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Prostaglandin E2 receptor PTGER4-expressing macrophages promote intestinal epithelial barrier regeneration upon inflammation.
Na, Yi Rang; Jung, Daun; Stakenborg, Michelle; Jang, Hyeri; Gu, Gyo Jeong; Jeong, Mi Reu; Suh, Soo Youn; Kim, Hak Jae; Kwon, Yoon Hey; Sung, Tae Sik; Ryoo, Seung Bum; Park, Kyu Joo; Im, Jong Pil; Park, Ji Yong; Lee, Yun Sang; Han, Heonjong; Park, Boyoun; Lee, Sungwook; Kim, Daesik; Lee, Ho Su; Cleynen, Isabelle; Matteoli, Gianluca; Seok, Seung Hyeok.
Afiliação
  • Na YR; Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Jung D; Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea.
  • Stakenborg M; Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Jang H; Department of Chronic Diseases and Metabolism (CHROMETA), KU Leuven, Leuven, Belgium.
  • Gu GJ; Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Jeong MR; Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Suh SY; Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Kim HJ; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
  • Kwon YH; Radiation Oncology, Seoul National University Hospital, Seoul, Republic of Korea.
  • Sung TS; Department of Surgery, Emergency Medical Center, Seoul National University Hospital, Seoul, Republic of Korea.
  • Ryoo SB; Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Park KJ; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Im JP; Department of Surgery, Seoul National University Hospital, Seoul, Republic of Korea.
  • Park JY; Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • Lee YS; Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
  • Han H; Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
  • Park B; Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
  • Lee S; Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
  • Kim D; Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
  • Lee HS; Division of Tumor Immunology, Research Institute, National Cancer Center, Goyang, Republic of Korea.
  • Cleynen I; Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
  • Matteoli G; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
  • Seok SH; Department of Human Genetics, KU Leuven, Leuven, Belgium.
Gut ; 70(12): 2249-2260, 2021 12.
Article em En | MEDLINE | ID: mdl-33558271
ABSTRACT

OBJECTIVE:

Dysfunctional resolution of intestinal inflammation and altered mucosal healing are essential features in the pathogenesis of inflammatory bowel disease (IBD). Intestinal macrophages are vital in the process of inflammation resolution, but the mechanisms underlying their mucosal healing capacity remain elusive.

DESIGN:

We investigated the role of the prostaglandin E2 (PGE2) receptor PTGER4 on the differentiation of intestinal macrophages in patients with IBD and mouse models of intestinal inflammation. We studied mucosal healing and intestinal epithelial barrier regeneration in Csf1r-iCre Ptger4fl/fl mice during dextran sulfate sodium (DSS)-induced colitis. The effect of PTGER4+ macrophage secreted molecules was investigated on epithelial organoid differentiation.

RESULTS:

Here, we describe a subset of PTGER4-expressing intestinal macrophages with mucosal healing properties both in humans and mice. Csf1r-iCre Ptger4fl/fl mice showed defective mucosal healing and epithelial barrier regeneration in a model of DSS colitis. Mechanistically, an increased mucosal level of PGE2 triggers chemokine (C-X-C motif) ligand 1 (CXCL1) secretion in monocyte-derived PTGER4+ macrophages via mitogen-activated protein kinases (MAPKs). CXCL1 drives epithelial cell differentiation and proliferation from regenerating crypts during colitis. Specific therapeutic targeting of macrophages with liposomes loaded with an MAPK agonist augmented the production of CXCL1 in vivo in conditional macrophage PTGER4-deficient mice, restoring their defective epithelial regeneration and favouring mucosal healing.

CONCLUSION:

PTGER4+ intestinal macrophages are essential for supporting the intestinal stem cell niche and regeneration of the injured epithelium. Our results pave the way for the development of a new class of therapeutic targets to promote macrophage healing functions and favour remission in patients with IBD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Inflamatórias Intestinais / Receptores de Prostaglandina E Subtipo EP4 / Mucosa Intestinal / Ativação de Macrófagos Limite: Animals Idioma: En Revista: Gut Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Doenças Inflamatórias Intestinais / Receptores de Prostaglandina E Subtipo EP4 / Mucosa Intestinal / Ativação de Macrófagos Limite: Animals Idioma: En Revista: Gut Ano de publicação: 2021 Tipo de documento: Article