Islet-expressed TLR2 and TLR4 sense injury and mediate early graft failure after transplantation.
Although islet transplantation is an effective treatment for Type 1 diabetes, primary engraftment failure contributes to suboptimal outcomes. We tested the hypothesis that islet isolation and transplantation activate innate immunity through TLR expressed on islets. Murine islets constitutively express TLR2 and TLR4, and TLR activation with peptidoglycan or LPS upregulates islet production of cytokines and chemokines. Following transplantation into streptozotocin-induced diabetic, syngeneic mice, islets exposed to LPS or peptidoglycan had primary graft failure with intra- and peri-islet mononuclear cell inflammation. The use of knockout mice showed that recipient CD8(+) T cells caused engraftment failure and did so in the absence of islet-derived DC. To mimic physiological islet injury, islets were transplanted with exocrine debris. Transplantation of TLR2/4(-/-) islets reduced proinflammatory cytokine production and improved islet survival. Stressed islets released the alarmin high-mobility group box protein 1 (HMGB1) and recombinant HMGB1 (rHMGB1) induced NFkB activation. NFkB activation was prevented in the absence of both TLR2 and TLR4. rHMGB1 pretreatment also prevented primary engraftment through a TLR2/4-dependent pathway. Our results show that islet graft failure can be initiated by TLR2 and TLR4 signaling and suggest that HMGB1 is one likely early mediator. Subsequent downstream signaling results in intra-islet inflammation followed by T-cell-mediated graft destruction.
Krüger
Bernd
B
Division of Nephrology, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
Yin
Na
N
Zhang
Nan
N
Yadav
Anju
A
Coward
William
W
Lal
Girdhari
G
Zang
Weiping
W
S Heeger
Peter
P
Bromberg
Jonathan S
JS
Murphy
Barbara
B
Schröppel
Bernd
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000628:therapy; D006084:Graft Rejection / Q000276:immunology*; D024243:HMGB1 Protein / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000637:transplantation*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000276:immunology*
D016207:Cytokines; D024243:HMGB1 Protein; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D012313:RNA
J Immunol. 2004 Mar 1;172(5):3173-80
14978124
FASEB J. 2007 Sep;21(11):2840-8
17475921
PLoS Med. 2006 Feb;3(2):e17
16354107
Diabetes. 1998 Mar;47(3):316-23
9519734
Transplantation. 2009 Nov 15;88(9):1075-80
19898202
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3390-5
19218437
J Leukoc Biol. 2007 Jan;81(1):67-74
17060363
Diabetes. 2004 Apr;53(4):963-70
15047611
Diabetes. 2004 Nov;53(11):2815-23
15504961
J Clin Invest. 2010 Mar;120(3):735-43
20124731
Shock. 2006 Aug;26(2):174-9
16878026
J Exp Med. 2007 Nov 26;204(12):2913-23
17984303
Diabetes. 2002 Jan;51(1):55-65
11756323
J Immunol. 1999 Apr 1;162(7):3749-52
10201887
Transplantation. 2001 Jan 15;71(1):125-32
11211177
J Immunol. 2000 Jul 15;165(2):618-22
10878331
Immunol Lett. 2010 Jan 4;127(2):119-25
19879295
Cell Transplant. 2005;14(1):67-76
15789664
Am J Transplant. 2003 Oct;3(10):1230-41
14510696
Immunity. 2002 Aug;17(2):211-20
12196292
Clin Exp Immunol. 2003 Aug;133(2):208-18
12869026
J Biol Chem. 2004 Feb 27;279(9):7370-7
14660645
Diabetes. 2006 Apr;55(4):1011-21
16567523
J Clin Invest. 2008 Feb;118(2):413-20
18246191
Transplantation. 2006 Sep 27;82(6):813-8
17006329
Transplant Proc. 1990 Apr;22(2):855-6
2109420
J Am Soc Nephrol. 2004 Jul;15(7):1853-61
15213273
Transplantation. 2002 Jan 15;73(1):7-12
11792971
N Engl J Med. 2006 Sep 28;355(13):1318-30
17005949
J Am Soc Nephrol. 2005 Feb;16(2):444-51
15601743
Nat Med. 2007 Nov;13(11):1324-32
17952090
Transplantation. 2008 Jul 15;86(1):1-9
18622268
Transplantation. 2000 Mar 15;69(5):761-6
10755523
Am J Physiol Cell Physiol. 2006 Mar;290(3):C917-24
16267105
Am J Physiol Endocrinol Metab. 2006 May;290(5):E771-9
16303846