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  3. A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis

A novel RIPK1 inhibitor reduces GVHD in mice via a nonimmunosuppressive mechanism that restores intestinal homeostasis

  • Blood. 2023 Mar 2;141(9):1070-1086. doi: 10.1182/blood.2022017262.
Xiaoliang Yu 1 2 3,  Haikuo Ma 4,  Bohan Li 5,  Yuting Ji 1 2 6,  Yayun Du 1 2,  Siying Liu 1 2,  Zhanhui Li 4,  Yongjin Hao 4,  Sheng Tian 4,  Cong Zhao 1 2,  Qian Du 1 2 3,  Zhongqin Jin 7,  Xueming Zhu 8,  Yuanyuan Tian 5 9,  Xin Chen 10,  Xue Sun 11,  Chengkui Yang 1 2,  Fang Zhu 1 2 12,  Jie Ju 1 2 3,  Yunjing Zheng 5,  Wei Zhang 1 2,  Jingrui Wang 1 2,  Tao Yang 1 2,  Xinhui Wang 1 2,  Jingjing Li 1 2,  Xiangping Xu 1 2,  Shujing Du 1 2,  Haohao Lu 1 2,  Feng Ma 1 2,  Haibing Zhang 13,  Yi Zhang 9 14,  Xiaohu Zhang 4,  Shaoyan Hu 5,  Sudan He 1 2 3 12
Affiliations

Affiliations

  • 1 Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 2 Suzhou Institute of Systems Medicine, Suzhou, China.
  • 3 Cyrus Tang Hematology Center and Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China.
  • 4 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 5 Department of Hematology, Jiangsu Pediatric Center of Hematology & Oncology, and The Children's Hospital of Soochow University, Suzhou, China.
  • 6 School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
  • 7 Department of Gastroenterology, The Children's Hospital of Soochow University, Suzhou, China.
  • 8 Department of Pathology, The Children's Hospital of Soochow University, Suzhou, China.
  • 9 Fels Institute and Department of Cancer Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA.
  • 10 Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 11 Department Of Intensive Care Unit, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 12 State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
  • 13 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 14 Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ.
PMID: 36356302 DOI: 10.1182/blood.2022017262
Abstract

Intestinal epithelial cells (IECs) are implicated in the propagation of T-cell-mediated inflammatory diseases, including graft-versus-host disease (GVHD), but the underlying mechanism remains poorly defined. Here, we report that IECs require receptor-interacting protein kinase-3 (RIPK3) to drive both gastrointestinal (GI) tract and systemic GVHD after allogeneic hematopoietic stem cell transplantation. Selectively inhibiting RIPK3 in IECs markedly reduces GVHD in murine intestine and liver. IEC RIPK3 cooperates with RIPK1 to trigger Mixed Lineage Kinase domain-like protein-independent production of T-cell-recruiting chemokines and major histocompatibility complex (MHC) class II molecules, which amplify and sustain alloreactive T-cell responses. Alloreactive T-cell-produced interferon gamma enhances this RIPK1/RIPK3 action in IECs through a JAK/STAT1-dependent mechanism, creating a feed-forward inflammatory cascade. RIPK1/RIPK3 forms a complex with JAK1 to promote STAT1 activation in IECs. The RIPK1/RIPK3-mediated inflammatory cascade of alloreactive T-cell responses results in intestinal tissue damage, converting the local inflammation into a systemic syndrome. Human patients with severe GVHD showed highly activated RIPK1 in the colon epithelium. Finally, we discover a selective and potent RIPK1 Inhibitor (Zharp1-211) that significantly reduces JAK/STAT1-mediated expression of chemokines and MHC class II molecules in IECs, restores intestinal homeostasis, and arrests GVHD without compromising the graft-versus-leukemia (GVL) effect. Thus, targeting RIPK1/RIPK3 in IECs represents an effective nonimmunosuppressive strategy for GVHD treatment and potentially for Other Diseases involving GI tract inflammation.

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