1,25-Dihydroxyvitamin D3 and 20-Hydroxyvitamin D3 Upregulate LAIR-1 and Attenuate Collagen Induced Arthritis

Jeoungeun J Park,David D Brand,Robert C Tuckey,Andrew H Kang,John D Kee,John M Stuart,Michael Winstead,Wei Li,Linda K Myers,Andrzej T Slominski,Sicheng Zhang,Arnold E Postlethwaite,Edward F Rosloniec,Ae-Kyung Yi

doi:10.3390/ijms222413342

Abstract

Vitamin D plays a crucial role in regulation of the immune response. However, treatment of autoimmune diseases with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] doses sufficient to be effective is prohibitive due to its calcemic and toxic effects. We use the collagen-induced arthritis (CIA) model to analyze the efficacy of the noncalcemic analog of vitamin D, 20S-hydroxyvitamin D3 [20S(OH)D3], as well as 1,25(OH)2D3, to attenuate arthritis and explore a potential mechanism of action. Mice fed a diet deficient in vitamin D developed a more severe arthritis characterized by enhanced secretion of T cell inflammatory cytokines, compared to mice fed a normal diet. The T cell inflammatory cytokines were effectively suppressed, however, by culture of the cells with 20S(OH)D3. Interestingly, one of the consequences of culture with 1,25(OH)2D3 or 20S(OH)D3, was upregulation of the natural inhibitory receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1 or CD305). Polyclonal antibodies which activate LAIR-1 were also capable of attenuating arthritis. Moreover, oral therapy with active forms of vitamin D suppressed arthritis in LAIR-1 sufficient DR1 mice, but were ineffective in LAIR-1−/− deficient mice. Taken together, these data show that the effect of vitamin D on inflammation is at least, in part, mediated by LAIR-1 and that non-calcemic 20S(OH)D3 may be a promising therapeutic agent for the treatment of autoimmune diseases such as Rheumatoid Arthritis.

Highlights

Human autoimmune arthritis causes significant joint damage due to dysregulated autoimmunity
To confirm that vitamin D plays a role in autoimmune arthritis, groups of DBA/1 mice were fed diets either deficient (VitD−) or sufficient in vitamin D (VitD+) beginning on day 21 when they were weaned
When mice were immunized with CII/complete Freund’s Adjuvant (CFA) to induce arthritis, those fed diets deficient in vitamin D had significantly more severe arthritis than those fed a normal diet (Figure 1)

Summary

Introduction

Human autoimmune arthritis causes significant joint damage due to dysregulated autoimmunity. Attempts to treat RA with 1,25(OH) D3 and its precursors, 25(OH)D3 have caused hypercalcemic toxicity when given chronically at the pharmacological doses needed to maximally suppress arthritis and autoimmunity [1] This side effect limits the amounts that can be given chronically to patients with autoimmune diseases such as RA. We have discovered a novel pathway of D3 metabolism operative in humans, initiated by cytochrome P450scc (CYP11A1), and with subsequent involvement of CYP27B1, which generates additional biologically active products [2–5]. These are at least as potent as classical 1,25(OH) D3 when tested in vitro and in vivo in several model systems and, like 1,25(OH) D3, bind to the vitamin D receptor (VDR) [6–13]. A major product of this pathway, 20S(OH)D3, is nontoxic (i.e., noncalcemic with limited effects on the hematopoietic system, liver, kidney, and heart) at doses as high as 60 μg/kg, while 25(OH)D3 or

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