Inhibitory receptor agonists: the future of autoimmune disease therapeutics?
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ABSTRACT:
SUBMITTER: Grebinoski S
PROVIDER: S-EPMC7744338 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The melanocortin system plays an essential role in the regulation of immune activity. The anti-inflammatory microenvironment of the eye is dependent on the expression of the melanocortin-neuropeptide alpha-melanocyte stimulating hormone (α-MSH). In addition, the melanocortin system may have a role in retinal development and retinal cell survival under conditions of retinal degeneration. We have found that treating experimental autoimmune uveitis (EAU) with α-MSH suppresses retinal inflammation. Also, this augmentation of the melanocortin system promotes immune tolerance and protection of the retinal structure. The benefit of α-MSH-therapy appears to be dependent on different melanocortin receptors. Therefore, we treated EAU mice with α-MSH-analogs with different melanocortin-receptor targets. This approach demonstrated which melanocortin-receptors suppress inflammation, preserve retinal structure, and induce immune tolerance in uveitis. At the chronic stage of EAU the mice were injected twice 1 day apart with 50 μg of α-MSH or an α-MSH-analog. The α-MSH-analogs were a pan-agonist PL8331, PL8177 (potent MC1r-only agonist), PL5000 (a pan-agonist with no MC5r functional activity), MT-II (same as PL5000) and PG901 (MC5r agonist, but also an antagonist to MC3r, and MC4r). Clinical EAU scores were measured until resolution in the α-MSH-treated mice, when the eyes were collected for histology, and spleen cells collected for retinal-antigen-stimulated cytokine production. Significant suppression of EAU was seen with α-MSH or PL8331 treatment. This was accompanied with significant preservation of retinal structure. A similar effect was seen in EAU-mice that were treated with PL8177, except the suppression of EAU was temporary. In EAU mice treated with PL5000, MTII, or PG901, there was no suppression of EAU with a significant loss in whole retina and outer-nuclear layer thickness. There was significant suppression of IL-17 with induction of IL-10 by retinal-antigen stimulated spleen T cells from EAU mice treated with α-MSH, PL8331, PL8177, or PL5000, but not from EAU mice treated with MT-II, or PG901. Our previous studies show the melanocortin system's importance in maintaining ocular immune privilege and that α-MSH-treatment accelerates recovery and induces retinal-antigen-specific regulatory immunity in EAU. Our current results show that this activity is centered around MC1r and MC5r. In addition, the results suggest that a therapeutic potential to target MC1r and MC5r together to suppress uveitis induces regulatory immunity with potentially maintaining a normal retinal structure.
| S-EPMC9050930 | biostudies-literature
Project description:BackgroundNarcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy.MethodsIn the first experiment, male homozygous B6-Taar1tm1(NLSLacZ)Blt (Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models.ResultsRO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy.ConclusionsThese results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.
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Project description:With the emergence of various classes of blood glucose-lowering agents, choosing the appropriate drug for each patient is emphasized in diabetes management. Among incretin-based drugs, glucagon-like peptide 1 (GLP-1) receptor agonists are a promising therapeutic option for patients with diabetic kidney disease (DKD). Several cardiovascular outcome trials have demonstrated that GLP-1 receptor agonists have beneficial effects on cardiorenal outcomes beyond their blood glucose-lowering effects in patients with type 2 diabetes mellitus (T2DM). The renal protective effects of GLP-1 receptor agonists likely result from their direct actions on the kidney, in addition to their indirect actions that improve conventional risk factors for DKD, such as reducing blood glucose levels, blood pressure, and body weight. Inhibition of oxidative stress and inflammation and induction of natriuresis are major renoprotective mechanisms of GLP-1 analogues. Early evidence from the development of dual and triple combination agents suggests that GLP-1 receptor agonists will probably become popular treatment options for patients with T2DM.
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Project description:Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPARalpha agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcription factor T-bet in vitro and directly ex vivo. These changes correlated with an increase in nuclear PPARalpha expression. Moreover, the protective effects of PPARalpha agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPARalpha was demonstrated, for the first time, to regulate the IL-4 and IL-5 genes and to bind the IL-4 promoter in the presence of steroid receptor coactivator-1, indicating that PPARalpha can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPARalpha agonists ameliorated clinically established EAE, suggesting that PPARalpha agonists may provide a treatment option for immune-mediated inflammatory diseases.
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Project description:The interrogation of intrinsic and adaptive resistance to cancer immunotherapy has identified lack of antigen presentation and type I interferon signaling as biomarkers of non-T-cell-inflamed tumors and clinical progression. A myriad of pre-clinical studies have implicated the cGAS/stimulator of interferon genes (STING) pathway, a cytosolic DNA-sensing pathway that drives activation of type I interferons and other inflammatory cytokines, in the host immune response against tumors. The STING pathway is also increasingly understood to have other anti-tumor functions such as modulation of the vasculature and augmentation of adaptive immunity via the support of tertiary lymphoid structure development. Many natural and synthetic STING agonists have entered clinical development with the first generation of intra-tumor delivered cyclic dinucleotides demonstrating safety but only modest systemic activity. The development of more potent and selective STING agonists as well as novel delivery systems that would allow for sustained inflammation in the tumor microenvironment could potentially augment response rates to current immunotherapy approaches and overcome acquired resistance. In this review, we will focus on the latest developments in STING-targeted therapies and provide an update on the clinical development and application of STING agonists administered alone, or in combination with immune checkpoint blockade or other approaches.
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Project description:Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.
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Project description:Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor (PPAR)-? agonists commonly used as insulin-sensitizing drugs for the treatment of type 2 diabetes. In the last decade, PPAR-? agonists have received increasing attention for their neuroprotective properties displayed in a variety of neurodegenerative diseases, including Parkinson's disease (PD), likely related to the anti-infammatory activity of these compounds. Recent studies indicate that neuroinflammation, specifically reactive microglia, plays important roles in PD pathogenesis. Moreover, after the discovery of infiltrating activated Limphocytes in the substantia nigra (SN) of PD patients, most recent research supports a role of immune-mediated mechanisms in the pathological process leading to chronic neuroinflammation and dopaminergic degeneration. PPAR-? are highly expressed in cells of both central and peripheral immune systems, playing a pivotal role in microglial activation as well as in monocytes and T cells differentiation, in which they act as key regulators of immune responses. Here, we review preclinical evidences of PPAR-?-induced neuroprotection in experimental PD models and highlight relative anti-inflammatory mechanisms involving either central or peripheral immunomodulatory activity. Specific targeting of immune functions contributing to neuroinflammation either directly (central) or indirectly (peripheral) may represent a novel therapeutic approach for disease modifying therapies in PD.
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Project description:The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression -794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls.These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases.
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