Exogenous IL‐10 posttreatment along with TLR4 and TNFR1 blockade improves tissue antioxidant status by modulating sepsis‐induced macrophage polarization

Abstract

Multi‐organ dysfunction is one of the major reasons behind the high mortality of sepsis throughout the world. With the pathophysiology of sepsis remaining largely unknown, the uncontrolled reactive oxygen species (ROS) production along with the decreased antioxidants contributes to the progression toward septic shock. Being the effector cells of the innate immunity system, macrophages secrete both pro‐inflammatory and anti‐inflammatory mediators during inflammation. Lipopolysaccharide (LPS) binding to toll‐like receptor 4 (TLR4) releases TNF‐α, which initiates pro‐inflammatory events through tumor necrosis factor receptor 1 (TNFR1) signaling. However, it is counteracted by the anti‐inflammatory interleukin 10 (IL‐10) causing decreased oxidative stress. Our study thus aimed to assess the effects of exogenous IL‐10 treatment post‐neutralization of TLR4 and TNFR1 (by anti‐TLR4 antibody and anti‐TNFR1 antibody, respectively) in an in vivo murine model of LPS‐sepsis. We have also examined the tissue‐specific antioxidant status in the spleen, liver, and lungs along with the serum cytokine levels in adult male Swiss albino mice to determine the functional association with the disease. The results showed that administration of recombinant IL‐10 post‐neutralization of the receptors was beneficial in shifting the macrophage polarization to the anti‐inflammatory M2 phenotype. IL‐10 treatment significantly downregulated the free radicals production resulting in diminished lipid peroxidase (LPO) levels. The increased antioxidant activities of superoxide dismutase (SOD), catalase (CAT), and glutathione reductase (GRX) conferred protection against LPS‐induced sepsis. Western blot data further confirmed diminished expressions of TLR4 and TNFR1 along with suppressed stress‐activated protein kinases/Jun amino‐terminal kinases (SAPK/JNK) and increased SOD and CAT expressions, which altogether indicated that neutralization of TLR4 and TNFR1 along with IL‐10 posttreatment might be a potential therapeutic measure for the treatment of sepsis.

Impact of Treatment with Antioxidants as an Adjuvant to Standard Therapy in Patients with Septic Shock: Analysis of the Correlation between Cytokine Storm and Oxidative Stress and Therapeutic Effects

“…Macrophages secrete proinflammatory and antiinflammatory mediators during the infectious process. The binding of lipopolysaccharide (LPS) to Toll-like receptor 4 (TLR4) releases TNF-α, which initiates proinflammatory events through tumor necrosis factor receptor 1 (TNFR1) signaling, which is an effect of IL-10 [65]. In humans with septic shock, the effect achieved with MT may be related to improving IL-10 levels.…”

“…Innate cytokines are attractive targets for therapeutic intervention [63]. They are essential in diseases whose pathogenesis is the result of a defective regulation of the cytokine network; therefore, cytokine-targeted therapies with monoclonal antibodies, soluble receptors, or small molecule inhibitors promise new possibilities for the treatment of patients resistant to standard drug regimens [64,65]. The proposal to add antioxidants to standard therapy in septic shock has been previously proposed for its benefits in terms of reduction in oxidative stress and an increase in antioxidant capacity.…”

The role of macrophages polarization in sepsis-induced acute lung injury

“…In macrophages, the main source of ROS is NADPH oxidase, which produces two superoxide radicals for each molecule of NADPH consumed ( 105 ). Scholars have pointed out that ROS is closely related to the pro-inflammatory phenotype M1 conversion of macrophages ( 106 ). During sepsis, FAM96A may mediate an immunometabolic shift in macrophages from oxidative phosphorylation (OXPHOS) to glycolysis, associated with reactive oxygen species (ROS) and glucose uptake ( 107 ).…”