Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis

Abstract

Background Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis. Methods EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1–20 (IRBP1–20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot. Results Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU. Conclusions Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis.

The Microbiota-Dependent Worsening Effects of Melatonin on Gut Inflammation

“…The impaired clinical recovery in both acute and repair phases of colitis in mice treated with MLT could be linked to the increase in circulating leukocyte and TNF production in the colon, despite reduced IL-17 cytokine, which is fundamental for gut immunity in the control of bacteria burden [ 9 ]. Corroborating our data, MLT was able to inhibit the differentiation of Th17 cells in an experimental model of necrotizing enterocolitis [ 37 ] and, in autoimmune uveitis, MLT suppressed Th17 differentiation through the reactive-oxygen species–TXNIP-HIF1α axis [ 38 ]. On the other hand, cytokines with an inflammatory profile intensify mucosal effector responses, though a consequent deterioration in the intestinal lamina propria due to excessive inflammation may occur [ 39 ].…”

Correlation Between Serum Melatonin Level and Other Indicators With Stages of Diabetic Retinopathy

“…Melatonin is produced from the pineal gland and, to some extent, from the retina [13]. It has antioxidant functions and a major role in neurovascular and cardiovascular diseases [14,15].…”

Melatonin in food allergy: Mechanism and potential therapy

“…Melatonin also increases the number of CD4 + FOXP3 + Treg cells and the surface expression of FOXP3, as well as decreases the production of Th2 cytokines in patients with systemic lupus erythematosus 60 . A recent study suggests that melatonin facilitates Treg cell differentiation in autoimmune diseases via ROS/thioredoxin binding protein (TXNIP)/HIF‐1α pathway 61 . In addition, recent studies have shown that melatonin enhances the differentiation of Treg cells via the AMP‐activated protein kinase (AMPK)/LINC01515/SIRT1 axis in necrotizing enterocolitis in human 62,63 .…”

“…60 A recent study suggests that melatonin facilitates Treg cell differentiation in autoimmune diseases via ROS/thioredoxin binding protein (TXNIP)/HIF-1α pathway. 61 In addition, recent studies have shown that melatonin enhances the differentiation of Treg cells via the AMP-activated protein kinase (AMPK)/LINC01515/ SIRT1 axis in necrotizing enterocolitis in human. 62,63 However, the effects of melatonin in cancer models are inconsistent compared to that in the inflammation models.…”