title: Cutting edge: FasL(+) immune cells promote resolution of fibrosis.
abstract: 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.
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. Electronic address: wallach-dayan@hadassah.org.il.
authors: Shulamit B
authors: SB
authors: Wallach-Dayan
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. Electronic address: lironelkayam@gmail.com.
authors: Liron
authors: L
authors: Elkayam
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. Electronic address: regina.golan-gerstl@mail.huji.ac.il.
authors: Regina
authors: R
authors: Golan-Gerstl
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. Electronic address: jenyak86@gmail.com.
authors: Jenya
authors: J
authors: Konikov
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. Electronic address: pzisman@gmail.com.
authors: Philip
authors: P
authors: Zisman
authors: Department of Emergency Medicine, Shaare Zedek Medical Center, Jerusalem, Israel. Electronic address: mdayanmd@gmail.com.
authors: Mark Richter
authors: MR
authors: Dayan
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. Electronic address: nissim.arish@gmail.com.
authors: Nissim
authors: N
authors: Arish
authors: Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah - Hebrew University Medical Center, Jerusalem, Israel; Department of Pathology, Boston University School of Medicine, Boston, MA, USA. Electronic address: Raffi@hadassah.org.il.
authors: Raphael
authors: R
authors: Breuer
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism*; D005355:Fibrosis; D016654:Genes, RAG-1 / Q000235:genetics; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D008168:Lung / Q000276:immunology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation
chemical_list: D019138:Antibodies, Blocking; D053222:Fas Ligand Protein
keywords: FasL; Immune cells; Lung fibrosis resolution; Myofibroblast apoptosis; sFasL