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.
Highlights
TH17 cells are a subset of CD4+ T cells characterized by the secretion of IL-17A, IL-17F, IL-21, and IL-22, and play an important role in the regulation of immune responses against bacterial and fungal infections [1,2,3]
Our studies suggest that T09 inhibits TH17 cell differentiation and function through both the RORs and liver X receptor (LXR), whereas LXR activity alone is responsible for the inhibition of the other CD4+ T cell subsets
The combination of TGFb and IL-6 increased the mRNA expression of IL-17A, IL-17F, IL-21, IL-22, and IL-23R in vehicle treated cells whereas T09 treated cells failed to significantly upregulate these TH17 mediated cytokines and cytokine receptors when evaluated by real-time PCR (RTPCR) (Fig. 1A)
Summary
TH17 cells are a subset of CD4+ T cells characterized by the secretion of IL-17A, IL-17F, IL-21, and IL-22, and play an important role in the regulation of immune responses against bacterial and fungal infections [1,2,3] These cells have been linked to the pathology of many autoimmune diseases, including multiple sclerosis, psoriasis, rheumatoid arthritis, and inflammatory bowel disease [3,4]. T09 represented the first identified high-affinity synthetic ligand that targets both RORa and RORc. its promiscuous activity limited utilization of this compound as a tool to examine the function of the RORs. using the benzenesulfonamide T09 scaffold as a lead compound, we developed a derivative, SR1001 that was devoid of all LXR activity yet retained its ability to suppress the activity of RORa and RORc. SR1001 was effective at suppressing TH17 cell differentiation and function in vitro and in vivo and delayed the onset and severity of EAE [8]. SR1001 was not as effective as T09 at inhibiting the onset and severity of EAE, suggesting that the mixed pharmacology of T09 was potentially affecting more than just TH17 cell differentiation and function[9,10]
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