M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture.

Autor: Abraham MN; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA., Nedeljkovic-Kurepa A; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA., Fernandes TD; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA., Yaipen O; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA., Brewer MR; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA.; Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA., Leisman DE; Department of Medicine, Massachusetts General Hospital, Boston, USA., Taylor MD; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA.; Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA., Deutschman CS; Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA. cdeutschman@northwell.edu.; Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA. cdeutschman@northwell.edu.; Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA. cdeutschman@northwell.edu.
Jazyk: angličtina
Zdroj: Molecular medicine (Cambridge, Mass.) [Mol Med] 2024 Feb 05; Vol. 30 (1), pp. 22. Date of Electronic Publication: 2024 Feb 05.
DOI: 10.1186/s10020-024-00787-x
Abstrakt: Background: The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis.
Methods: In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline.
Results: At 48 h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα + and ILβ + neutrophils and ILβ + monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4 + and CD8 + T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα + neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1β + neutrophils, IL-1β + monocytes, cDCs, CD4 + T cells and CD8 + T cells were similar in xanomeline-treated and untreated post-CLP mice.
Conclusion: Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.
(© 2024. The Author(s).)
Databáze: MEDLINE
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