Scrutinizing Mechanisms of the 'Obesity Paradox in Sepsis': Obesity Is Accompanied by Diminished Formation of Neutrophil Extracellular Traps (NETs) Due to Restricted Neutrophil-Platelet Interactions.

Iwona Cichon,Michal Santocki,Weronika Ortmann,Elzbieta Kolaczkowska,Malgorzata Opydo-Chanek

doi:10.3390/cells10020384

Abstract

Systemic inflammation is a detrimental condition associated with high mortality. However, obese individuals seem to have higher chances of surviving sepsis. To elucidate what immunological differences exist between obese and lean individuals we studied the course of endotoxemia in mice fed high-fat diet (HFD) and ob/ob animals. Intravital microscopy revealed that neutrophil extracellular trap (NET) formation in liver vasculature is negligible in obese mice in sharp contrast to their lean counterparts (ND). Unlike in lean individuals, neutrophil influx is not driven by leptin or interleukin 33 (IL-33), nor occurs via a chemokine receptor CXCR2. In obese mice less platelets interact with neutrophils forming less aggregates. Platelets transfer from ND to HFD mice partially restores NET formation, and even further so upon P-selectin blockage on them. The study reveals that in obesity the overexaggerated inflammation and NET formation are limited during sepsis due to dysfunctional platelets suggesting their targeting as a therapeutic tool in systemic inflammation.

Highlights

Sepsis is “life-threatening organ dysfunction caused by a dysregulated host response to infection” [1]
In order to verify if the difference in ability of platelets to activate neutrophils to cast neutrophil extracellular trap (NET) results from altered integrin expression on the latter cells, we evaluated expression of LFA-1 (b2(CD18)/aL(CD11a)) (Supplementary Figure S8A,B)
Endotoxins are found in the blood of patients with sepsis and their presence is associated with shock and multiple organ dysfunction [52]

Summary

Introduction

Sepsis is “life-threatening organ dysfunction caused by a dysregulated host response to infection” [1]. The excessive release of NETs causes liver injury, and in particular neutrophil elastase [15,16] and histones [7,17] of NET origin were shown to directly cause bystander cytotoxicity or contribute to microthrombosis. Their inappropriate formation and/or clearance further add to the pathology of sepsis [18]. Liver damage is independent of the inducing agent, be it

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