title: Heme Oxygenase-1 Induction Prevents Autoimmune Diabetes in Association With Pancreatic Recruitment of M2-Like Macrophages, Mesenchymal Cells, and Fibrocytes.
abstract: Immunoregulatory and regenerative processes are activated in the pancreas during the development of type 1 diabetes (T1D) but are insufficient to prevent the disease. We hypothesized that the induction of cytoprotective heme oxygenase-1 (HO-1) by cobalt protophoryrin (CoPP) would prevent T1D by promoting anti-inflammatory and pro-repair processes. Diabetes-prone BioBreeding rats received ip CoPP or saline twice per week for 3 weeks, starting at 30 days and were monitored for T1D. Immunohistochemistry, confocal microscopy, quantitative RT-PCR, and microarrays were used to evaluate postinjection pancreatic changes at 51 days, when islet inflammation is first visible. T1D was prevented in CoPP-treated rats (29% vs 73%). Pancreatic Hmox1 was up-regulated along with islet-associated CD68(+)HO-1(+) cells, which were also observed in a striking peri-lobular interstitial infiltrate. Most interstitial cells expressed the mesenchymal marker vimentin and the hematopoietic marker CD34. Spindle-shaped, CD34(+)vimentin(+) cells coexpressed collagen V, characteristic of fibrocytes. M2 macrophage factors Krüppel-like factor 4, CD163, and CD206 were expressed by interstitial cells, consistent with pancreatic upregulation of several M2-associated genes. CoPP upregulated islet-regenerating REG genes and increased neogenic REG3β(+) and insulin(+) clusters. Thus, short-term induction of HO-1 promoted a protective M2-like milieu in the pancreas and recruited mesenchymal cells, M2 macrophages, and fibrocytes that imparted immunoregulatory and pro-repair effects, preventing T1D.
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Husseini
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Wang
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Christopher
authors.initials: C
authors.lastname: Patrick
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Crookshank
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: MacFarlane
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: J Ariana
authors.initials: JA
authors.lastname: Noel
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Alexander
authors.initials: A
authors.lastname: Strom
authors.affiliation: Chronic Disease Program (M.H., G.-S.W., C.P., J.A.C., J.A.N., A.S., F.W.S.), Ottawa Hospital Research Institute, Ottawa, Ontario, Canada K1H 8L6 and Departments of Biochemistry, Microbiology, and Immunology (M.H., C.P., A.J.M., J.A.N., F.W.S.) and Medicine (F.W.S.), University of Ottawa, Ottawa, Ontario, Canada K1H 8L6; Food Directorate (A.J.M.), Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Fraser W
authors.initials: FW
authors.lastname: Scott
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D024062:Collagen Type V / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018613:Microscopy, Confocal; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014746:Vimentin / Q000378:metabolism; D000098902:CD163 Antigen; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015214:Antigens, Differentiation, Myelomonocytic; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D024062:Collagen Type V; D051547:Heme Oxygenase-1; D007328:Insulin; D000090062:Kruppel-Like Factor 4; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D000073718:Pancreatitis-Associated Proteins; D011524:Protoporphyrins; D011956:Receptors, Cell Surface; D014746:Vimentin; D000098902:CD163 Antigen; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C000715467:KLF4 protein, human; C000715469:Klf4 protein, rat; C000612141:REG3A protein, human; C007095:cobaltiprotoporphyrin