title: Haptoglobin activates innate immunity to enhance acute transplant rejection in mice.
abstract: Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammatory responses in DCs than did nontransplanted lysates, suggesting DC-mediated responses are triggered by factors released during transplantation. Analysis of transplanted lysates identified haptoglobin as one of the proteins upregulated during transplantation. Expression of donor haptoglobin enhanced the onset of acute skin transplant rejection, whereas haptoglobin-deficient skin grafts showed delayed acute rejection and antidonor T cell priming in a MyD88-dependent graft rejection model. Thus, our results show that haptoglobin release following skin necrosis contributes to accelerated transplant rejection, with potential implications for the development of localized immunosuppressive therapies.
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine,New Haven, Connecticut, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Colangelo
authors.forename: Terence
authors.initials: T
authors.lastname: Wu
authors.forename: Can
authors.initials: C
authors.lastname: Bruce
authors.forename: Gaia
authors.initials: G
authors.lastname: Scabia
authors.forename: Anjela
authors.initials: A
authors.lastname: Galan
authors.forename: Margherita
authors.initials: M
authors.lastname: Maffei
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Goldstein
mesh_terms: D000208:Acute Disease; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006242:Haptoglobins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016038:Skin Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D006242:Haptoglobins; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha