The Role of TSC1 in the Macrophages Against Vibrio vulnificus Infection.

Xian-Hui Huang,Liu-Ying Wu,Meng-Meng Zheng,Na Chen,Yao Ma,Han Lou,Yong-Liang Lou,Dan-Li Xie,Ting Zhang,Yi-Ju Chen

doi:10.3389/fcimb.2020.596609

Abstract

Vibrio vulnificus (V. vulnificus) is an estuarine bacterium that is capable of causing rapidly fatal infection in humans. Proper polarization and bactericidal activity of macrophages play essential roles in defending against invading pathogens. How macrophages limit V. vulnificus infection remains not well understood. Here we report that tuberous sclerosis complex 1 (TSC1) is crucial for the regulation of V. vulnificus-induced macrophage polarization, bacterial clearance, and cell death. Mice with myeloid-specific deletion of TSC1 exhibit a significant reduction of survival time after V. vulnificus infection. V. vulnificus infection induces both M1 and M2 polarization. However, TSC1 deficient macrophages show enhanced M1 response to V. vulnificus infection. Interestedly, the absence of TSC1 in myeloid cells results in impaired bacterial clearance both in vivo and in vitro after V. vulnificus infection. Inhibition of the mammalian target of rapamycin (mTOR) activity significantly reverses V. vulnificus-induced hypersensitive M1 response and resistant bactericidal activity both in wild-type and TSC1-deficient macrophages. Moreover, V. vulnificus infection causes cell death of macrophages, possibly contributes to defective of bacterial clearance, which also exhibits in a mTORC1-dependent manner. These findings highlight an essential role for the TSC1-mTOR signaling in the regulation of innate immunity against V. vulnificus infection.

Highlights

Vibrio vulnificus (V. vulnificus) is an emerging estuarine bacterium of coastal waters worldwide, such as the United States, Japan, China, South Korea, and Mexico (Zhao et al, 2015; Heng et al, 2017)
Our results indicate that tuberous sclerosis complex 1 (TSC1) mediated mammalian target of rapamycin complex 1 (mTORC1) activity plays a crucial role in the regulation of the macrophage viability, polarization, and bacterial clearance, which might contribute to host defense in V. vulnificus infection
Converging the result that macrophages polarized to both M1 and M2 after Vibrio vulnificus infection, we hypothesize that TSC1 is critical for regulation of macrophage polarization by Vibrio vulnificus

Summary

Introduction

Vibrio vulnificus (V. vulnificus) is an emerging estuarine bacterium of coastal waters worldwide, such as the United States, Japan, China, South Korea, and Mexico (Zhao et al, 2015; Heng et al, 2017). Macrophage Polarization Against V. vulnificus Infection prominent cell lineages of innate immunity, which play an important role as sentinels against microbes (Ishii et al, 2008; Diacovich and Gorvel, 2010). M1 and M2 macrophages are functionally polarized in response to bacterial infection (Mege et al, 2011). M1 macrophages are activated by LPS and IFN-g to elaborate proinflammatory cytokine production and tissue inflammation to promote cell apoptosis (Mosser and Edwards, 2008). After LPS stimulation, M1 macrophages produce proinflammatory cytokines, such as TNF-a, IL-6, IL-12, and IL-1b (Mogensen, 2009; Patel et al, 2017). Macrophages are polarized toward an M1 response to kill the invading organisms and activate adaptive immunity in the early stage of bacterial infection (Liu et al, 2014). An mammalian target of rapamycin complex 1 (mTORC1) inhibitor, was reported to inhibit M2 macrophage polarization (Jin et al, 2018)

Methods

Results

Conclusion