Obesity and Type 2 Diabetes mellitus induce lipopolysaccharide tolerance in rat neutrophils

Abstract

Obesity and diabetes implicate in various health complications and increased mortality caused by infection. Innate immune system is broadly affected by these diseases, leading the patients to an immunosuppressive state. A mechanism that leads innate immune cells to a less capacity of killing microorganism is the impaired TLR4 activation. TLR4 recognizes a component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS), and when activated increases the production of inflammatory substances. Neutrophils are components of the innate immune system and are the first responders to an invading agent. The correct activation of TLR4 in these cells is required for the initiation of the inflammatory process and elimination of the microorganisms. The aim of this study was to evaluate the influence of type 2 diabetes and obesity in the TLR4 pathway in rat neutrophils. Two experimental models were used: Goto-Kakizaki rats and high-fat-diet induced obese Wistar rats. To evaluate neutrophil response to LPS, intratracheal LPS instillation was used. Neutrophils from obese and diabetic animals exhibited tolerance to LPS, mainly by the impaired production of cytokines and chemokines and the low content of phospho-NFκB and phospho-IKBα. Neutrophils from both experimental models had increased cell death, impaired in vivo migration and myeloperoxidase activity.

Abnormal Peripheral Neutrophil Transcriptome in Newly Diagnosed Type 2 Diabetes Patients

“…Type 2 diabetes is associated with worse outcomes and mortality caused by infection [31] due to impaired innate immune functions, including phagocytosis, cytokine and reactive oxygen species (ROS) production, bactericidal activity, and chemotaxis [32]. In our study, the GO analysis showed that the diabetic neutrophil response to molecules of bacterial origin, such as LPS, and inflammatory response were decreased.…”

“…These data demonstrate that neutrophils from patients with diabetes may also exhibit impaired migration because of the downregulated chemotaxis, which may explain why some patients with diabetes have increased infection rates. Kuwabara et al showed that neutrophils had an impaired response to LPS in a type 2 diabetes and obesity animal model, and neutrophils from the GK rats were not capable of migrating to the site of inflammation due to the impaired expression of adhesion proteins after LPS stimulation [32]. In addition, a defect in the chemotaxis of leukocytes in patients with diabetes has been identified, which could contribute to increased infections in these patients [33,34], and high blood glucose induces a defective leukocyte-endothelial interaction in rats [35].…”

Effects of a multispecies synbiotic on glucose metabolism, lipid marker, gut microbiome composition, gut permeability, and quality of life in diabesity: a randomized, double-blind, placebo-controlled pilot study

“…In T2D and obesity, neutrophils react with less production of reactive oxygen species upon PMA stimulation compared to metabolically healthy obese individuals [66]. Furthermore, a tolerance to LPS has been described in animal models of diabetes and obesity [67]. This innate immune dysfunction contributes to the high risk of infections in T2D and obesity [68].…”

Neutrophil Function Impairment Is a Host Susceptibility Factor to Bacterial Infection in Diabetes

“…Indeed, GK rats exhibited a decrease in IL1-β, IL-6, and TNF-α concentration in BAL and also a reduction in the expression of adhesion molecules, such as LFA-1 and ICAM-2, on neutrophils. All these alterations were associated with a reduction in the TLR4 expression and activation in neutrophils [54].…”