RORγt inhibitor SR1001 alleviates acute pancreatitis by suppressing pancreatic IL‐17‐producing Th17 and γδ‐T cells in mice with ceruletide‐induced pancreatitis

Abstract

The management of acute pancreatitis (AP) remains a challenge to clinicians worldwide for limited effective interventions. Retinoid orphan receptor gamma t (RORγt) is a therapeutic target for several diseases; however, it is unclear whether inhibiting RORγt can ameliorate AP. The relative expression of RORγt, IL‐17 and IL‐23 in the peripheral blood mononuclear cells of AP patients was measured by RT‐PCR. An AP mouse model was induced by ceruletide, and SR1001 was injected before ceruletide administration. RORγt+ cells, T helper 17 cells (Th17), regulatory T cells (Tregs) and γδ T cells were assessed in the pancreas and spleen by flow cytometry. Higher RORγt expression in patients indicated the potential role of RORγt in AP progression. Analyses of the IL‐17/IL‐23 axis confirmed its role. SR1001 significantly alleviated AP histologically in the mouse model. Serum levels of amylase, IL‐6, TNFalpha, IL‐17 and IL‐23 decreased upon SR1001 treatment. SR1001 selectively decreased the number of RORγt+, Th17, Tregs and γδ T cells in the pancreas but not the spleen. Collectively, these results showed that SR1001 exerted therapeutic effects on AP by suppressing IL‐17‐secreting Th17 and γδ T cells in the pancreas. Thus, SR1001 may be a promising drug for the treatment of AP in the clinic.

Integrative proteomics, phosphoproteomics and acetylation proteomics analyses of acute pancreatitis in rats

“…Th17 cells are increased in AP 36 . Conversely, another study showed that the Th1/Th17 axis is not activated at the early stage of SAP, and patients with SAP exhibit a diminished Th1/Th17 response 37 . A balance between the anti-inflammatory type-2 immune response and proinflammation might start from the early stage of SAP.…”

Fasudil and SR1001 synergistically protect against sepsis-associated pancreatic injury by inhibiting RhoA/ROCK pathway and Th17/IL-17 response

“…It is also known that SR1001 specifically inhibits the development of Th17 cells and IL-17 expression [ 56 , 57 ]. Recent findings by Wang and colleagues indicated that SR1001 significantly alleviated acute pancreatitis of the mouse model by selectively decreased the Th17/IL-17 [ 58 ]. Similarly, our data also confirmed the therapeutic effect of SR1001 on SPI.…”

A new method for the treatment of myocardial ischemia-reperfusion injury based on γδT cell-mediated immune response

“…SR1001 is a traditional RORγt inhibitor. Its mechanism is to inhibit the activation and over-expression of γδT cells and inhibit the secretion of IL-17 by inhibiting RORγt transcription ( 107 , 108 ). Therefore, the development of more types of RORγt inhibitors in the future can expand the therapeutic application in autoimmune diseases and provide new thinking for the prevention and treatment of MIRI.…”