that involves the generation of specialized pro-resolving mediators (SPMs), and other factors including proteins, gases, and nucleotides. SPMs comprise a superfamily of lipid mediators that includes lipoxins, resolvins, maresins and protectins. SPMs act through distinct G protein-coupled receptors (GPCRs) and have been extensively studied in animal models of cardiovascular diseases. An emerging body of literature suggests that SPMs have protective roles in atherosclerosis as demonstrated using specific SPM as well as mice deficient in their receptors. This review will highlight a relatively new pro-resolving signaling axis, namely Resolvin D2-GPR18, and how understanding detailed mechanisms and cellular specificity of this signaling axis may help inform the development of more targeted pro-resolution therapies for atherosclerosis and related cardiovascular pathologies.

Introduction/Objective:Dysregulated inflammation-resolution programs are associated with atherosclerosis progression. Inflammation-resolution is in part mediated by Resolvins, including Resolvin D2 (RvD2). RvD2, which activates a G-protein coupled receptor (GPCR) called GPR18, limits plaque progression. Cellular targets of RvD2 are not known.Approach and Results:Here we developed humanized GPR18 floxed ("fl/fl") and a myeloid (Lysozyme M Cre) GPR18 knockout (mKO) mouse. We functionally validated this model by assessing efferocytosis in bone marrow derived macrophages (BMDMs) and found that RvD2 enhanced efferocytosis in the fl/fl, but not in the mKO BMDMs. We employed two different models to evaluate the role of GPR18 in atherosclerosis. We first used the PCSK9-gain of function approach and found increased necrosis in the plaques of the mKO mice compared with fl/fl mice. Next, we performed a bone marrow transfer of fl/fl or mKO bone marrow into Ldlr -/- recipients. For these experiments, we treated each genotype with either Veh or RvD2 (25 ng/mouse, 3 times/week for 3 weeks). Myeloid loss of GPR18 resulted in significantly more necrosis and cleaved caspase-3 + cells compared with fl/fl transplanted mice. RvD2 treatment decreased plaques necrosis and cleaved caspase-3 + cells in fl/fl, but not in the mKO transplanted mice.Conclusions:These results are the first to suggest a causative role for endogenous RvD2 signaling on myeloid cells in limiting plaque necrosis. Moreover, these results provide a mechanistic basis for RvD2 as a therapy limiting plaque necrosis.

Background:Specialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties.Methods:We investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays. NPs were also characterized in a rat model of carotid angioplasty.Results:PLGA NPs based on a 75/25 lactic to glycolic acid ratio demonstrated optimal loading (507.3 pg 17R-RvD1/mg NP; P = ns) and release of RvD1 (153.1 pg 17R-RvD1/mg NP; P < .05). NPs incorporating the targeting peptide adhered to immobilized TF with greater avidity than NPs with scrambled peptide (50 nM: 41.6 ± 0.52 vs 32.66 ± 0.34; 100 nM: 35.67 ± 0.95 vs 23.5 ± 0.39; P < .05). NPs loaded with 17R-RvD1 resulted in a trend toward blunted vascular smooth muscle cell migration in a scratch assay. In a rat model of carotid angioplasty, 16-fold more NPs were present after treatment with TF-targeted NPs compared with scrambled NPs (P < .01), with a corresponding trend toward higher tissue levels of 17R-RvD1 (P = .06). Benzo-RvD1 was also detectable in arteries treated with targeted NP delivery and accumulated at 10 times higher levels than NP loaded with 17R-RvD1. There was a trend toward decreased CD45 immunostaining in vessels treated with NP containing benzo-RvD1 (0.76 ± 0.38 cells/mm2 vs 122.1 ± 22.26 cells/mm2; P = .06). There were no significant differences in early arterial inflammatory and cytokine gene expression by reverse transcription-polymerase chain reaction.Conclusions:TF-targeting peptides enhanced NP-mediated delivery of SPM to injured artery. TF-targeted delivery of SPMs may be a promising therapeutic approach to attenuate the vascular injury response.

Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein–coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lacked GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages. Treatment of MA mice with RvD2 reduced steatosis and decreased hepatic fibrosis, correlating with increased Mac2+ macrophages, increased monocyte-derived macrophages, and elevated numbers of monocytes in the liver, blood, and bone marrow. RvD2 acted directly on the bone marrow to increase monocyte-macrophage progenitors. A transplantation assay further demonstrated that bone marrow from old mice facilitated hepatic collagen accumulation in young mice. Transient RvD2 treatment to mice transplanted with bone marrow from old mice prevented hepatic collagen accumulation. Together, this study demonstrates that RvD2-GPR18 signaling controls steatosis and fibrosis and provides a mechanistic-based therapy for promoting liver repair in aging.