Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy

Lu Gao^1#, Qian-Han Xu^1#, Li-Na Ma^1#, Jing Luo¹, Kahindo P. Muyayalo¹, Li-Ling Wang¹, Dong-Hui Huang¹, Xian-Jin Xiao¹, Shi-Bin Cheng², Gil Mor^1,3, Ai-Hua Liao^1✉

1. Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, P.R. China.
2. Departments of Pediatrics, Obstetrics and Gynecology and Pathology, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.
3. C.S. Mott Center for Human Growth and Development, Wayne State University school of Medicine, Detroit, MI 48201, USA.
#These authors have contributed equally to this work.

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Citation:
Gao L, Xu QH, Ma LN, Luo J, Muyayalo KP, Wang LL, Huang DH, Xiao XJ, Cheng SB, Mor G, Liao AH. Trophoblast-derived Lactic Acid Orchestrates Decidual Macrophage Differentiation via SRC/LDHA Signaling in Early Pregnancy. Int J Biol Sci 2022; 18(2):599-616. doi:10.7150/ijbs.67816. Available from https://www.ijbs.com/v18p0599.htm

Abstract

Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.

Keywords: lactic acid, trophoblast, early pregnancy, decidual macrophage, recurrent pregnancy loss