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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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At 48\u00a0h. 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 TNF\u03b1, IL-1\u03b2, MIP-1\u03b1, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNF\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      and IL\u03b2\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils and IL\u03b2\n                      <jats:sup>+<\/jats:sup>\n                      monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      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 TNF\u03b1, IL-1\u03b2, and MIP-1\u03b1, 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 TNF\u03b1\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1\u03b2\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils, IL-1\u03b2\n                      <jats:sup>+<\/jats:sup>\n                      monocytes, cDCs, CD4\n                      <jats:sup>\n                        <jats:bold>+<\/jats:bold>\n                      <\/jats:sup>\n                      T cells and CD8\n                      <jats:sup>\n                        <jats:bold>+<\/jats:bold>\n                      <\/jats:sup>\n                      T cells were similar in xanomeline\u2014treated and untreated post-CLP mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s10020-024-00787-x","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T10:05:41Z","timestamp":1707127541000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture"],"prefix":"10.1186","volume":"30","author":[{"given":"Mabel N.","family":"Abraham","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana","family":"Nedeljkovic-Kurepa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tiago D.","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Omar","family":"Yaipen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana R.","family":"Brewer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel E.","family":"Leisman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew D.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-4024","authenticated-orcid":false,"given":"Clifford S.","family":"Deutschman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"issue":"5","key":"787_CR1","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1097\/CCM.0b013e31819dee81","volume":"37","author":"AS Abcejo","year":"2009","unstructured":"Abcejo AS, Andrejko KM, Raj NR, Deutschman CS. 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CSD and MDT hold faculty appointments in the Institute for Molecular Medicine at the FIMR. CSD receives an annual stipend from the Society of Critical Care Medicine to serve as Scientific Editor for the journal <i>Critical Care Medicine<\/i>. He is an unpaid member of the editorial board of the journal <i>Shock<\/i>. CSD has received consultant\u2019s fees from the Siemens Healthcare Diagnostics Inc. (Tarrytown NY, USA). He received stock options in Enlivex Co. (Jerusalem, Israel) as a consult and ICON Clinical Research LLC for participation on a Data Safety Management Board. He has received royalties from Elsevier Inc. as Editor of the textbook <i>Evidence-based Practice of Critical Care<\/i>. MDT and CSD have received Giapreza (angiotensin II) for experimental use from La Jolla Pharmaceuticals (La Jolla CA).","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22"}}