Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors
Sepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chron...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2017-12-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01673/full |
| _version_ | 1818970082842247168 |
|---|---|
| author | Nahla Zaghloul Nahla Zaghloul Meghan E. Addorisio Harold A. Silverman Harold A. Silverman Hardik L. Patel Sergio I. Valdés-Ferrer Sergio I. Valdés-Ferrer Sergio I. Valdés-Ferrer Kamesh R. Ayasolla Kurt R. Lehner Peder S. Olofsson Mansoor Nasim Christine N. Metz Christine N. Metz Ping Wang Ping Wang Mohamed Ahmed Mohamed Ahmed Sangeeta S. Chavan Sangeeta S. Chavan Betty Diamond Betty Diamond Kevin J. Tracey Kevin J. Tracey Kevin J. Tracey Valentin A. Pavlov Valentin A. Pavlov Valentin A. Pavlov |
| author_facet | Nahla Zaghloul Nahla Zaghloul Meghan E. Addorisio Harold A. Silverman Harold A. Silverman Hardik L. Patel Sergio I. Valdés-Ferrer Sergio I. Valdés-Ferrer Sergio I. Valdés-Ferrer Kamesh R. Ayasolla Kurt R. Lehner Peder S. Olofsson Mansoor Nasim Christine N. Metz Christine N. Metz Ping Wang Ping Wang Mohamed Ahmed Mohamed Ahmed Sangeeta S. Chavan Sangeeta S. Chavan Betty Diamond Betty Diamond Kevin J. Tracey Kevin J. Tracey Kevin J. Tracey Valentin A. Pavlov Valentin A. Pavlov Valentin A. Pavlov |
| author_sort | Nahla Zaghloul |
| collection | DOAJ |
| description | Sepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP)-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL)-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT)-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex) and increased Il1b and Il6 gene expression (in the cortex), and Il1b gene expression (in the hippocampus) were observed in mouse sepsis survivors. Furthermore, microglial activation was linked to decreased cortical ChAT protein expression and increased AChE activity. These results reinforce the notion of persistent inflammation-immunosuppression and catabolic syndrome in sepsis survivors and characterize a previously unrecognized relationship between forebrain cholinergic dysfunction and neuroinflammation in sepsis survivors. This insight is of interest for new therapeutic approaches that focus on brain cholinergic signaling for patients with chronic sepsis illness, a problem with no specific treatment. |
| first_indexed | 2024-12-20T14:30:50Z |
| format | Article |
| id | doaj.art-9864326b5681488aba16570a120fc9fc |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T14:30:50Z |
| publishDate | 2017-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9864326b5681488aba16570a120fc9fc2022-12-21T19:37:38ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-12-01810.3389/fimmu.2017.01673318767Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis SurvivorsNahla Zaghloul0Nahla Zaghloul1Meghan E. Addorisio2Harold A. Silverman3Harold A. Silverman4Hardik L. Patel5Sergio I. Valdés-Ferrer6Sergio I. Valdés-Ferrer7Sergio I. Valdés-Ferrer8Kamesh R. Ayasolla9Kurt R. Lehner10Peder S. Olofsson11Mansoor Nasim12Christine N. Metz13Christine N. Metz14Ping Wang15Ping Wang16Mohamed Ahmed17Mohamed Ahmed18Sangeeta S. Chavan19Sangeeta S. Chavan20Betty Diamond21Betty Diamond22Kevin J. Tracey23Kevin J. Tracey24Kevin J. Tracey25Valentin A. Pavlov26Valentin A. Pavlov27Valentin A. Pavlov28Cohen Children’s Medical Center, Northwell Health, New Hyde Park, NY, United StatesNeonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United StatesNeonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesLaboratory of Neurobiology of Systemic Illness, Department of Neurology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, MexicoLaboratory of Neurobiology of Systemic Illness, Department of Infectious Diseases, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, MexicoNeonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesNeuropathology-Anatomic Pathology, Northwell Health, New Hyde Park, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United StatesCenter for Immunology and Inflammation, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCohen Children’s Medical Center, Northwell Health, New Hyde Park, NY, United StatesNeonatology Research Laboratory, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCenter for Bioelectronic Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United States0Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United StatesCenter for Bioelectronic Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesCenter for Biomedical Science, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesDonald and Barbara Zucker School of Medicine at Hofstra/Northwell, NY, United StatesCenter for Bioelectronic Medicine, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United StatesSepsis, a complex disorder characterized by immune, metabolic, and neurological dysregulation, is the number one killer in the intensive care unit. Mortality remains alarmingly high even in among sepsis survivors discharged from the hospital. There is no clear strategy for managing this lethal chronic sepsis illness, which is associated with severe functional disabilities and cognitive deterioration. Providing insight into the underlying pathophysiology is desperately needed to direct new therapeutic approaches. Previous studies have shown that brain cholinergic signaling importantly regulates cognition and inflammation. Here, we studied the relationship between peripheral immunometabolic alterations and brain cholinergic and inflammatory states in mouse survivors of cecal ligation and puncture (CLP)-induced sepsis. Within 6 days, CLP resulted in 50% mortality vs. 100% survival in sham-operated controls. As compared to sham controls, sepsis survivors had significantly lower body weight, higher serum TNF, interleukin (IL)-1β, IL-6, CXCL1, IL-10, and HMGB1 levels, a lower TNF response to LPS challenge, and lower serum insulin, leptin, and plasminogen activator inhibitor-1 levels on day 14. In the basal forebrain of mouse sepsis survivors, the number of cholinergic [choline acetyltransferase (ChAT)-positive] neurons was significantly reduced. In the hippocampus and the cortex of mouse sepsis survivors, the activity of acetylcholinesterase (AChE), the enzyme that degrades acetylcholine, as well as the expression of its encoding gene were significantly increased. In addition, the expression of the gene encoding the M1 muscarinic acetylcholine receptor was decreased in the hippocampus. In parallel with these forebrain cholinergic alterations, microglial activation (in the cortex) and increased Il1b and Il6 gene expression (in the cortex), and Il1b gene expression (in the hippocampus) were observed in mouse sepsis survivors. Furthermore, microglial activation was linked to decreased cortical ChAT protein expression and increased AChE activity. These results reinforce the notion of persistent inflammation-immunosuppression and catabolic syndrome in sepsis survivors and characterize a previously unrecognized relationship between forebrain cholinergic dysfunction and neuroinflammation in sepsis survivors. This insight is of interest for new therapeutic approaches that focus on brain cholinergic signaling for patients with chronic sepsis illness, a problem with no specific treatment.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01673/fullsepsissepsis survivalcytokinesinflammationbrain cholinergic systemneuroinflammation |
| spellingShingle | Nahla Zaghloul Nahla Zaghloul Meghan E. Addorisio Harold A. Silverman Harold A. Silverman Hardik L. Patel Sergio I. Valdés-Ferrer Sergio I. Valdés-Ferrer Sergio I. Valdés-Ferrer Kamesh R. Ayasolla Kurt R. Lehner Peder S. Olofsson Mansoor Nasim Christine N. Metz Christine N. Metz Ping Wang Ping Wang Mohamed Ahmed Mohamed Ahmed Sangeeta S. Chavan Sangeeta S. Chavan Betty Diamond Betty Diamond Kevin J. Tracey Kevin J. Tracey Kevin J. Tracey Valentin A. Pavlov Valentin A. Pavlov Valentin A. Pavlov Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors Frontiers in Immunology sepsis sepsis survival cytokines inflammation brain cholinergic system neuroinflammation |
| title | Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors |
| title_full | Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors |
| title_fullStr | Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors |
| title_full_unstemmed | Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors |
| title_short | Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors |
| title_sort | forebrain cholinergic dysfunction and systemic and brain inflammation in murine sepsis survivors |
| topic | sepsis sepsis survival cytokines inflammation brain cholinergic system neuroinflammation |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01673/full |
| work_keys_str_mv | AT nahlazaghloul forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT nahlazaghloul forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT meghaneaddorisio forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT haroldasilverman forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT haroldasilverman forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT hardiklpatel forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT sergioivaldesferrer forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT sergioivaldesferrer forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT sergioivaldesferrer forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT kameshrayasolla forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT kurtrlehner forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT pedersolofsson forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT mansoornasim forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT christinenmetz forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT christinenmetz forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT pingwang forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT pingwang forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT mohamedahmed forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT mohamedahmed forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT sangeetaschavan forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT sangeetaschavan forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT bettydiamond forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT bettydiamond forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT kevinjtracey forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT kevinjtracey forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT kevinjtracey forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT valentinapavlov forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT valentinapavlov forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors AT valentinapavlov forebraincholinergicdysfunctionandsystemicandbraininflammationinmurinesepsissurvivors |