Wang, Yaodong;
Zhang, Caiyan;
Liu, Tingyan;
Yu, Zhenhao;
Wang, Kexin;
Ying, Jiayun;
Wang, Yao;
... Lu, Guoping; + view all
(2024)
Malat1 regulates PMN-MDSC expansion and immunosuppression through p-STAT3 ubiquitination in sepsis.
International Journal of Biological Sciences
, 20
(4)
pp. 1529-1546.
10.7150/ijbs.92267.
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Abstract
Myeloid-derived suppressor cells (MDSCs) expand during sepsis and contribute to the development of persistent inflammation-immunosuppression-catabolism syndrome. However, the underlying mechanism remains unclear. Exploring the mechanisms of MDSCs generation may provide therapeutic targets for improving immune status in sepsis. Here, a sepsis mouse model is established by cecal ligation and perforation. Bone marrow cells at different sepsis time points are harvested to detect the proportion of MDSCs and search for differentially expressed genes by RNA-sequence. In lethal models of sepsis, polymorphonuclear-MDSCs (PMN-MDSCs) decrease in early but increase and become activated in late sepsis, which is contrary to the expression of metastasis-associated lung adenocarcinoma transcript 1 (Malat1). In vivo, Malat1 inhibitor significantly increases the mortality in mice with late sepsis. And in vitro, Malat1 down-regulation increases the proportion of PMN-MDSCs and enhanced its immunosuppressive ability. Mechanistically, Malat1 limits the differentiation of PMN-MDSCs by accelerating the degradation of phosphorylated STAT3. Furthermore, Stattic, an inhibitor of STAT3 phosphorylation, improves the survival of septic mice by inhibiting PMN-MDSCs. Overall, the study identifies a novel insight into the mechanism of sepsis-induced MDSCs and provides more evidence for targeting MDSCs in the treatment of sepsis.
| Type: | Article |
|---|---|
| Title: | Malat1 regulates PMN-MDSC expansion and immunosuppression through p-STAT3 ubiquitination in sepsis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7150/ijbs.92267 |
| Publisher version: | http://dx.doi.org/10.7150/ijbs.92267 |
| Language: | English |
| Additional information: | ©2024 Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Experimental sepsis, Polymorphonuclear myeloid-derived suppressor cell, Malat1, STAT3 pathway, Ubiquitination |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10187631 |
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