Endogenous melatonin promotes rhythmic recruitment of neutrophils toward an injury in zebrafish

Abstract

Neutrophil recruitment to injured tissue appears to be an evolutionarily conserved strategy for organisms to fight against exogenous insults. Recent studies have shown rhythmic migration of neutrophils and several factors, including melatonin, have been implicated in regulating this rhythmic migration. The mechanisms underlying how endogenous melatonin regulates rhythmic neutrophils migration, however, are unclear. Here we generated a zebrafish annat2 mutant that lacks endogenous melatonin and, subsequently, a Tg(lyz:EGFP);aanat2 −/− transgenic line that allows for monitoring neutrophils migration visually in live zebrafish. We observed that migrating neutrophils are significantly reduced in aanat2 −/− mutant zebrafish under a light/dark condition, and the disrupted migrating rhythmicity of neutrophils in aanat2 −/− zebrafish is independent of the circadian clock. Further, we also found that endogenous melatonin enhances neutrophils migration likely by inducing the expression of cytokines such as interleukin-8 and interleukin-1β. Together, our findings provide evidence that endogenous melatonin promotes rhythmic migration of neutrophils through cytokines in zebrafish.

Seasonal simulated photoperiods influence melatonin release and immune markers of pike perch Sander lucioperca

“…For instance, several immune markers including peroxidase, phagocytic ability and cytotoxic activity of head kidney leucocytes as well as the expression of immune genes in head kidney (il-1β, major histocompatibility complex, and interferon-regulatory factor-1) are increased in gilthead seabream (Sparus aurata) following intraperitoneal injection of melatonin 20 . And, in zebrafish, endogenous melatonin enhances neutrophil migration following increase in cytokine expressions such as Il-8 and Il-1β 22 .…”

“…However, such immunomodulatory effects of melatonin have little been investigated in fish. Nevertheless, the available information supports an immune regulation by the melatonin hormone in teleosts 3,[19][20][21][22] . In pike perch, a potential dual action of cortisol and melatonin hormones on immune defenses was described 23,24 .…”

Circadian regulation of innate immunity in animals and humans and implications for human disease

“…The avian analogue of neutrophils, heterophils, is also observed to have a diurnal acrophase [66], whilst neutrophil injury recruitment in fish also has a circadian phenotype [87] suggesting these features are well preserved in different animals. The latter is influenced by melatonin, which has extensive pathways, reviewed with respect to immunity and inflammation previously [12,14,101,110].…”

The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators

“…This effect was counteracted significantly when treated with melatonin as shown in the elevated expression of redox sensor–nuclear factor erythroid–derived factor 2 (Nrf2), decreased expression of thymic stromal lymphopoietin (TSLP), and up‐regulation of antioxidant genes‐heme oxygenase 1 (HO‐1) and nicotinamide adenine dinucleotide (phosphate) NAD(P)H‐quinone oxidoreductase 1 (NQO) 94 . Using aanat2 −/− zebrafish larvae lacking melatonin, Ren et al 95 suggested endogenous melatonin promotes migration of neutrophils through cytokine signaling, in particular the downregulation of inflammatory cytokines IL‐1β and IL‐8. Recently, melatonin was reported to disrupt the IL‐1β/NF‐κB/NLRP3 inflammasome positive feedback loop leading to the inhibition of NLR pyrin domain–containing 3 (NLRP3), p20, and IL‐1β synthesis 96 .…”