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

Abstract

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.

Auranofin Modulates Thioredoxin Reductase/Nrf2 Signaling in Peripheral Immune Cells and the CNS in a Mouse Model of Relapsing–Remitting EAE

“…AFN was reported to cause a reduction in IL-6 levels; therefore, the reduction in IL-17A expression in CD4+ T cells could be due to a reduction in IL-6 from peripheral myeloid cells. This could result from the upregulation of Nrf2 signaling in T cells, which was shown to reduce Th17-related immune responses in different preclinical disease models including an EAE model [ 22 , 24 , 26 , 38 , 44 , 45 ].…”

“…iNOS and MPO contained in neutrophils may be destructive during the autoimmune inflammation observed in RR-EAE. This might lead to the dysfunction of endothelial cells adjacent to neutrophils due to the elevated levels of peroxynitrite that results in an increased expression of adhesion molecules [ 22 , 32 , 44 , 45 , 48 ]. Such cells might represent a preferential site for adhesion and migration of additional neutrophils as well as for transendothelial migration, which could be responsible for BBB impairment [ 48 , 49 ].…”

Exposure to Methylmercury at Juvenile Stage Worsens Autism-like Symptoms in Adult BTBR T+tf/J Mice Due to Lack of Nuclear Factor Erythroid 2-Related Factor 2 Signaling Upregulation in Periphery and Brain

“…A single-cell suspension was created from splenic tissue using established protocols outlined in previous studies for flow cytometry analysis [ 17 , 25 ]. To label the leukocytes in the splenic cell suspension, cell surface monoclonal antibodies against GR-1 were used, which were conjugated to FITC, APC, or APC-Cy7 [Biolegend (San Diego, CA, USA) and Santa Cruz Biotech (Dallas, TX, USA)].…”

“…To assess the Nrf2 trans-activation binding activity to the antioxidant response element (ARE) in the cortex, the Trans-AM Nrf2 kit from Active Motif (Carlsbad, CA, USA) was employed, following the methodology outlined in the previous study [ 25 ]. The assay aimed to determine the binding activity of Nrf2 to its specific ARE sequence, which is 5′-GTCACAGTACTCAGCAGAATCTG-3′.…”

Mechanism of baixiangdan capsules on anti-neuroinflammation: combining dry and wet experiments

“…If for some reason the inflammatory response goes excessively uncontrolled or persists over time, it causes pathological neuroinflammation, which increases blood-cerebrospinal fluid barrier permeability and peripheral immune cell infiltration, and elevated levels of classical inflammatory cytokines, leading to cell death and histopathological damage [ 1 , 4 ]. Neuroinflammation plays a central role in many complex health problems, such as neurodegenerative diseases [ 5 , 6 ], autoimmune diseases (e.g., multiple sclerosis [ 7 ]), infections [ 8 ], strokes [ 9 ], traumatic injuries [ 10 ], inflammatory pain [ 11 ], postoperative cognitive impairment [ 12 ], epilepsy [ 13 ], and depression [ 14 ].…”