Related Experiment Video
Updated: May 21, 2025
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Spleen-Heart Cross-Talk Through CD23-Mediated Signal Promotes Cardiac Remodeling
Yufan Feng1, Yang Yang1, Hongqin Yang1
1Department of Pathophysiology, Chinese Academy of Medical Sciences, School of Basic Medicine, Institute of Basic Medicine, Peking Union Medical College, Beijing (Y.F., Y.Y., H.Y., J.S., J.Z., Q.C., Yingge Zhang, Yarong Zhang, Z.L., Y.X., J.C., C.G., H.Z., J.W.).
Background:
Elevated levels of IgE are implicated in pathological cardiac remodeling. However, the origin of IgE remains unknown. In the current study, we aim to explore the source of IgE and the mechanisms underlying IgE production in the context of pathological cardiac remodeling.
Methods:
Flow cytometry was used to assess the changes of IgE-producing B cells in different organs/tissues, including the spleen, lymph nodes, bone marrow, peripheral blood, vasculature, and heart, in mice with cardiac remodeling induced by transverse aortic constriction (TAC). The role of IgE low-affinity receptor FcεRII (Fc epsilon receptor II, also named CD23) in IgE-producing B cells during cardiac remodeling was evaluated in mice with loss-of-CD23 or gain-of-CD23. The therapeutic potential of the CD23-neutralizing antibody was evaluated. The factors involved in organ cross-talk, which regulate IgE production, were identified and validated both in vitro and in vivo.
Results:
We found that splenic IgE-producing cells were significantly elevated in the TAC mice. CD23, as a negative regulator of IgE production, was decreased in splenic B cells of TAC mice. Global knockout of CD23 in mice aggravated TAC-induced IgE synthesis and cardiac remodeling in vivo. In contrast, global or B-cell-specific CD23 overexpression in mice reduced IgE synthesis and alleviated TAC-induced cardiac remodeling. Mechanistically, CD23 was cleaved by ADAM10 (A disintegrin and metalloproteinase domain 10) in the spleen. Screening assay with data-independent acquisition mass spectrometry-based proteomics and ELISA identified Ltf (lactotransferrin), released from the heart shortly after TAC stimulation, as a contributor to ADAM10 upregulation through binding to Ltf receptor Ncl (nucleolin). Meanwhile, Ltf administration promoted IgE elevation, accompanied by increased ADAM10 expression and decreased CD23 expression in vitro and in vivo. Furthermore, the plasma Ltf levels were positively correlated with TAC-induced cardiac remodeling, serum IgE, and sCD23 (soluble CD23). Consistently, Ltf levels were elevated in patients with heart failure with reduced ejection fraction and also positively correlated with serum IgE and sCD23.
Conclusions:
Our findings indicate a critical role of the Ltf-ADAM10-CD23 axis in regulating IgE production through cross-talk between the heart and spleen. The Ltf-ADAM10-CD23 axis may represent new molecular targets for IgE-mediated pathological cardiac remodeling.
