Natural Resistance to Ovarian Hyperstimulation Syndrome in Estrildid Finches Reveals Macrophage GPR183 as a Potential Therapeutic Target

  • Adv Sci (Weinh). 2026 May 5:e75523. doi: 10.1002/advs.75523.
Xiaofei Yan  1  2 ,  Yongjie Huang  1  2 ,  Jiabao Yang  1 ,  Su Ma  1 ,  Songsong Liu  1 ,  Xuan Huang  3 ,  Juergen Brosius  2 ,  Huaping Zheng  2  4 ,  Bing Yao  3 ,  Li Chen  3 ,  Shanshan Lai  1 ,  Cheng Deng  2  4  5
Affiliations
  • 1. Jiangsu Key Laboratory for Biodiversity and Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, P. R. China.
  • 2. Department of High Altitude Medicine, Center for High Altitude Medicine, Collage of Life Sciences, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China.
  • 3. Center of Reproductive Medicine, Nanjing Jinling Hospital, Clinical School of Medical College, Nanjing University, Nanjing, Jiangsu, P. R. China.
  • 4. Institute of High Altitude Medicine, High Altitude Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, P. R. China.
  • 5. Center For High Altitude Medicine, Xining, Qinghai, P. R. China.
PMID: 42085637 DOI: 10.1002/advs.75523
Abstract

Spontaneous ovarian hyperstimulation syndrome (OHSS) is closely associated with follicle stimulating hormone receptor (FSHR) functional mutations. We observed that estrildid finches naturally carry the gain-of-function FSHR p.Thr449Ala mutation found in humans, yet do not develop OHSS, thereby providing a novel and system to study aspects of OHSS prevention. Cross-species single-cell analysis revealed that macrophages, the most abundant immune cells in ovaries, play a pivotal role in OHSS progression. Macrophage depletion exacerbates the manifestations of OHSS in both birds and rats. Pharmacological activation of the G protein-coupled receptor 183 (GPR183) in ovarian macrophages, significantly alleviates OHSS symptoms. Mechanistically, GPR183 activation in macrophages maintains ovarian immune homeostasis by downregulating inflammatory factors (Interleukin 1 alpha: IL1A, Interleukin 6: IL6, Interleukin 1 beta: IL1B) and upregulating immune regulators responsive to external stimuli (sphingomyelin phosphodiesterase acid like 3A: Smpdl3a, Macrophage-expressed gene 1: Mpeg1, Epithelial stromal interaction 1: Epsti1, Unc-93 homolog B1: Unc93b1, Apolipoprotein B mRNA editing enzyme catalytic subunit 1: Apobec1). It markedly altered CD44 molecule (CD44)/Syndecan-4 (SDC4) -mediated intercellular communication between macrophages and endothelial/stromal cells, thereby modulating the ovarian microenvironment. This study identifies ovarian macrophages as a key therapeutic target for OHSS and proposes GPR183 as a novel receptor target for precision macrophage-based interventions.

Keywords
GPR183; OHSS; estrildidae; evolutionary medicine; macrophage; physiological adaptation; scRNA‐seq.
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