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FAM96A knock-out promotes alternative macrophage polarization and protects mice against sepsis

Authors :
Lu Wang
Ang Yin
Lulu Cao
Qi Li
Wei Chen
Xiaoxin Zhu
Source :
Clin Exp Immunol
Publication Year :
2020
Publisher :
Oxford University Press (OUP), 2020.

Abstract

Summary Sepsis is an intractable clinical syndrome characterized by organ dysfunction when the body over-responds to an infection. Sepsis has a high fatality rate and lacks effective treatment. Family with sequence similarity 96 member A (FAM96A) is an evolutionarily conserved protein with high expression in the immune system and is related to cytosolic iron assembly and tumour suppression; however, research has been rarely conducted on its immune functions. Our study found that Fam96a−/− mice significantly resisted lesions during sepsis simulated by caecal ligation and puncture (CLP) or endotoxicosis models. After a challenge with lipopolysaccharide (LPS) or infection, Fam96a−/− mice exhibited less organ damage, longer survival and better bacterial clearance with decreased levels of proinflammatory cytokines. While screening several subsets of immune cells, FAM96A-expressing macrophages as the key cell type inhibited sepsis development. In-vivo macrophage depletion or adoptive transfer experiments abrogated significant differences in the survival of sepsis between Fam96a−/− and wild-type mice. Results of the bone marrow-derived macrophage (BMDM) polarization experiment indicated that FAM96A deficiency promotes the transformation of uncommitted monocytes/macrophages (M0) into M2 macrophages, secreting fewer proinflammatory cytokines. FAM96A may mediate an immunometabolism shift – from oxidative phosphorylation (OXPHOS) to glycolysis – in macrophages during sepsis, mirrored by reactive oxygen species (ROS) and glucose uptake. These data demonstrate that FAM96A regulates inflammatory response and provide a novel genomic insight for sepsis treatment.

Details

ISSN :
13652249 and 00099104
Volume :
203
Database :
OpenAIRE
Journal :
Clinical and Experimental Immunology
Accession number :
edsair.doi.dedup.....0b591f645ba796ca13414f83c7e92da7
Full Text :
https://doi.org/10.1111/cei.13555