PMID- 22156194
OWN - NLM
STAT- MEDLINE
DCOM- 20120306
LR  - 20211021
IS  - 1558-8238 (Electronic)
IS  - 0021-9738 (Print)
IS  - 0021-9738 (Linking)
VI  - 122
IP  - 1
DP  - 2012 Jan
TI  - Haptoglobin activates innate immunity to enhance acute transplant rejection in 
      mice.
PG  - 383-7
LID - 58344 [pii]
LID - 10.1172/JCI58344 [doi]
AB  - 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-alpha. 
      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.
FAU - Shen, Hua
AU  - Shen H
AD  - Department of Internal Medicine, Yale University School of Medicine,New Haven, 
      Connecticut, USA.
FAU - Song, Yang
AU  - Song Y
FAU - Colangelo, Christopher M
AU  - Colangelo CM
FAU - Wu, Terence
AU  - Wu T
FAU - Bruce, Can
AU  - Bruce C
FAU - Scabia, Gaia
AU  - Scabia G
FAU - Galan, Anjela
AU  - Galan A
FAU - Maffei, Margherita
AU  - Maffei M
FAU - Goldstein, Daniel R
AU  - Goldstein DR
LA  - eng
GR  - R01 AI064660/AI/NIAID NIH HHS/United States
GR  - R56 AI064660/AI/NIAID NIH HHS/United States
GR  - AI064660/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111212
PL  - United States
TA  - J Clin Invest
JT  - The Journal of clinical investigation
JID - 7802877
RN  - 0 (Haptoglobins)
RN  - 0 (Interleukin-6)
RN  - 0 (Myd88 protein, mouse)
RN  - 0 (Myeloid Differentiation Factor 88)
RN  - 0 (Tlr2 protein, mouse)
RN  - 0 (Tlr4 protein, mouse)
RN  - 0 (Toll-Like Receptor 2)
RN  - 0 (Toll-Like Receptor 4)
RN  - 0 (Tumor Necrosis Factor-alpha)
SB  - IM
MH  - Acute Disease
MH  - Animals
MH  - Dendritic Cells/immunology/metabolism
MH  - Female
MH  - Graft Rejection/*etiology/immunology/metabolism/pathology
MH  - Haptoglobins/deficiency/genetics/*metabolism
MH  - Immunity, Innate/*physiology
MH  - Interleukin-6/biosynthesis
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Differentiation Factor 88/deficiency/genetics/metabolism
MH  - Necrosis
MH  - Skin/immunology/metabolism/pathology
MH  - Skin Transplantation/immunology/pathology/physiology
MH  - T-Lymphocytes/immunology
MH  - Toll-Like Receptor 2/deficiency/genetics/metabolism
MH  - Toll-Like Receptor 4/deficiency/genetics/metabolism
MH  - Tumor Necrosis Factor-alpha/biosynthesis
PMC - PMC3248290
EDAT- 2011/12/14 06:00
MHDA- 2012/03/07 06:00
PMCR- 2011/12/12
CRDT- 2011/12/14 06:00
PHST- 2011/04/15 00:00 [received]
PHST- 2011/10/26 00:00 [accepted]
PHST- 2011/12/14 06:00 [entrez]
PHST- 2011/12/14 06:00 [pubmed]
PHST- 2012/03/07 06:00 [medline]
PHST- 2011/12/12 00:00 [pmc-release]
AID - 58344 [pii]
AID - 10.1172/JCI58344 [doi]
PST - ppublish
SO  - J Clin Invest. 2012 Jan;122(1):383-7. doi: 10.1172/JCI58344. Epub 2011 Dec 12.