Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1
Dendritic Cell Function in Transplantation Arteriosclerosis Is Regulated by Heme Oxygenase 1
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DOI：
10.1161/circresaha.110.216945
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发表时间：
2010-05-28
影响因子：
20.1
通讯作者：
Duckers, Henricus J.
中科院分区：
文献类型：
--
作者：
Cheng, Caroline;Noorderloos, M.;Duckers, Henricus J.
血红素氧合酶1（HO 1）是一种重要的生理功能调节因子，具有细胞保护作用.虽然以前在大鼠模型中，HO 1与响应于HO 1的药物诱导的血管同种异体移植物的存活改善相关，但是HO 1发挥其保护功能的确切机制仍有待阐明。目的：我们试图确定HO 1在树突状细胞（DCs）功能中的作用，所述树突状细胞（DCs）功能支配移植相关血管病发展的同种免疫应答。DC中HO 1的缺失或小干扰RNA沉默导致主要组织相容性复合物II类（MHCII）通过CIITA驱动的转录调控和STAT 1（信号转导和转录激活因子1）磷酸化上调。因此，HO 1（-/-）DC的MHCII同种抗原提呈增加，将初级T细胞反应优先导向CD 4（+）T细胞，而不是CD 8（+）T细胞反应。在移植动脉硬化的小鼠模型中，在同种异体移植前过继转移HO 1（-/-）DC确实与明显的移植物内CD 4（+）T细胞浸润和增加的IgG沉积相关，提示血管病变向慢性期的加速发展。HO 1在DC介导的T细胞活化中的作用通过抑制同种异体移植物受体中的内源性HO 1进一步验证。HO 1在DCs中的抑制加重了移植动脉硬化的发展，通过增加内膜增生，并通过激活由MHCII上调介导的CD 4（+）T细胞同种异体移植物应答，结论：这些发现表明HO 1在DCs引起的血管同种免疫应答的遗传调节中起重要作用。(Circ Res. 2010;106：1656-1666）。
Rationale: 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.Methods and 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 amurine 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. (Circ Res. 2010;106:1656-1666.)