Exogenous melatonin inhibits neutrophil migration through suppression of ERK activation

Ren, Da-long; Sun, Ai-Ai; Li, Yajuan; Chen, Min; Ge, Shuchao; Hu, Bing

doi:10.1530/joe-15-0329

Cited by 46 publications

(23 citation statements)

References 42 publications

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“…These findings are consistent with other reports that ERK is necessary for adhesion and migration (6, 29, 30), but contradict the model of p38 as a go signal and ERK as a stop signal for chemotactic neutrophils (1) moving within an f MLP gradient. Instead, we found in experiments with BIRB-796, which has high specificity for p38 and blocks multiple isoforms of p38 (14), that p38 inhibited neutrophil migration up a gradient of f MLP (Fig.…”

Section: Discussionsupporting

confidence: 90%

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Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

Zhang

Liu

et al. 2016

Sci. Signal.

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The directed migration (chemotaxis) of neutrophils toward the bacterial peptide N-formyl-Met-Leu-Phe (fMLP) is a crucial process in immune defense against invading bacteria. While navigating through a gradient of increasing concentrations of fMLP, neutrophils and neutrophil-like HL-60 cells switch from exhibiting directional migration at low fMLP concentrations to exhibiting circuitous migration at high fMLP concentrations. The extracellular signal–regulated kinase (ERK) pathway is implicated in balancing this fMLP concentration–dependent switch in migration modes. We investigated the role and regulation of ERK signaling through single-cell analysis of neutrophil migration in response to different fMLP concentrations over time. We found that ERK exhibited gradated, rather than all-or-none, responses to fMLP concentration. Maximal ERK activation occurred in response to about 100 nM fMLP, and ERK inactivation was promoted by p38. Furthermore, we found that directional migration of neutrophils reached a maximal extent at about 100 nM fMLP and that ERK, but not p38, was required for neutrophil migration. Thus, our data suggest that, in chemo-tactic neutrophils responding to fMLP, ERK displays gradated activation and p38-dependent inhibition and that these ERK dynamics promote neutrophil migration.

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Section: Discussionsupporting

confidence: 90%

“…Controversy has further arisen over whether ERKs are necessary for (5, 6) or inhibit (1) neutrophil migration. Here, we used the selective inhibitors PD0325901 [MEK (MAPK kinase)] (7) and SCH772984 (ERK) (8) to demonstrate that ERK was required for neutrophil migration.…”

Section: Introductionmentioning

confidence: 99%

Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

Zhang

Liu

et al. 2016

Sci. Signal.

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“…In other fish species, the expression of melatonin receptors has been shown to be widely distributed in the brain and extra-brain tissues [28,61]. Indeed, in zebrafish, exogenous melatonin was shown to gate cell proliferation during development [59], inhibit injury-induced neutrophil migration [62], modify gene expression in the liver and gonads [63,64], and directly affect ovarian oocytes [63]. These reports indicate that melatonin exerts peripheral functions in zebrafish.…”

Section: Discussionmentioning

confidence: 99%

Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

et al. 2016

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The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior.

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“…Zebrafish larval tail fin was transected at the end of the spinal cord by a sterile blade on a plastic petri dish after being anesthetized with Tricaine methane-sulfonate 22 (Sigma, USA). The injured larvae were recovered at 28.5 °C in embryo medium until live imaging.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the role of melatonin in regulating inflammation is controversial 24 . Exogenous melatonin was reported to cause anti-inflammatory effects in various animals 22, 25 . In contrast, inflammatory effects were not observed in pinealectomized rodents whose endogenous melatonin is dramatically depleted 26–28 .…”

Section: Introductionmentioning

confidence: 99%

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

Ren

Wang

et al. 2017

Sci Rep

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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.

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Exogenous melatonin inhibits neutrophil migration through suppression of ERK activation

Cited by 46 publications

References 42 publications

Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

Chemoattractant concentration–dependent tuning of ERK signaling dynamics in migrating neutrophils

Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

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

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