Cargando…

Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice

Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction us...

Descripción completa

Detalles Bibliográficos
Autores principales: Algahtani, Mohammad M., Alshehri, Samiyah, Alqarni, Sana S., Ahmad, Sheikh F., Al-Harbi, Naif O., Alqarni, Saleh A., Alfardan, Ali S., Ibrahim, Khalid E., Attia, Sabry M., Nadeem, Ahmed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10179574/
https://www.ncbi.nlm.nih.gov/pubmed/37175808
http://dx.doi.org/10.3390/ijms24098101
_version_ 1785041130074669056
author Algahtani, Mohammad M.
Alshehri, Samiyah
Alqarni, Sana S.
Ahmad, Sheikh F.
Al-Harbi, Naif O.
Alqarni, Saleh A.
Alfardan, Ali S.
Ibrahim, Khalid E.
Attia, Sabry M.
Nadeem, Ahmed
author_facet Algahtani, Mohammad M.
Alshehri, Samiyah
Alqarni, Sana S.
Ahmad, Sheikh F.
Al-Harbi, Naif O.
Alqarni, Saleh A.
Alfardan, Ali S.
Ibrahim, Khalid E.
Attia, Sabry M.
Nadeem, Ahmed
author_sort Algahtani, Mohammad M.
collection PubMed
description Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NFkB, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS.
format Online
Article
Text
id pubmed-10179574
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-101795742023-05-13 Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice Algahtani, Mohammad M. Alshehri, Samiyah Alqarni, Sana S. Ahmad, Sheikh F. Al-Harbi, Naif O. Alqarni, Saleh A. Alfardan, Ali S. Ibrahim, Khalid E. Attia, Sabry M. Nadeem, Ahmed Int J Mol Sci Article Sepsis affects millions of people worldwide and is associated with multiorgan dysfunction that is a major cause of increased morbidity and mortality. Sepsis is associated with several morbidities, such as lung, liver, and central nervous system (CNS) dysfunction. Sepsis-associated CNS dysfunction usually leads to several mental problems including depression. IL-17A is one of the crucial cytokines that is expressed and secreted by Th17 cells. Th17 cells are reported to be involved in the pathogenesis of depression and anxiety in humans and animals. One of the protein tyrosine kinases that plays a key role in controlling the development/differentiation of Th17 cells is ITK. However, the role of ITK in sepsis-associated neuroinflammation and depression-like symptoms in mice has not been investigated earlier. Therefore, this study investigated the efficacy of the ITK inhibitor, BMS 509744, in sepsis-linked neuroinflammation (ITK, IL-17A, NFkB, iNOS, MPO, lipid peroxides, IL-6, MCP-1, IL-17A) and a battery of depression-like behavioral tests, such as sucrose preference, tail suspension, and the marble burying test. Further, the effect of the ITK inhibitor on anti-inflammatory signaling (Foxp3, IL-10, Nrf2, HO-1, SOD-2) was assessed in the CNS. Our data show that sepsis causes increased ITK protein expression, IL-17A signaling, and neuroinflammatory mediators in the CNS that are associated with a depression-like state in mice. ITK inhibitor-treated mice with sepsis show attenuated IL-17A signaling, which is associated with the upregulation of IL-10/Nrf2 signaling and the amelioration of depression-like symptoms in mice. Our data show, for the first time, that the ITK inhibition strategy may counteract sepsis-mediated depression through a reduction in IL-17A signaling in the CNS. MDPI 2023-04-30 /pmc/articles/PMC10179574/ /pubmed/37175808 http://dx.doi.org/10.3390/ijms24098101 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Algahtani, Mohammad M.
Alshehri, Samiyah
Alqarni, Sana S.
Ahmad, Sheikh F.
Al-Harbi, Naif O.
Alqarni, Saleh A.
Alfardan, Ali S.
Ibrahim, Khalid E.
Attia, Sabry M.
Nadeem, Ahmed
Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice
title Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice
title_full Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice
title_fullStr Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice
title_full_unstemmed Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice
title_short Inhibition of ITK Signaling Causes Amelioration in Sepsis-Associated Neuroinflammation and Depression-like State in Mice
title_sort inhibition of itk signaling causes amelioration in sepsis-associated neuroinflammation and depression-like state in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10179574/
https://www.ncbi.nlm.nih.gov/pubmed/37175808
http://dx.doi.org/10.3390/ijms24098101
work_keys_str_mv AT algahtanimohammadm inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT alshehrisamiyah inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT alqarnisanas inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT ahmadsheikhf inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT alharbinaifo inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT alqarnisaleha inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT alfardanalis inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT ibrahimkhalide inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT attiasabrym inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice
AT nadeemahmed inhibitionofitksignalingcausesameliorationinsepsisassociatedneuroinflammationanddepressionlikestateinmice