Negative Modulation of B Cell Activation by Melanocortin 1 Receptor Signaling Protects against Membranous Nephropathy.

Autor:	Chen B; Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio.; Current address: Blood Purification Center, Institute of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China., Guan X; Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio., Gunning WT; Department of Pathology, University of Toledo Medical Center, Toledo, Ohio., Ge Y; Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio., Gohara AF; Department of Pathology, University of Toledo Medical Center, Toledo, Ohio., Dworkin LD; Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio.; Division of Kidney Disease and Hypertension, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island., Gong R; Division of Nephrology, University of Toledo College of Medicine, Toledo, Ohio.; Division of Kidney Disease and Hypertension, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, Rhode Island.; Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio.; Center for Diabetes and Endocrine Research, University of Toledo Medical Center, Toledo, Ohio.
Jazyk:	angličtina
Zdroj:	Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2023 Mar 01; Vol. 34 (3), pp. 467-481. Date of Electronic Publication: 2022 Nov 29.
DOI:	10.1681/ASN.2022050605
Abstrakt:	Significance Statement: Emerging evidence suggests that melanocortin neuropeptides-specifically adrenocorticotropic hormone-offer a novel, steroidogenic-independent therapeutic modality for membranous nephropathy (MN). The molecular mechanism underlying this beneficial effect, however, remains largely elusive. To investigate whether melanocortins modulate humoral immunity, the authors induced passive Heymann nephritis, a model of human MN, in wild-type and melanocortin 1 receptor (MC1R) knockout rats and treated them with melanocortin agents. Additional rats received adoptive transfer of bone marrow-derived cells beforehand from wild-type or MC1R knockout rats. The findings indicate that MC1R signaling plays a key role in negative modulation of B-cell activation and thereby suppresses humoral immune responses in passive Heymann nephritis, and suggest that MC1R signaling might offer a novel B cell-targeted therapeutic strategy for MN. Background: Emerging evidence suggests that the pituitary neuropeptide melanocortins-specifically, adrenocorticotropic hormone-offer a novel nonsteroidogenic therapeutic modality for membranous nephropathy (MN). However, the mechanism(s) of action remains elusive. Methods: To investigate whether melanocortins modulate humoral immunity, we induced passive Heymann nephritis (PHN), a model of MN, in wild-type (WT) and melanocortin 1 receptor (MC1R) knockout (KO) rats. We treated the animals with melanocortin agents-repository corticotropin injection, the nonsteroidogenic pan-melanocortin receptor agonist [Nle 4 , DPhe 7 ]-α-melanocyte stimulating hormone, the selective MC1R agonist MS05, vehicle gel, or phosphate-buffered saline-and evaluated kidney function, histology, and molecular changes. Additional rats received adoptive transfer of syngeneic bone marrow-derived cells beforehand from WT or MC1R KO rats. Results: KO of MC1R worsened PHN and this was associated with increased deposition of autologous immunoglobulin G (IgG) and complement C5b-9 in glomeruli and higher circulating levels of autologous IgG-evidence of a sensitized humoral immune response. Melanocortin therapy ameliorated PHN in WT rats, coinciding with reduced glomerular deposition of autologous IgG and C5b -9. The beneficial efficacy of melanocortins was blunted in KO rats but restored by adoptive transfer of syngeneic bone marrow-derived cells derived from WT rats. Mechanistically, MC1R was expressed in B lymphocytes and was negatively associated with B cell activation. MC1R agonism triggered the expression of microphthalmia-associated transcription factor in activated B cells in a cAMP-dependent mode and also repressed the expression of interferon regulatory factor 4 (a lymphoid transcription factor essential for B-cell development and maturation), resulting in suppressed plasma cell differentiation and IgG production. Conclusions: MC1R signaling negatively modulates B cell activation and suppresses humoral immune responses in PHN, suggesting that MC1R signaling might offer a novel therapeutic target for MN. (Copyright © 2022 by the American Society of Nephrology.)
Databáze:	MEDLINE
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