Microglial Histaminergic Signaling Promotes Interleukin-10 Production and Ameliorates Motor Dysfunction in...

Histamine functions as a neurotransmitter regulating multiple neural processes, whereas interleukin-10 (IL-10) is an anti-inflammatory cytokine with recognized neuroprotective properties. Previous research suggests that histamine can stimulate the release of various inflammatory mediators, including IL-10. However, the precise molecular mechanisms governing the interaction between histamine and IL-10, particularly their role in safeguarding dopaminergic neurons in Parkinson's disease (PD), have not been fully elucidated. The current findings suggest that, within the context of PD, histamine levels are elevated in the substantia nigra pars compacta (SNc) microglia, leading to an upregulation of IL-10 expression through activation of the H2 receptor and the downstream cAMP/PKA/p38β/CREB signaling cascade. However, the increased histamine concentration was negatively regulated by the IL-10 expression, allowing a limited increase in its concentration. Furthermore, the H2R-IL-10 pathway activation inhibited microglial activation and the production of inflammatory factors. Moreover, the H2R-IL-10 signaling axis modulated both membrane resistance and the expression of cleaved caspase-3 mRNA in dopaminergic neurons, contributing to the improvement of motor deficits in LPS-induced mouse models. These observations suggest that, in the pathological context of PD, microglia in the SNc exhibit increased production of histamine and IL-10 in a mutually regulatory manner. Elevated histamine levels further enhance IL-10 expression, which confers neuroprotection to dopaminergic neurons through its anti-inflammatory actions, ultimately alleviating motor impairments associated with PD.