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

• Published in: International journal of molecular sciences 2023-04, Vol.24 (9), p.8101
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants; Cell differentiation; Central nervous system; Cytokines; depression; Depression - drug therapy; Depression - etiology; Depression, Mental; Foxp3 protein; Health aspects; Helper cells; Hospital costs; IL-17A; Infection; Inflammation; Interleukin 10; Interleukin 6; Interleukin-17 - metabolism; ITK; Itk protein; Kinases; Lipids; Lymphocytes; Lymphocytes T; Mental depression; Mice; MnSOD gene; Monocyte chemoattractant protein 1; Morbidity; Mortality; neuroinflammation; Neuroinflammatory Diseases; NF-E2-Related Factor 2; NF-κB protein; Nitric-oxide synthase; Peroxides; Proteins; Sepsis; Sepsis - complications; Sucrose; Tyrosine
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms24098101

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, NF B, 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.