Shuhei Kii1,2, Hidemitsu Kitamura3, Shinichi Hashimoto4, Kazuho Ikeo5, Nobuki Ichikawa2, Tadashi Yoshida2, Shigenori Homma2, Mishie Tanino6, Akinobu Taketomi2. 1. Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. 2. Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan. 3. Division of Functional Immunology, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. kitamura@igm.hokudai.ac.jp. 4. Department of Molecular Pathophysiology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan. 5. DNA Data Analysis Laboratory, National Institute of Genetics, Mishima, Japan. 6. Department of Surgical Pathology, Asahikawa Medical University, Asahikawa, Japan.
Abstract
BACKGROUND: The development of inflammatory bowel diseases is thought to be multifactorial, but the exact steps in pathogenesis are poorly understood. In this study, we investigated involvement of the activation of STAT1 signal pathway in the pathogenesis of an acute colitis model. METHODS: A dextran sulfate sodium-induced acute colitis model was established by using wild-type C57BL/6 mice and STAT1-deficient mice. Disease indicators such as body weight loss and clinical score, induction of cytokines, chemokines, and inflammatory cells were evaluated in the acute colitis model. RESULTS: Disease state was significantly improved in the acute colitis model using STAT1-deficient mice compared with wild-type mice. The induction of Ly6c-highly expressing cells in colorectal tissues was attenuated in STAT1-deficient mice. IL-6, CCL2, and CCR2 gene expressions in Ly6c-highly expressing cells accumulated in the inflamed colon tissues and were significantly higher than in Ly6c-intermediate-expressing cells, whereas TNF-α and IFN-α/β gene expression was higher in Ly6c-intermediate-expressing cells. Blockade of CCR2-mediated signaling significantly reduced the disease state in the acute colitis model. CONCLUSIONS: Two different types of Ly6c-expressing macrophages are induced in the inflamed tissues through the IFN-α/β-STAT1-mediated CCL2/CCR2 cascade and this is associated with the pathogenesis such as onset, exacerbation, and subsequent chronicity of acute colitis.
BACKGROUND: The development of inflammatory bowel diseases is thought to be multifactorial, but the exact steps in pathogenesis are poorly understood. In this study, we investigated involvement of the activation of STAT1 signal pathway in the pathogenesis of an acute colitis model. METHODS: A dextran sulfate sodium-induced acute colitis model was established by using wild-type C57BL/6 mice and STAT1-deficient mice. Disease indicators such as body weight loss and clinical score, induction of cytokines, chemokines, and inflammatory cells were evaluated in the acute colitis model. RESULTS: Disease state was significantly improved in the acute colitis model using STAT1-deficient mice compared with wild-type mice. The induction of Ly6c-highly expressing cells in colorectal tissues was attenuated in STAT1-deficient mice. IL-6, CCL2, and CCR2 gene expressions in Ly6c-highly expressing cells accumulated in the inflamed colon tissues and were significantly higher than in Ly6c-intermediate-expressing cells, whereas TNF-α and IFN-α/β gene expression was higher in Ly6c-intermediate-expressing cells. Blockade of CCR2-mediated signaling significantly reduced the disease state in the acute colitis model. CONCLUSIONS: Two different types of Ly6c-expressing macrophages are induced in the inflamed tissues through the IFN-α/β-STAT1-mediated CCL2/CCR2 cascade and this is associated with the pathogenesis such as onset, exacerbation, and subsequent chronicity of acute colitis.
Authors: Ziad Al Nabhani; Sophie Dulauroy; Rute Marques; Clara Cousu; Shahed Al Bounny; François Déjardin; Tim Sparwasser; Marion Bérard; Nadine Cerf-Bensussan; Gérard Eberl Journal: Immunity Date: 2019-03-19 Impact factor: 31.745
Authors: Ashwin N Ananthakrishnan; Charles N Bernstein; Dimitrios Iliopoulos; Andrew Macpherson; Markus F Neurath; Raja A Raja Ali; Stephan R Vavricka; Claudio Fiocchi Journal: Nat Rev Gastroenterol Hepatol Date: 2017-10-11 Impact factor: 46.802
Authors: Jason M Norman; Scott A Handley; Megan T Baldridge; Lindsay Droit; Catherine Y Liu; Brian C Keller; Amal Kambal; Cynthia L Monaco; Guoyan Zhao; Phillip Fleshner; Thaddeus S Stappenbeck; Dermot P B McGovern; Ali Keshavarzian; Ece A Mutlu; Jenny Sauk; Dirk Gevers; Ramnik J Xavier; David Wang; Miles Parkes; Herbert W Virgin Journal: Cell Date: 2015-01-22 Impact factor: 41.582
Authors: Siew C Ng; Hai Yun Shi; Nima Hamidi; Fox E Underwood; Whitney Tang; Eric I Benchimol; Remo Panaccione; Subrata Ghosh; Justin C Y Wu; Francis K L Chan; Joseph J Y Sung; Gilaad G Kaplan Journal: Lancet Date: 2017-10-16 Impact factor: 79.321
Authors: José Luís Fachi; Jaqueline de Souza Felipe; Laís Passariello Pral; Bruna Karadi da Silva; Renan Oliveira Corrêa; Mirella Cristiny Pereira de Andrade; Denise Morais da Fonseca; Paulo José Basso; Niels Olsen Saraiva Câmara; Éricka Lorenna de Sales E Souza; Flaviano Dos Santos Martins; Suzana Eiko Sato Guima; Andrew Maltez Thomas; João Carlos Setubal; Yuli Thamires Magalhães; Fábio Luis Forti; Thamiris Candreva; Hosana Gomes Rodrigues; Marcelo Bispo de Jesus; Sílvio Roberto Consonni; Alessandro Dos Santos Farias; Patrick Varga-Weisz; Marco Aurélio Ramirez Vinolo Journal: Cell Rep Date: 2019-04-16 Impact factor: 9.423
Authors: Tao Zuo; Xiao-Juan Lu; Yu Zhang; Chun Pan Cheung; Siu Lam; Fen Zhang; Whitney Tang; Jessica Y L Ching; Risheng Zhao; Paul K S Chan; Joseph J Y Sung; Jun Yu; Francis K L Chan; Qian Cao; Jian-Qiu Sheng; Siew C Ng Journal: Gut Date: 2019-03-06 Impact factor: 23.059