Leukadherin-1-Mediated Activation of CD11b Inhibits LPS-Induced Pro-inflammatory Response in Macrophages and Protects Mice Against Endotoxic Shock by Blocking LPS-TLR4 Interaction.

Fenglian Yan,Huabao Xiong,Xingqin Fu,Chuanping Si,Jun Dai,Hui Shi,Chunxia Li,Bo Wang,Junfeng Zhang,Xiangzhi Meng,Feng Hong,Guanjun Dong,Yonghong Yang,Xiaoying Yao,Zhaochen Ning,Jian Ming ,Zhihua Liu ,Ye Zhu ,Qun Ma,Xuehui Li,Hui Zhang,Qingqing Zhang

doi:10.3389/fimmu.2019.00215

Abstract

Dysregulation of macrophage has been demonstrated to contribute to aberrant immune responses and inflammatory diseases. CD11b, expressed on macrophages, plays a critical role in regulating pathogen recognition, phagocytosis, and cell survival. In the present study, we explored the effect of leukadherin-1 (LA1), an agonist of CD11b, on regulating LPS-induced pro-inflammatory response in macrophages and endotoxic shock. Intriguingly, we found that LA1 could significantly reduce mortalities of mice and alleviated pathological injury of liver and lung in endotoxic shock. In vivo studies showed that LA1-induced activation of CD11b significantly inhibited the LPS-induced pro-inflammatory response in macrophages of mice. Moreover, LA1-induced activation of CD11b significantly inhibited LPS/IFN-γ-induced pro-inflammatory response in macrophages by inhibiting MAPKs and NF-κB signaling pathways in vitro. Furthermore, the mice injected with LA1-treated BMDMs showed fewer pathological lesions than those injected with vehicle-treated BMDMs in endotoxic shock. In addition, we found that activation of TLR4 by LPS could endocytose CD11b and activation of CD11b by LA1 could endocytose TLR4 in vitro and in vivo, subsequently blocking the binding of LPS with TLR4. Based on these findings, we concluded that LA1-induced activation of CD11b negatively regulates LPS-induced pro-inflammatory response in macrophages and subsequently protects mice from endotoxin shock by partially blocking LPS-TLR4 interaction. Our study provides a new insight into the role of CD11b in the pathogenesis of inflammatory diseases.

Highlights

Endotoxic shock, characterized by poor tissue perfusion and multi-organ dysfunction, is a fatal condition caused by a disordered immune response to bacterial infection [1]
Our study reveals a crucial role of CD11b, in the regulation of LPS-induced pro-inflammatory response in macrophages, and subsequently, protection of mice from endotoxic shock, thereby providing novel insights into the role of CD11b in the pathogenesis of inflammatory diseases
We found that silencing of CD11b inhibited the pathogenesis of LPS-induced endotoxin shock and the pro-inflammatory response of macrophages and DCs (Figure S1), suggesting that CD11b participates in the pathogenesis of endotoxic shock

Summary

Introduction

Endotoxic shock, characterized by poor tissue perfusion and multi-organ dysfunction, is a fatal condition caused by a disordered immune response to bacterial infection [1]. CD14 transfers LPS to the TLR4/MD-2 complex and mediates TLR4 internalization, which dimerizes and triggers MyD88- and TRIF-dependent production of pro-inflammatory cytokines, and type I interferons [12,13,14,15,16,17]. These studies proved that macrophages are activated in the early stages of endotoxin shock, and lead to tissue damage by inducing increased production of pro-inflammatory cytokines. There is an urgent need to investigate the underlying regulatory mechanisms of LPS-induced pro-inflammatory response in macrophages during endotoxic shock

Methods

Results

Conclusion