Abstract
Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease where activated glia release pro-inflammatory cytokines that trigger a vicious cycle of neurodegeneration in the absence of resolution of inflammation. Given the well-established role of histamine as a neuron-to-glia alarm signal implicated in brain disorders, the aim of this study was to investigate the expression and regulation of the histaminergic pathway in microglial activation in ALS mouse model and in humans. By examining the contribution of the histaminergic system to ALS, we found that particularly via H1 and H4 receptors, histamine promoted an anti-inflammatory profile in microglia from SOD1-G93A mice by modulating their activation state. A decrease in NF-κB and NADPH oxidase 2 with an increase in arginase 1 and P2Y12 receptor was induced by histamine only in the ALS inflammatory environment, but not in the healthy microglia, together with an increase in IL-6, IL-10, CD163, and CD206 phenotypic markers in SOD1-G93A cells. Moreover, histaminergic H1, H2, H3, and H4 receptors, and histamine metabolizing enzymes histidine decarboxylase, histamine N-methyltransferase, and diamine oxidase were found deregulated in spinal cord, cortex, and hypothalamus of SOD1-G93A mice during disease progression. Finally, by performing a meta-analysis study, we found a modulated expression of histamine-related genes in cortex and spinal cord from sporadic ALS patients. Our findings disclose that histamine acts as anti-inflammatory agent in ALS microglia and suggest a dysregulation of the histaminergic signaling in ALS.
Highlights
The biogenic amine histamine is synthesized by decarboxylation of l-histidine by histidine decarboxylase (HDC) and catabolized by histamine N-methyltransferase (HNMT) and diamine oxidase (DAO, or AOC), enzymes that are distributed in all CNS areas
Statistically significant higher expression of H2R and lower expression of H3R and H4R was demonstrated by western blotting (WB) in SOD1G93A with respect to WT microglia (Figure 1B), together with significant upregulation of HNMT and DAO, but not of HDC, in SOD1-G93A compared to WT (Figure 2B)
Because P2Y12 receptor is among the signaling pathways controlling microglia migration [31, 32], we demonstrated that histamine-induced SOD1-G93A migration was dependent on P2Y12, receptor being inhibited by the specific inhibitor MRS2395 (Figure 6B)
Summary
The biogenic amine histamine is synthesized by decarboxylation of l-histidine by histidine decarboxylase (HDC) and catabolized by histamine N-methyltransferase (HNMT) and diamine oxidase (DAO, or AOC), enzymes that are distributed in all CNS areas. While histamine-producing neurons are found mainly in the hypothalamus, histamine acts as an ubiquitous transmitter and Abbreviations: ALS, amyotrophic lateral sclerosis; HDC, histidine decarboxylase; HNMT, histamine N-methyltransferase; DAO, diamine oxidase; NOX2, NADPH oxidase 2; sALS, sporadic ALS; WT, wild-type. As proven by human postmortem and animal model studies, the histaminergic system becomes altered in several brain disorders, and histaminergic abnormalities are hypothesized to contribute to neurodegenerative disorders, such as Parkinson’s and Alzheimer’s diseases [2, 4,5,6]. The involvement of histamine is basically unexplored in amyotrophic lateral sclerosis (ALS), a late-onset neurodegenerative/neuroinflammatory disease characterized by progressive loss of motor neurons in the motor cortex, brain stem, and ventral horns of the spinal cord
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