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.