Macrophage LMO7 deficiency facilitates inflammatory injury via metabolic-epigenetic reprogramming.
10.1016/j.apsb.2023.09.012
- Author:
Shixin DUAN
1
;
Xinyi LOU
1
;
Shiyi CHEN
1
;
Hongchao JIANG
1
;
Dongxin CHEN
1
;
Rui YIN
1
;
Mengkai LI
1
;
Yuseng GOU
1
;
Wenjuan ZHAO
1
;
Lei SUN
1
;
Feng QIAN
1
Author Information
1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
- Publication Type:Journal Article
- Keywords:
Inflammatory bowel disease;
JMJD3;
LMO7;
Macrophage;
PFKFB3;
Ubiquitination
- From:
Acta Pharmaceutica Sinica B
2023;13(12):4785-4800
- CountryChina
- Language:English
-
Abstract:
Inflammatory bowel disease (IBD) is a formidable disease due to its complex pathogenesis. Macrophages, as a major immune cell population in IBD, are crucial for gut homeostasis. However, it is still unveiled how macrophages modulate IBD. Here, we found that LIM domain only 7 (LMO7) was downregulated in pro-inflammatory macrophages, and that LMO7 directly degraded 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) through K48-mediated ubiquitination in macrophages. As an enzyme that regulates glycolysis, PFKFB3 degradation led to the glycolytic process inhibition in macrophages, which in turn inhibited macrophage activation and ultimately attenuated murine colitis. Moreover, we demonstrated that PFKFB3 was required for histone demethylase Jumonji domain-containing protein 3 (JMJD3) expression, thereby inhibiting the protein level of trimethylation of histone H3 on lysine 27 (H3K27me3). Overall, our results indicated the LMO7/PFKFB3/JMJD3 axis is essential for modulating macrophage function and IBD pathogenesis. Targeting LMO7 or macrophage metabolism could potentially be an effective strategy for treating inflammatory diseases.
