Abstract
Inflammatory conditions characterized by excessive peripheral immune responses are associated with diverse alterations in brain function, and brain-derived neural pathways regulate peripheral inflammation. Important aspects of this bidirectional peripheral immune-brain communication, including the impact of peripheral inflammation on brain region-specific cytokine responses, and brain cholinergic signaling (which plays a role in controlling peripheral cytokine levels), remain unclear. To provide insight, we studied gene expression of cytokines, immune cell markers and brain cholinergic system components in the cortex, cerebellum, brainstem, hippocampus, hypothalamus, striatum and thalamus in mice after an intraperitoneal lipopolysaccharide injection. Endotoxemia was accompanied by elevated serum levels of interleukin (IL)-1β, IL-6 and other cytokines and brain region-specific increases in Il1b (the highest increase, relative to basal level, was in cortex; the lowest increase was in cerebellum) and Il6 (highest increase in cerebellum; lowest increase in striatum) mRNA expression. Gene expression of brain Gfap (astrocyte marker) was also differentially increased. However, Iba1 (microglia marker) mRNA expression was decreased in the cortex, hippocampus and other brain regions in parallel with morphological changes, indicating microglia activation. Brain choline acetyltransferase (Chat ) mRNA expression was decreased in the striatum, acetylcholinesterase (Ache) mRNA expression was decreased in the cortex and increased in the hippocampus, and M1 muscarinic acetylcholine receptor (Chrm1) mRNA expression was decreased in the cortex and the brainstem. These results reveal a previously unrecognized regional specificity in brain immunoregulatory and cholinergic system gene expression in the context of peripheral inflammation and are of interest for designing future antiinflammatory approaches.
Highlights
Dysregulated peripheral immune responses and cytokine release mediate pathogenesis in sepsis, type 2 diabetes, rheumatoid arthritis, lupus and other inflammatory and autoimmune conditions [1,2,3,4]
The results reveal a somewhat surprising brain region–specific profile of Il1b and Il6 gene expression in parallel with differential alterations in glial fibrillary acidic protein (Gfap), ionized calciumbinding adapter molecule1 (Iba1), choline acetyltransferase (Chat), Ache, and Chrm1 gene expression during peripheral systemic inflammation, accompanied by high-serum IL1β, IL-6 and other cytokine levels
The gene expression of choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and the M1 subtype of muscarinic acetylcholine receptor (M1 mAChR) were studied
Summary
Dysregulated peripheral immune responses and cytokine release mediate pathogenesis in sepsis, type 2 diabetes, rheumatoid arthritis, lupus and other inflammatory and autoimmune conditions [1,2,3,4]. We and others have shown that brain cholinergic signaling is an important component in this regulation during inflammatory conditions [19,20,21,22,23]. This bidirectional peripheral immune–brain communication in inflammatory disorders is a topic of significant interest with potential therapeutic implications [18,24,25,26,27,28,29]. Providing insight into specific aspects of this communication is necessary and important
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