CD40-CD40 Ligand Pathway is a Major Component of Acute Neuroinflammation and Contributes to Long-term Cognitive Dysfunction after Sepsis.

Monique Michels,Dhébora Dall’Igna,Joäo Quevedo,Francieli Vuolo,Fabrícia Petronilho,Andriele Vieira,Drielly Florentino,Beatriz Sonai,Tatiana Barichello,Letícia Galant,Bruna Pescador,Diogo Dominguini,Franciele Mina,Felipe Dal-Pizzol,Lucinéia Gainski Danieslki

doi:10.2119/molmed.2015.00070

Abstract

Sepsis-associated encephalopathy (SAE) is associated with an increased rate of morbidity and mortality. It is not understood what the exact mechanism is for the brain dysfunction that occurs in septic patients, but brain inflammation and oxidative stress are a possible theory. Such events can occur through the alteration of molecules that perpetuate the inflammatory response. Thus, it is possible to postulate that CD40 may be involved in this process. The aim of this work is to evaluate the role of CD40-CD40L pathway activation in brain dysfunction associated with sepsis in an animal model. Microglia activation induces the upregulation of CD40-CD40L, both in vitro and in vivo. The inhibition of microglia activation decreases levels of CD40-CD40L in the brain and decreases brain inflammation, oxidative damage and blood brain barrier dysfunction. Despite this, anti-CD40 treatment does not improve mortality in this model. However, it is able to improve long-term cognitive impairment in sepsis survivors. In conclusion, there is a major involvement of the CD40-CD40L signaling pathway in long-term brain dysfunction in an animal model of sepsis.

Highlights

Sepsis and its consequences are the most common causes of mortality in intensive care units [1,2]
The in vitro activation of microglia by LPS was able to increase the cellular expression of CD40 and the secretion of CD40L (Figure 1)
The upregulation of CD40–CD40L seems to be dependent of microglia activation in vivo, since the inhibition of microglia by minocycline was able to abrogate sepsis-induced upregulation of CD40–CD40L 24 h after cecal ligation and puncture (CLP)

Summary

Introduction

Sepsis and its consequences are the most common causes of mortality in intensive care units [1,2]. The exact mechanism to explain brain dysfunction in septic patients is not fully understood, but it appears to involve different mechanisms that include oxidative stress, cerebral energy dysfunction, blood–brain barrier (BBB) disruption and disturbances in neurotransmission [2,6,7,8]. All these alterations could be related to an inappropriate activation of the immune system [5]. The activation of the CD40–CD40L pathway could interfere in inflamma-

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