Antagonism of Cerebral High Mobility Group Box 1 Ameliorates Dendritic Cell Dysfunction in Sepsis.

Chao Ren,Jun-Cong Li,Yao Wu,Ning Dong,Yong-Ming Yao,Yong-Wen Feng,Li-Xue Wang,Kun-Wei Chen,Ren-Qi Yao

doi:10.3389/fphar.2021.665579

Abstract

Sepsis has emerged as a global health issue, and accounts for millions of deaths in intensive care units. Dysregulation of the immune response reportedly contributes to the pathogenesis and progression of this lethal condition, which involves both the dysfunction of immune cells and incompetent immunomodulatory mechanisms. High mobility group box 1 (HMGB1) is known as a later inflammatory mediator and is critically involved in the severity and prognosis of sepsis by inducing intractable inflammation and dysfunction of various immune cells. In the present study, we found that intracerebroventricular (ICV) injection of Box A, a specific antagonist of HMGB1, restored the dysregulated response of splenic dendritic cells (DCs) in septic mice by enhancing the expression of surface molecules, including CD80, CD86, and MHC-II, as well as improving DC priming of T lymphocytes. Cerebral HMGB1 was also confirmed to have potent inhibitory effects on DC functions when administrated by ICV injection in normal mice. The brain cholinergic system was found to mediate the immunomodulatory effects of central HMGB1, as it exhibited enhanced activity with persistent HMGB1 exposure. Furthermore, the inhibitory effects of cerebral HMGB1 on the response of peripheral DCs were also blocked by α7nAchR gene knockout. These findings provide novel insight into the relationship between cerebral HMGB1 and splenic DC dysfunction during sepsis, which is, at least in part, dependent on cholinergic system activity.

Highlights

Sepsis has been recognized as a critical health issue worldwide and remains one of the leading causes of mortality in intensive care units
We have previously identified that increased expression of cerebral high mobility group box-1 protein (HMGB1) was one of the major causes of sepsis induced brain injury, as shown by abnormal structure of brain tissues, massive neuronal apoptosis, and cognitive impairment, and these effects were alleviated by administration of BoxA (Ren et al, 2017b)
The suppressed expression of CD80, CD86, and major histocompatibility complex-II (MHC-II) was reversed by inhibiting cerebral HMGB1 at 48 h after sepsis

Summary

Introduction

Sepsis has been recognized as a critical health issue worldwide and remains one of the leading causes of mortality in intensive care units. Dysregulation of the immune response reportedly contributes to the pathogenesis and progression of this lethal condition, according to the new definition of sepsis-3 (Rhodes et al, 2017). Abnormal immunological performance, including uncontrolled production of inflammatory mediators, dysfunctional immune cells, and dysregulated neuroendocrine immune networks, are commonly noted during sepsis (Hotchkiss et al, 2013). Dendritic cells (DCs) are the most important antigen-presenting cells and play an essential role in initiating the adaptive immune response. The impaired function of dendritic cell is critically involved in the development of sepsis-induced immunosuppression (Poehlmann et al, 2009; Bouras et al, 2018). The specific mechanism for sepsis-induced DC dysfunction remains unclarified

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Results

Conclusion