Resolving Inflammation in Nonalcoholic Steatohepatitis
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COMMENTARY The Journal of Clinical Investigation Resolving inflammation in nonalcoholic steatohepatitis Matthew Spite Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. as other SPMs such as resolvins and pro- tectins, resolve chronic inflammation and Chronic unresolved inflammation contributes to the development of improve systemic metabolism and hepatic nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, steatosis in mouse models of obesity and fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et type 2 diabetes (8–11). In this issue, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates al. add new insights into the regulation of NASH by reprograming macrophages to an antiinflammatory phenotype. MaR1 biosynthesis in obesity and identify Mechanistically, they identified retinoic acid–related orphan receptor downstream pathways engaged by MaR1 in α (RORα) as both a target and autocrine regulator of MaR1 production. macrophages that could, in part, underlie Because NASH is associated with many widely occurring metabolic diseases, its protective actions (12). including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications. Nonresolving inflammation in nonalcoholic steatohepatitis While acute inflammation normally resolves, accumulating evidence indicates Inflammation and its Maresins (macrophage mediators in that maladaptive unresolved inflamma- resolution: role of maresins resolving inflammation) were originally tion contributes to several chronic diseas- Acute inflammation is a temporally coordi- discovered by Serhan et al. in resolving es, including nonalcoholic steatohepatitis nated host response to invading pathogens inflammatory exudates as novel proresolv- (NASH) (13). The development of NASH and tissue injury. Instructed by endoge- ing molecules (2). Their complete struc- is associated with diseases of altered sys- nous mediators, distinct leukocyte subsets tures with stereochemical assignments temic metabolism, such as type 2 diabetes, sequentially follow defined routes, carry have been systematically elucidated, and obesity, and hyperlipidemia. Lipotoxic- out specialized tasks, and ultimately clear the mechanisms of their biosynthesis have ity in hepatocytes occurs as a result of an from the tissue so that its function can be been defined. Maresin 1 (MaR1) is biosyn- imbalance between lipogenesis, secre- restored. Proinflammatory mediators, such thesized from docosahexaenoic acid (DHA) tion, and fatty acid β-oxidation, and can as chemokines and lipid mediators (e.g., via 12-lipoxygenase–mediated (12-LOX– lead to apoptosis and necrosis. Release of leukotrienes, prostaglandins), promote mediated) production of a 14-hydroperoxy endogenous damage-associated molec- vascular permeability, amplify leukocyte intermediate that undergoes enzymatic ular patterns (DAMPs) initiates a sterile infiltration, and stimulate the release of epoxidation to form 13S, 14S-epoxy mares- inflammatory response characterized by substances that assist in pathogen eradi- in (eMaR) (2, 3). This epoxide is enzy- robust proinflammatory cytokine produc- cation. Resolution of inflammation begins matically converted to MaR1 (7R, 14S-di- tion and accumulation of leukocytes (e.g., with the biosynthesis of mediators that hydroxy-4Z,8E,10E,12Z,16Z,19Z-doco- neutrophils, macrophages, dendritic cells, terminate neutrophil infiltration and proin- sahexaenoic acid) and MaR2, or can be or Th17 cells). Macrophages polarized to a flammatory mediator production to prevent conjugated with glutathione to produce the proinflammatory state play a critical role in excessive damage to healthy tissue. These newly characterized cysteinyl SPM (2–5). the progression of NASH, both in perpet- specialized proresolving mediators (SPMs), Maresins blunt neutrophil chemotaxis uating chronic inflammatory signaling via such as the maresins, also stimulate phago- and promote macrophage efferocytosis the production of inflammatory cytokines cytes to clear dead cells and bacteria, and in animal models of acute inflammation. (e.g., TNF-α and IL-1β) and in promoting they actively engage tissue reparative pro- They have direct actions on human macro- fibrosis via the release of profibrotic cyto- grams (1). Thus, SPMs are host-protective phages, are organ protective, and stimulate kines (i.e., TGF-β1) (13). In contrast, polar- mediators that temper inflammation with- tissue regeneration (2, 6, 7). Earlier studies ization of liver macrophages to an antiin- out causing immunosuppression. have also determined that MaR1, as well flammatory (i.e., M2) phenotype protects against the progression of NASH. Previous studies determined a crit- Related Article: p. 1684 ical role of the nuclear receptor retinoic acid–related orphan receptor (ROR ) Conflict of interest: The author has declared that no conflict of interest exists. α α Copyright: © 2019 American Society for Clinical Investigation in the regulation of lipid metabolism and Reference information: J Clin Invest. 2019;129(4):1524–1526. https://doi.org/10.1172/JCI127583. inflammation in NASH (14–16). In a pre- 1524 jci.org Volume 129 Number 4 April 2019 The Journal of Clinical Investigation COMMENTARY Figure 1. In macrophages, 12-LOX con- verts DHA to a 14-hydroperoxy DHA (hpDHA) intermediate that undergoes enzymatic epoxidation and hydrolysis to form MaR1. Han et al. found that MaR1 binds to and activates RORα, which leads to an antiinflammatory macrophage phenotype that blunts the progression of NASH. In addition, autoregulation of 12-LOX expres- sion by RORα establishes a positive feed-forward circuit. Biological actions of MaR1 that are key during resolution of inflammation, such as macro- phage phagocytosis, were found to be independent of RORα. Illustration by Rachel Davidowitz. vious study, Han et al. reported that RORα for RORα. While DHA increased a RORα Like DHA and consistent with prior stud- is important for polarizing liver macro- reporter gene, DHA itself was not a direct ies, treatment of obese mice with MaR1 phages to an antiinflammatory phenotype ligand for RORα based on failure to recruit prevented the development of NASH, as during NASH (17). In their present study, a coactivator peptide as compared with a evidenced by reduced liver weight, hepat- Han et al. hypothesized that, because of synthetic RORα agonist. Because DHA is ic triglyceride levels, markers of liver inju- the interplay between RORα and lipid known to be converted in macrophages ry, and expression of profibrotic proteins. metabolism and inflammation in the liv- to bioactive lipid mediators that resolve Similarly, MaR1 treatment increased the er, lipid-derived mediators may regulate inflammation (1), the authors tested wheth- appearance of M2 polarized macrophages RORα activation for resolution. Since er specific SPMs regulated RORα in mac- in the liver of obese mice. Notably, these DHA has been shown to improve NASH rophages. From these studies, the authors protective effects were lost in RORα-MKO and chronic inflammation in several oth- determined that MaR1, but not other SPMs mice, establishing causality in the activa- er contexts (11), they questioned wheth- (i.e., resolvin D1), increased expression of tion of this pathway by MaR1 in vivo. er RORα contributes to these protective RORα coincident with an increase in M2 The activation of RORα by MaR1 is actions. In initial studies, they found that macrophage polarization, which was both surprising because most SPMs, as well as DHA increased expression of RORα and time- and dose-dependent. Of note, these other lipid mediators, elicit their biolog- that this was associated with increased results are consistent with prior studies ical actions by binding to and activation M2 macrophage polarization. Similar showing that MaR1 regulates a proresolv- of plasma membrane G protein–coupled results were obtained in fat-1 transgenic ing macrophage phenotype (3). The reg- receptors, rather than nuclear recep- mice, which have high endogenous lev- ulation of M2 polarization was abolished tors (19, 20). Nonetheless, using surface els of DHA in the liver. Interestingly, the by genetic deficiency of Rora. Consistent plasmon resonance, fluorescence reso- regulation of macrophage polarization by with activation of RORα, MaR1 promoted nance energy transfer assays, and molec- DHA was lost in macrophages from mice binding of coactivator p300 concomitant ular modeling, Han et al. systematically with myeloid-specific deficiency of RORα with decreased binding of NCoR1, a core- demonstrated that MaR1 is likely an ago- (RORα-MKO), establishing that activation pressor of RORα. Structure function analy- nist of RORα. Transcriptome profiling of RORα mediates, in part, the role of DHA sis demonstrated that several other closely of macrophages stimulated with MaR1 in this context. related SPMs (e.g., RvD1, RvD2, and pro- showed some overlap with genes induced tectin D1) did not modulate RORα and that by a synthetic RORα agonist (i.e., SR1078), MaR1: a novel agonist activation of RORα by MaR1 was specific, although it should be noted that MaR1 dis- for RORα? as other nuclear receptors including RORβ, tinctly regulated a large subset of genes Earlier studies reported that DHA acti- RORγ, retinoid X receptor α, peroxisome as well. In