RORγt-specific transcriptional interactomic inhibition suppresses autoimmunity associated with T _H 17 cells

Abstract

Significance T H 17 cells are a subset of CD4 + T helper cells that secrete the cytokine IL-17 and play a role in autoimmunity. RORγt is identified as a key transcription factor driving the T H 17 differentiation. Sequence analysis indicated that transcription factor contains several conserved DNA-binding domain and isotype-specific domain that we termed transcription modulation domain (TMD). We designed a novel therapeutics, tRORγt-TMD, to deliver RORγt-TMD efficiently into the nucleus of the cells that regulates T H 17 cell functions and T H 17-mediated autoimmune diseases. With the same concept, tTbet-TMD also can regulate T H 1 functions. In conclusion, tRORγt-TMD/tTbet-TMD can be novel and highly specific therapeutics for the treatment of T H 17/T H 1-mediated inflammatory disease and further allows us to discover new function of RORγt/Tbet in animals without genetic alteration.

Inhibition of Bromodomain and Extraterminal Domain Family Proteins Ameliorates Experimental Renal Damage

“…Studies of genetically modified mice or using neutralizing antibodies against IL-17A or its receptor have shown the involvement of Th17 immune responses in chronic inflammatory diseases, [55][56][57][58][59][60] including immune and nonimmune experimental renal damage. 47,48 The presence of Th17 cells in UUO-damaged kidneys has been described.…”

Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism

“…Additional studies by multiple groups have suggested that the STAT6/IL4 pathway in Th2 cells is protective in AKI and enhances repair, while the STAT4/IFN-γ pathway of Th1 cells plays a modest contributory role toward inflammation in I/R induced AKI 38 39 40 . Recently, a new proinflammatory T helper subset, referred to as the Th17 cell, has been associated with various immune disorders 41 - 43 . It has recently reported that there is infiltration of Th17 cells following acute ureteral obstruction 44 .…”

Pharmacological Inhibition of Bromodomain Proteins Suppresses Retinal Inflammatory Disease and Downregulates Retinal Th17 Cells

“…Inhibition of Th17 cell differentiation and functions using a variety of different approaches, such as applying neutralizing cytokine Abs (27,(57)(58)(59)(60)(61)(62), blocking Th17 migration via CCR6-CCL20 blockade (53), inhibiting transcription factors RORgt/ RORc using peptide tRORgt-transcriptional modulation domain (31), or applying RNA interference techniques to suppress the transcription factor, were all therapeutically beneficial in both treatment and prevention settings in some inflammatory autoimmune diseases/models but had little or no impact in others. Poor responses to treatment and delivery issues of protein-based drugs are both challenges in the field.…”

“…Th17 cells are characterized by secretion of IL-17 and IL-22, as well as expression of chemokine receptor CCR6 and transcription factor retinoic acid-related orphan receptor (ROR)gt (28,29). As such, it is well recognized that inhibition of Th17 cell differentiation and/or downstream function represents an additional potential treatment approach for such inflammatory and autoimmune diseases (30)(31)(32)(33). However, a recent study observed that their pathogenicity can also be limited by Foxp3 + T regulatory (Treg) and Treg type 1 cells (34).…”