Dendritic cell function in transplantation arteriosclerosis is regulated by heme oxygenase 1.
BACKGROUND
Heme oxygenase (HO)1 is an important modulator of physiological function with cytoprotective properties. Although HO1 has previously been associated with an improved survival of the vascular allograft in rat models in response to pharmaceutical induction of HO1 the exact mechanism by which HO1 exerts it protective function remains to be elucidated.


OBJECTIVE
We sought to define the role of HO1 in dendritic cells (DCs) function that governs the alloimmune response underlying the development of transplantation associated vasculopathy.


RESULTS
Loss of HO1 in DCs or by small interfering RNA silencing resulted in major histocompatibility complex class II (MHCII) upregulation by CIITA- driven transcriptional regulation and by STAT1 (signal transducers and activators of transcription 1) phosphorylation. As a result, increased MHCII alloantigen presentation by HO1(-/-) DCs directed the primary T-cell response preferentially toward a CD4(+) T-cell, rather than a CD8(+) T-cell reaction. In a murine model for transplantation arteriosclerosis, adoptive transfer of HO1(-/-) DCs before allograft transplantation was indeed associated with pronounced intragraft CD4(+) T-cell infiltration and increased IgG deposition, suggestive of an accelerated development of vasculopathy toward the chronic phase. The role of HO1 in DC-mediated T cell activation was further validated by inhibition of endogenous HO1 in allograft recipients. Inhibition of HO1 in DCs aggravated transplant arteriosclerosis development, by increasing intima hyperplasia, and by activation of a CD4(+) T cells allograft response, mediated by MHCII upregulation.


CONCLUSIONS
These findings demonstrate that HO1 plays an important role in the genetic regulation of the vascular alloimmune response elicited by DCs.
Cheng
Caroline
C
Molecular Cardiology Laboratory, Department of Experimental Cardiology, Thoraxcenter, Erasmus University Medical Center, Rotterdam, The Netherlands.
Noorderloos
M
M
van Deel
Elza D
ED
Tempel
Dennie
D
den Dekker
Wijnand
W
Wagtmans
Kim
K
Duncker
Dirk J
DJ
Soares
Miguel P
MP
Laman
Jon D
JD
Duckers
Henricus J
HJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D020868:Gene Silencing; D051547:Heme Oxygenase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D014184:Transplantation, Homologous / Q000276:immunology
D007074:Immunoglobulin G; D034741:RNA, Small Interfering; D051547:Heme Oxygenase-1