Canonical and non-canonical vitamin D activation pathways in systemic lupus

点击翻译按钮获取中文摘要

Project Summary In systemic lupus erythematosus (SLE) the deficiency in vitamin D3 (D3), an essential regulator of immune system, is common and is associated with disease severity and fatigue. However, responses to vitamin D supplementation ranged from some benefit to no benefit even in situations where normal serum levels of 25(OH)D3 (liver vitamin D3 metabolite) was achieved. The underlying mechanism/s for this variable response is unknown and represents a critical gap in our knowledge. This proposal will test a very novel hypothesis that efficient regulation of immune response requires immune cell intrinsic metabolism of D3. The proposed mechanism strikingly contrasts the current dogma, e.g., D3 is first activated in the liver by hydroxylation into 25(OH)D3 followed by a second hydroxylation at C1α by CYP27B1 in kidneys to produce 1,25(OH)2D3 that by interacting with vitamin D receptor (VDR) in innate and adaptive immune cells initiates a signaling cascade that is immunoregulatory. What has not been appreciated is the recent discovery of a non-canonical metabolic pathway of vitamin D activation that starts with hydroxylation of D3 by the steroidogenic enzyme CYP11A1 at C20 and produces 20(OH)D3 as the first metabolite that can down regulate T cell responses without the need for VDR. Importantly, CYP11A1 is expressed in T cells and other immune cells, providing an alternative mechanism for immune cell intrinsic production of non-canonical liver-independent active forms of D3 with critical role in immune regulation. Defects in this non-canonical pathway will have the phenotypic effects of vitamin D deficiency that cannot be rectified by canonical supplementation. Mechanistically, CYP11A1- dependent endogenously produced (20(OH)D3 and 20,23(OH)2D3 can exert immunoregulatory activity by (i) antagonizing NF-κB through classical pathway (VDR-dependent) and by (ii) suppressing Il17 expression through action as inverse agonists on RORα and RORγ. These pathways have not been considered as the mechanism for loss of vitamin D dependent regulation in SLE, which is the goal of this proposal. To address this challenge, the following aims are proposed: (1) To determine if canonical and/or non-canonical components of vitamin D signaling are decreased in immune cells from patients with SLE, and (2) To evaluate the hypothesis that the vitamin D3-dependent attenuation of NFκB and/or RORγ/α signaling pathways is defective in immune cells from SLE patients in comparison to normal subjects. The latter will include a highly mechanistic approach. The findings from this proposal will greatly advance the field with respect to vitamin D regulatory activity in T cells, B cells and monocytes within the context of SLE/autoimmunity. In addition, it is expected that they will pave the way for use of non-calcemic vitamin D derivatives for therapy of autoimmune disorders.