Jin-Kyu Park1,2, Mingjie Shao1,3, Moon Young Kim1,4, Soon Koo Baik4, Mee Yon Cho5, Teruo Utsumi1, Ayano Satoh6, Xinsho Ouyang1, Chuhan Chung1,7, Yasuko Iwakiri1. 1. Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT. 2. Department of Veterinary Pathology, College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea. 3. Transplantation Surgery Center, Third Xiangya Hospital, Central South University, Changsha, P.R. China. 4. Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea. 5. Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea. 6. The Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan. 7. VA CT Healthcare System, West Haven, CT.
Abstract
Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALD patients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed a control or Lieber-DeCarli ethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALD patients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo-B-positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = -0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells. CONCLUSION: Nogo-B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017;65:1720-1734).
Nogo-B (Reticulon 4B) is an endoplasmic reticulum (ER) resident protein that regulates ER structure and function. Because ER stress is known to induce M2 macrophage polarization, we examined whether Nogo-B regulates M1/M2 polarization of Kupffer cells and alters the pathogenesis of alcoholic liver disease (ALD). M1 and M2 phenotypes were assessed in relation to Nogo-B expression and disease severity in liver specimens from ALDpatients (NCT01875211). Liver specimens from wild-type (WT) and Nogo-B knockout (KO) mice fed a control or Lieber-DeCarliethanol liquid diet (5% ethanol) for 6 weeks were analyzed for liver injury and steatosis. Kupffer cells isolated from WT and Nogo-B KO mice were assessed for M1 and M2 activation. A significant positive correlation was observed between Nogo-B positive Kupffer cells and disease severity in ALDpatients (n = 30, r = 0.66, P = 0.048). Furthermore, Nogo-B-positive Kupffer cells were correlated with M1 activation (inducible nitric oxide synthase) (r = 0.50, P = 0.05) and negatively with markers of M2 status (CD163) (r = -0.48, P = 0.07) in these patients. WT mice exhibited significantly increased liver injury (P < 0.05) and higher hepatic triglyceride levels (P < 0.01) compared with Nogo-B KO mice in response to chronic ethanol feeding. Nogo-B in Kupffer cells promoted M1 polarization, whereas absence of Nogo-B increased ER stress and M2 polarization in Kupffer cells. CONCLUSION:Nogo-B is permissive of M1 polarization of Kupffer cells, thereby accentuating liver injury in ALD in humans and mice. Nogo-B in Kupffer cells may represent a new therapeutic target for ALD. (Hepatology 2017;65:1720-1734).
Authors: Lisette Acevedo; Jun Yu; Hediye Erdjument-Bromage; Robert Qing Miao; Ji-Eun Kim; David Fulton; Paul Tempst; Stephen M Strittmatter; William C Sessa Journal: Nat Med Date: 2004-03-21 Impact factor: 53.440
Authors: Yoon Ok Jang; Young Ju Kim; Soon Koo Baik; Moon Young Kim; Young Woo Eom; Mee Yon Cho; Hong Jun Park; So Yeon Park; Bo Ra Kim; Jae Woo Kim; Hyun Soo Kim; Sang Ok Kwon; Eun Hee Choi; Yong Man Kim Journal: Liver Int Date: 2013-06-19 Impact factor: 5.828
Authors: Jiajia Cui; Alexandra S Piotrowski-Daspit; Junwei Zhang; Mingjie Shao; Laura G Bracaglia; Teruo Utsumi; Young-Eun Seo; Jenna DiRito; Eric Song; Christine Wu; Asuka Inada; Gregory T Tietjen; Jordan S Pober; Yasuko Iwakiri; W Mark Saltzman Journal: J Control Release Date: 2019-05-01 Impact factor: 9.776
Authors: Bichen Zhang; Min-Dian Li; Ruonan Yin; Yuyang Liu; Yunfan Yang; Kisha A Mitchell-Richards; Jin Hyun Nam; Rui Li; Li Wang; Yasuko Iwakiri; Dongjun Chung; Marie E Robert; Barbara E Ehrlich; Anton M Bennett; Jun Yu; Michael H Nathanson; Xiaoyong Yang Journal: JCI Insight Date: 2019-11-01
Authors: Lei Tian; Weiyang Li; Le Yang; Na Chang; Xiaoting Fan; Xiaofang Ji; Jieshi Xie; Lin Yang; Liying Li Journal: Front Immunol Date: 2017-09-28 Impact factor: 7.561