Immune‐pineal axis protects rat lungs exposed to polluted air

Abstract

Environmental pollution in the form of particulate matter <2.5 μm (PM2.5) is a major risk factor for diseases such as lung cancer, chronic respiratory infections, and major cardiovascular diseases. Our goal was to show that PM2.5 eliciting a proinflammatory response activates the immune‐pineal axis, reducing the pineal synthesis and increasing the extrapineal synthesis of melatonin. Herein, we report that the exposure of rats to polluted air for 6 hours reduced nocturnal plasma melatonin levels and increased lung melatonin levels. Melatonin synthesis in the lung reduced lipid peroxidation and increased PM2.5 engulfment and cell viability by activating high‐affinity melatonin receptors. Diesel exhaust particles (DEPs) promoted the synthesis of melatonin in a cultured cell line (RAW 264.7 cells) and rat alveolar macrophages via the expression of the gene encoding for AANAT through a mechanism dependent on activation of the NFκB pathway. Expression of the genes encoding AANAT, MT1, and MT2 was negatively correlated with cellular necroptosis, as disclosed by analysis of Gene Expression Omnibus (GEO) microarray data from the human alveolar macrophages of nonsmoking subjects. The enrichment score for antioxidant genes obtained from lung gene expression data (GTEx) was significantly correlated with the levels of AANAT and MT1 but not the MT2 melatonin receptor. Collectively, these data provide a systemic and mechanistic rationale for coordination of the pineal and extrapineal synthesis of melatonin by a standard damage‐associated stimulus, which activates the immune‐pineal axis and provides a new framework for understanding the effects of air pollution on lung diseases.

Melatonin restores neutrophil functions and prevents apoptosis amid dysfunctional glutathione redox system

“…104 Recently, melatonin is shown to alleviate air pollution-induced oxidative stress by regulating the expression of SOD and CAT via MT1. 105 These studies endorse the protective effect of physiological melatonin through receptor-mediated mechanisms. In contrary, exogenously administered melatonin (μmol/L range) functions by direct ROS scavenging via electron donor mechanism; nevertheless, receptor-mediated regulation of antioxidant enzymes cannot be ignored.…”

Melatonin-Index as a biomarker for predicting the distribution of presymptomatic and asymptomatic SARS-CoV-2 carriers

“…The phagocyted material is expelled together with mucous, protecting the individual against infection and the mounting of immune defense response. Melatonin synthesized in the respiratory tract by resident or monocyte-derived macrophages, besides impairing the mounting of innate immune responses against particulate material of polluted air and microorganisms, potentiates phagocytosis (17,(29)(30)(31). Considering that the MEL-Index score in healthy rats was directly related to melatonin content, we decided to explore whether the MEL-Index score from healthy human lung could be implicated in the biology of asymptomatic carriers.…”

“…The previous studies with melatonin did not consider lung synthesized melatonin as a relevant source for allowing the first stages of invasion and infection, opening the possibility that lung melatonin could be relevant for defining the distribution of presymptomatic and asymptomatic carriers. Considering that melatonin synthesized by rodent alveolar macrophages exposed to pathogen-and damage-associated molecular patterns (PAMPs, DAMPs) impairs their activation (17). A two-gene index score (MEL-Index) that predicts the severity of human glioma (18,19) was used as a biomarker for estimating the expression of genes related to airborne SARS-CoV-2 invasion and infection in normal human lungs RNAseq data deposited in the Genotype-Tissue Expression (GTEx).…”

Melatonin and Depression: A Translational Perspective From Animal Models to Clinical Studies

“…It is the daily pattern of melatonin secretion that carries information for circadian and seasonal temporal organization (32). Melatonin is also synthesized by the skin, guts, and lungs in a constitutive manner, and on-demand by activated immune-competent cells, such as monocyte-derived and resident macrophages, microglia and lymphocytes (1,33,34).…”