Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
Department of Emergency Medicine, Shaare Zedek Medical Center, Jerusalem, Israel.
J Autoimmun. 2015 May;59:67-76. doi: 10.1016/j.jaut.2015.02.006. Epub 2015 Mar 23.
Immune cells, particularly those expressing the ligand of the Fas-death receptor (FasL), e.g. cytotoxic T cells, induce apoptosis in 'undesirable' self- and non-self-cells, including lung fibroblasts, thus providing a means of immune surveillance. We aimed to validate this mechanism in resolution of lung fibrosis. In particular, we elucidated whether FasL(+) immune cells possess antifibrotic capabilities by induction of FasL-dependent myofibroblast apoptosis and whether antagonists of membrane (m) and soluble (s) FasL can inhibit these capabilities. Myofibroblast interaction with immune cells and its FasL-dependency, were investigated in vitro in coculture with T cells and in vivo, following transplantation into lungs of immune-deficient syngeneic Rag-/- as well as allogeneic SCID mice, and into lungs and air pouches of FasL-deficient (gld) mice, before and after reconstitution of the mice with wild-type (wt), FasL(+) immune cells. We found that myofibroblasts from lungs resolving fibrosis undergo FasL-dependent T cell-induced apoptosis in vitro and demonstrate susceptibility to in vivo immune surveillance in lungs of reconstituted, immune- and FasL-deficient, mice. However, immune-deficient Rag-/- and SCID mice, and gld-mice with FasL-deficiency, endure the accumulation of transplanted myofibroblasts in their lungs with subsequent development of fibrosis. Concomitantly, gld mice, in contrast to chimeric FasL-deficient mice with wt immune cells, accumulated transplanted myofibroblasts in the air pouch model. In humans we found that myofibroblasts from fibrotic lungs secrete sFasL and resist T cell-induced apoptosis, whereas normal lung myofibroblasts are susceptible to apoptosis but acquire resistance upon addition of anti-s/mFasL to the coculture. Immune surveillance, particularly functional FasL(+) immune cells, may represent an important extrinsic component in myofibroblast apoptosis and serve as a barrier to fibrosis. Factors interfering with Fas/FasL-immune cell-myofibroblast interaction such as sFasL secreted by fibrotic-lung myofibroblasts, may abrogate immune surveillance during fibrosis. Annulling these factors may pave a new direction to control human lung fibrosis.
免疫细胞，特别是表达 Fas 死亡受体（FasL）配体的细胞，例如细胞毒性 T 细胞，可诱导“不需要的”自身和非自身细胞凋亡，包括肺成纤维细胞，从而提供了一种免疫监视的手段。我们旨在验证该机制在肺纤维化的消退中是否具有作用。具体而言，我们通过诱导 FasL 依赖性成肌纤维细胞凋亡来阐明 FasL(+)免疫细胞是否具有抗纤维化能力，以及膜（m）和可溶性（s）FasL 的拮抗剂是否可以抑制这些能力。我们在体外与 T 细胞共培养以及在体内，将免疫缺陷的同基因 Rag-/-以及同种异体 SCID 小鼠的肺、以及 FasL 缺陷（gld）小鼠的肺和气囊中移植后，研究了成肌纤维细胞与免疫细胞的相互作用及其 FasL 依赖性，在对 FasL 缺陷的小鼠进行野生型（wt）、FasL(+)免疫细胞重建之前和之后。我们发现，从正在消退纤维化的肺中分离出的成肌纤维细胞在体外经历 FasL 依赖性 T 细胞诱导的凋亡，并在免疫和 FasL 缺陷的重构小鼠的肺中显示出对体内免疫监视的敏感性。然而，免疫缺陷的 Rag-/-和 SCID 小鼠以及 FasL 缺陷的 gld 小鼠在其肺中积累了移植的成肌纤维细胞，随后发生纤维化。同时，与具有 wt 免疫细胞的嵌合 FasL 缺陷小鼠相比，gld 小鼠在气囊模型中积累了移植的成肌纤维细胞。在人类中，我们发现来自纤维化肺的成肌纤维细胞分泌 sFasL 并抵抗 T 细胞诱导的凋亡，而正常肺成肌纤维细胞对凋亡敏感，但在共培养物中加入抗 s/mFasL 后获得抗性。免疫监视，特别是功能性 FasL(+)免疫细胞，可能是成肌纤维细胞凋亡的重要外在成分，并作为纤维化的障碍。干扰 Fas/FasL-免疫细胞-成肌纤维细胞相互作用的因素，例如纤维化肺成肌纤维细胞分泌的 sFasL，可能会在纤维化过程中破坏免疫监视。消除这些因素可能为控制人类肺纤维化开辟新的方向。
