LXR-Mediated Inhibition of CD4+ T Helper Cells

Abstract

TH17 cells, which require the expression of both retinoic acid receptor-related orphan receptors α and γt (RORαand RORγt) for full differentiation and function, have been implicated as major effectors in the pathogenesis of inflammatory and autoimmune diseases. We recently demonstrated that the Liver X Receptor (LXR) agonist, T0901317 (T09), also displays high-affinity RORα and RORγ inverse activity, potentially explaining its effectiveness in various TH17-mediated autoimmune disease models. However, recent studies suggest that in conjunction with the RORs, LXR mediates a negative regulatory effect on TH17 cell differentiation. Since T09 acts on both LXRs and RORs, it presents as a valuable tool to understand how compounds with mixed pharmacology affect potential pathological cell types. Therefore, using T09, we investigated the mechanism by which the LXRs and RORs affect TH17 cell differentiation and function. Here we demonstrate that T09 activity at RORα and γ, not LXR, is facilitating the inhibition of TH17 cell differentiation and function. We also demonstrate that LXR activity inhibits the differentiation and function of TH1, TH2 and iTreg cells. Finally, T09 inhibited T cell proliferation and induced cell death. These data help explain much of the efficacy of T09 in inflammatory models and suggest that the generation of synthetic ligands with graded, combined LXR and ROR activity may hold utility in the treatment of inflammatory and autoimmune diseases where targeting both TH17 and TH1 cells is required.

IL-17A and Th17 Cells in Lung Inflammation: An Update on the Role of Th17 Cell Differentiation and IL-17R Signaling in Host Defense against Infection

“…The understanding of Th17 cell differentiation has been applied to the development of therapies targeted to Th17-mediated autoimmune diseases [71]. Synthetic or natural forms of ROR γ t inverse agonists have been studied to suppress IL-17A expression.…”

Disrupting myeloid-specific LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

“…LXRs are known modulators of cell proliferation in other disease conditions where cell proliferation is critical, including cancer (28). For instance, LXR activation inhibits proliferation of B and T cells and macrophages (29)(30)(31) and several cancer cell lines including prostate (LNCaP)(32), breast (MCF7) (33) and colon (HTC111) (34). Identified anti-proliferative mechanisms by classic LXR agonists appear to be independent of the lipogenic activity of LXR (33), but rather linked to βcatenin activity(34), cyclins (32) and sterol metabolism (31).…”

Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus

“…Work from our lab and others suggests that LXR signaling facilitates the clearance of apoptotic bodies while suppressing inflammatory gene expression (21,22). Likewise, LXRs can suppress proliferative capacity and differentiation of T lymphocytes (23,24), likely through their ability to regulate cellular cholesterol. Thus, LXRs appear to be critical for coordination between self-tolerance and lipid metabolism.…”