The University of Toledo Translation Journal of Medical Sciences 
Nephrology Abstract, Department of Medicine Research Symposium UTJMS 2023 May 5; 11(1):e1-e1 

https://dx.doi.org/10.46570/utjms.vol11-2023-764 

Negative Modulation of B Cell Activation 
by MC1R Signaling Protects Against 
Membranous Nephropathy 
Bohan Chen1*, Xuejing Guan1, Yan Ge1, Lance Dworkin1, Rujun Gong1 

1Division of Infectious Diseases, Department of Medicine, The University of Toledo, 
Toledo, OH 43614 

*Corresponding author: lance.dworkin@utoledo.edu

Published: 05 May 2023 

Background: The pituitary neuropeptide melanocortins, represented by ACTH, have recently emerged 
as a novel therapeutic modality for membranous nephropathy (MN). However, the mechanism of action 
remains elusive.  

Methods: Passive Heymann nephritis (PHN), a model of MN, was induced in wild-type (WT) rats and 
melanocortin 1 receptor (MC1R) knockout (KO) rats generated by using the CRISPR/Cas9 technology, 
followed by treatment with various melanocortin agents, including the Repository Corticotropin 
Injection, the non-steroidogenic pan-MCR agonist NDP-MSH, and the selective MC1R agonist MS05. 
Some rats received adoptive transfer of syngeneic bone marrow-derived cells (BMDC) beforehand. 
Kidney function and injuries were evaluated.  

Results: MC1R KO exacerbated proteinuria, podocyte injury and glomerulopathy, associated with 
enhanced glomerular deposition of autologous IgG and the C5b-9 complement complex, denoting a 
sensitized autologous humoral immune response. Melanocortin therapy ameliorated PHN in WT rats, 
coinciding with diminished glomerular deposition of autologous IgG and C5b-9. The beneficial efficacy 
of melanocortin therapy was blunted in KO rats but was restored by adoptive transfer of syngeneic 
BMDC derived from WT rats. Mechanistically, MC1R was evidently expressed in B lymphocytes, and 
negatively associated with B cell activation as revealed by gene set enrichment analysis. MC1R agonism 
triggered MITF induction in activated B cells in a cAMP-dependent mode, and repressed the expression 
of IRF4, resulting in suppressed plasma cell differentiation and IgG production.  

Conclusion: MC1R signaling plays a key role in negative modulation of B cell activation and 
suppresses humoral immune response in PHN, representing a novel therapeutic target for MN. 

https://dx.doi.org/10.46570/utjms.vol11-2023-764
mailto:lance.dworkin@utoledo.edu