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Review
. 2021 Nov 10;22(22):12143.
doi: 10.3390/ijms222212143.

Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense

Regina P Markus  1 , Kassiano S Sousa  1 , Sanseray da Silveira Cruz-Machado  2 , Pedro A Fernandes  1 , Zulma S Ferreira  1
Affiliations
Review

Possible Role of Pineal and Extra-Pineal Melatonin in Surveillance, Immunity, and First-Line Defense

Regina P Markus et al. Int J Mol Sci. .

Abstract

Melatonin is a highly conserved molecule found in prokaryotes and eukaryotes that acts as the darkness hormone, translating environmental lighting to the whole body, and as a moderator of innate and acquired defense, migration, and cell proliferation processes. This review evaluates the importance of pineal activity in monitoring PAMPs and DAMPs and in mounting an inflammatory response or innate immune response. Activation of the immune-pineal axis, which coordinates the pro-and anti-inflammatory phases of an innate immune response, is described. PAMPs and DAMPs promote the immediate suppression of melatonin production by the pineal gland, which allows leukocyte migration. Monocyte-derived macrophages, important phagocytes of microbes, and cellular debris produce melatonin locally and thereby initiate the anti-inflammatory phase of the acute inflammatory response. The role of locally produced melatonin in organs that directly contact the external environment, such as the skin and the gastrointestinal and respiratory tracts, is also discussed. In this context, as resident macrophages are self-renewing cells, we explore evidence indicating that, besides avoiding overreaction of the immune system, extra-pineal melatonin has a fundamental role in the homeostasis of organs and tissues.

Keywords: first-line defense; immune–pineal axis; resident macrophages.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 3
Figure 3
Tissue-resident macrophages and melatonin production—resident macrophages respond to the first defense line against PAMPs and DAMPs. These cells are phenotypically adapted to each tissue and, in most cases, impair the mounting of innate immune responses. All the cells listed above synthesize melatonin. Although the physiological role of tissue-resident macrophages is not yet disclosed in many tissues, in some tissues, as in the bone marrow (BM), it is essential for maintaining a reserve of long-lasting hematopoietic stem cells (see the text).
Figure 1
Figure 1
Pineal gland involvement over the time-course of an inflammatory response. BCG injection in a mice paw triggers an acute inflammatory response. A fast increase in the paw size due to swelling and migration of neutrophils and macrophages is followed by the formation of a granuloma. The inhibition of the pineal gland synthesis of melatonin that occurs in the first night is followed by a late recovery of nocturnal melatonin synthesis sustained by the increase in adrenal glucocorticoids. Melatonin rhythm imposes a daily rhythm in paw size [2,4,5].
Figure 2
Figure 2
Pineal gland as a reporter of environmental lighting and a sensor of PAMPs and DAMPs. (Upper Panel) The retinohypothalamic tract conveys lighting information to the suprachiasmatic nuclei (SCN). Pineal sympathetic input driven by a polysynaptic pathway via the paraventricular nuclei (PVN) of the hypothalamus and the cervical superior ganglion (CSG) releases noradrenaline (NAd) and ATP. The pineal gland is composed of pinealocytes, astrocytes, and microglia. Astrocytes are localized around the blood vessels, and microglia are dispersed along the pinealocytes. The immunopositive labeling of TNF-R1 throughout the pineal parenchyma is shown in green. The astrocytes (GFAP-labeled, in red) are restricted to the proximal region near the pineal stalk, and most of them express TNFR1 (yellow). Microglia (ED-1-labeled, in red) co-localize with TNF-R1 and pinealocytes also express TNF-R1. Scale bar = 200 μm [16]. (Lower Panel) PAMPs and DAMPs block transcription of SNAT. Left side (healthy conditions): NAd acts on β-adrenoceptors, triggering the adenylyl cyclase/ cAMP/ protein kinase A (PKA) pathway. PKA phosphorylates CREB (cyclic AMP-related responsive element binding protein), which binds to CRE sequences in the Snat (serotonin N-acetyltransferase) promoter, inducing the gene’s transcription. The synthesized protein SNAT is activated by PKA phosphorylation. ATP triggers P2Y1 receptors that activate phospholipase C, increasing intracellular Ca2+ and potentiating PKA activity. Thus, the conversion of serotonin into N-acetylserotonin (NAS) by P-SNAT occurs at night. NAS is then converted into melatonin by ASMT (acetylserotonin-O methyltransferase). Right side (acute inflammation—1st night): PAMPs and DAMPs activate their receptors in pinealocytes, inducing the nuclear translocation of the NFκB dimer p50/p50, which blocks Snat transcription and melatonin synthesis. This is an essential step for mounting acute inflammatory responses at night, as melatonin, via blocking of quinone reductase 2 or activating MT-2 receptors, impairs the migration of leukocytes from the blood to the injured tissue. This 1st-night effect was observed in rodents and humans and is an essential step for mounting an effective innate immune response [13,16,20,21,22].
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