Inhibition of IL-1 Receptor-Associated Kinase 1 Decreases Murine Acute Graft-versus-Host Disease While Preserving the Graft-versus-Lymphoma Effect

Gao, Jun; Xu, Yan; Ma, Sha; Liang, Yiqing; Liu, Cong; Shen, Jingyi; Sun, Zengtian; Niu, Mingshan; Xu, Kailin; Pan, Bin

doi:10.1016/j.jtct.2021.12.001

Cited by 3 publications

(1 citation statement)

References 43 publications

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“…This occurs when the transplanted cells attack the recipient tissues, leading to various health issues. IRAK1 controls the activation of antigen-presenting cells (APCs) under inflammatory conditions, and suppressing IRAK1 may potentially reduce APC activation and alleviate acute graft-versus-host disease (aGVHD) [33]. IRAK1 inhibition indicates its potential to impede T-cell differentiation.…”

Section: Gvhdmentioning

confidence: 99%

Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects

Kim,

Hwang,

Hyun

et al. 2024

Molecules

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Interleukin receptor-associated kinase (IRAK) proteins are pivotal in interleukin-1 and Toll-like receptor-mediated signaling pathways. They play essential roles in innate immunity and inflammation. This review analyzes and discusses the physiological functions of IRAK1 and its associated diseases. IRAK1 is involved in a wide range of diseases such as dry eye, which highlights its potential as a therapeutic target under various conditions. Various IRAK1 inhibitors, including Pacritinib and Rosoxacin, show therapeutic potential against malignancies and inflammatory diseases. The covalent IRAK1 inhibitor JH-X-119-01 shows promise in B-cell lymphomas, emphasizing the significance of covalent bonds in its activity. Additionally, the emergence of selective IRAK1 degraders, such as JNJ-101, provides a novel strategy by targeting the scaffolding function of IRAK1. Thus, the evolving landscape of IRAK1-targeted approaches provides promising avenues for increasingly safe and effective therapeutic interventions for various diseases.

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Section: Gvhdmentioning

confidence: 99%

Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects

Kim,

Hwang,

Hyun

et al. 2024

Molecules

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Thrombin receptor activating peptide-6 decreases acute graft-versus-host disease through activating GPR15

Liu,

Lan,

Cao

et al. 2024

Leukemia

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Aryl hydrocarbon receptor regulates IL-22 receptor expression on thymic epithelial cell and accelerates thymus regeneration

Shen,

Wang,

Zheng

et al. 2023

npj Regen Med

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Improving regeneration of damaged thymus is important for reconstituting T-cell immunity. Interleukin-22 (IL-22) was proved to improve thymus regeneration through recovering thymic epithelial cells (TECs). The IL-22 receptor IL-22RA1 is crucial for mediating IL-22 functions. Mechanism that regulates IL-22RA1 expression is unknown. Through using TECs-conditional knockout mice, we found aryl hydrocarbon receptor (AHR) is important for thymus regeneration, because Foxn1-cre-mediated AHR knockout (AhrKO) significantly blocks recovery of thymus cells. Giving mice the AHR inhibitor CH-223191 or the AHR agonist FICZ blocks or accelerates thymus regeneration, respectively. AhrKO-mediated blockade of thymus regeneration could not be rescued by giving exogenous IL-22. Mechanistically, AhrKO mice shows decreased IL-22RA1 expression. In the murine TECs cell line mTEC1 cells, targeting AHR shows an impact on IL-22RA1 mRNA levels. Using chromatin immunoprecipitation and luciferase reporter assays, we find AHR co-operates with STAT3, binds the promotor region of IL-22RA1 gene and transcriptionally increases IL-22RA1 expression in mTEC1 cells. Foxn1-cre-mediated IL-22RA1 knockout (Il22ra1KO) blocks thymus regeneration after irradiation. Furthermore, targeting AHR or IL-22RA1 has significant impacts on severity of murine chronic graft-versus-host disease (cGVHD), which is an autoimmune-like complication following allogeneic hematopoietic cell transplantation. Giving FICZ decreases cGVHD, whereas Il22ra1KO exacerbates cGVHD. The impacts on cGVHD are associated with thymus regeneration and T-cell immune reconstitution. In conclusion, we report an unrecognized function of TECs-expressed AHR in thymus regeneration and AHR transcriptionally regulates IL-22RA1 expression, which have implications for improving thymus regeneration and controlling cGVHD.

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Inhibition of IL-1 Receptor-Associated Kinase 1 Decreases Murine Acute Graft-versus-Host Disease While Preserving the Graft-versus-Lymphoma Effect

Cited by 3 publications

References 43 publications

Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects

Recent Advances in IRAK1: Pharmacological and Therapeutic Aspects

Thrombin receptor activating peptide-6 decreases acute graft-versus-host disease through activating GPR15

Aryl hydrocarbon receptor regulates IL-22 receptor expression on thymic epithelial cell and accelerates thymus regeneration

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