Paricalcitol promotes the maturation of immune granulomas in an experimental model of superoxide dismutase A-induced inflammation

Abstract

Background: - Granulomatous inflammation is a hallmark of several chronic inflammatory diseases, characterized by the formation of immune granulomas. The vitamin D receptor (VDR) and its ligands, such as paricalcitol, have demonstrated immunomodulatory effects on various immune cell subpopulations, including macrophages, dendritic cells, and T-cells. However, the precise role of VDR activation in granuloma formation and the associated immune regulatory pathways, including the PD-1/PD-L1 axis, remains poorly understood. This study aimed to evaluate the effects of paricalcitol, a selective VDR agonist, on granuloma formation and immune cell composition in an experimental model of superoxide dismutase A (SoDA)-induced inflammation, with a focus on antigen-presenting cells (including CD68 + and CD1a + cells), T- and B-cell populations, and PD-L1 expression.

Materials and methods: - The study involved 90 male Wistar rats divided into control and experimental groups. Experimental animals received paricalcitol intraperitoneally at different time points relative to sensitization with SoDA and complete Freund's adjuvant. Granulomatous infiltrates were evaluated histologically, and the cellular composition was assessed via immunohistochemistry using markers such as CD68, CD3, CD1a, CD20, and PD-L1. Statistical analysis included quantitative morphometry and group comparisons.

Results: - Paricalcitol administration significantly influenced granuloma development, with groups receiving treatment before (E1) or at the time of sensitization (E2) showing a reduction in immature granulomas and an increase in mature granulomas compared to the control groups. Enhanced macrophage differentiation, characterized by increased multinucleated giant cells and epithelioid cells, was observed. Additionally, there was a significant increase in PD-L1 expression in granulomatous infiltrates of treated groups, particularly in peripherally located immune cells. These effects were accompanied by a modulation of T-cell responses, including a reduction in CD3 + T-cell population.

Conclusion: - The findings suggest that paricalcitol promotes granuloma stabilization and maturation by modulating VDR-mediated immune pathways, including maturation and transformation of macrophages into epithelioid and giant multinucleated cells, increase in number of CD1a + cells, and PD-1/PD-L1 axis regulation. The ability of paricalcitol to enhance PD-L1 expression through the VDR-mediated pathways provides additional evidence for its role in preventing excessive immune responses and highlights the therapeutic potential of VDR agonists in managing granulomatous inflammation.

Keywords: Dendritic cells; Granuloma; Macrophages; PD-1/PD-L1 pathway; T-cells; Vitamin D; Vitamin D receptors.