Melatonin Inhibits Antibody-Secreting Cells and Improves Systemic Lupus Erythematosus via Modulation of the PKA-CREB Signaling Pathway.

Systemic lupus erythematosus (SLE) is an autoimmune disorder featuring abnormal B cell differentiation and excessive autoantibody production, leading to multiorgan damage. Despite advances in understanding SLE pathogenesis, the molecular mechanisms driving aberrant B cell differentiation remain elusive. Melatonin, a neuroendocrine hormone with immunomodulatory properties, has been shown to regulate immune responses, but its role in B cell differentiation and SLE is poorly understood. This study investigates the role of melatonin and its receptors in B cell differentiation and SLE pathogenesis. We observed reduced serum melatonin levels and decreased expression of melatonin receptors in B cells from SLE patients and MRL/Lpr mice. Activation of melatonin receptors inhibited the protein kinase A (PKA) signaling pathway and reduced phosphorylation of cyclic-AMP response binding protein (CREB), leading to epigenetic downregulation of PRDM1 and IRF4, key transcription factors for plasmablast and plasma cell differentiation. Consequently, melatonin receptor activation suppressed abnormal B cell differentiation into antibody-secreting cells. Our findings highlight melatonin and its receptor signaling as potential therapeutic targets for SLE and other autoimmune diseases mediated by aberrant antibody-secreting cell activity. This study provides novel insights into the protective role of melatonin in SLE and offers a promising avenue for developing targeted therapies.