Contribution of hypoxia inducible factor, HIF1α, to vascular inflammation and remodeling in giant cell arteritis (GCA). Effects of GM-CSF receptor blockade on HIF1α stabilization
[eng] Giant Cell Arteritis (GCA) is an immune-mediated disease affecting large and medium sized arteries. Its pathophysiology is not fully understood and its present treatment relies on glucocorticoids, which have important side effects. Therefore, studying the disease and finding new treatments is...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/185408 |
| Acceso en línea: | https://hdl.handle.net/2445/185408 http://hdl.handle.net/10803/674184 |
| Access Level: | acceso abierto |
| Palabra clave: | Vasculitis Inflamació Arteritis de cèl·lules gegants Anoxèmia Inflammation Giant cell arteritis Anoxemia |
| Sumario: | [eng] Giant Cell Arteritis (GCA) is an immune-mediated disease affecting large and medium sized arteries. Its pathophysiology is not fully understood and its present treatment relies on glucocorticoids, which have important side effects. Therefore, studying the disease and finding new treatments is an unmet medical need. GCA lesions undergo several changes during the development of the disease. Thickening and remodeling of the vascular wall are due to the aberrant inflammatory infiltrate. These changes promote angiogenesis. Angiogenesis is one of the main consequences of hypoxia, through stabilization and induction of Hypoxia Inducible Factor 1 alpha (HIF1α). Several inflammatory molecules such as IL6, IL1β, TNFα and IFNγ, present in GCA lesions, have been demonstrated to be able to stabilize HIF1α. Moreover, several HIF1α target genes like IL6 and other proinflammatory molecules are present in GCA lesions. Moreover, vascular smooth muscle cells (VSMC) are able to express HIF1α under certain conditions. GM-CSF is an important inflammatory mediator expressed by several inflammatory and vascular resident cells. It downstream pathway includes JAK/STAT activation. Regarding GCA, GM-CSF can be affecting several important points of its pathogenesis, from initial dendritic cells activation to leucocyte recruitment and giant cell formation. Considering all these together, our hypothesis for the present thesis is as follows: HIF1⍺ and GM-CSF play an important role in vascular inflammation and remodeling in GCA, through independent or inter-related mechanisms. The objectives are to determine the presence/absence of HIF1α in GCA lesions as well as triggers and consequences of it. To analyze the effect of anti-cytokine targeted therapies in this pathway. To investigate GM-CSF pathway in GCA and the effect of its blockade with mavrilimumab. In the present thesis we demonstrate the presence of hypoxia in the GCA lesions as well as the presence of HIF1α in the media layer of GCA temporal arteries. We validate that VSMC, the cells present in the media layer of the artery, are able to stabilize HIF1α under an inflammatory microenvironment with an in-vitro model of the disease. Under this inflammatory microenvironment VSMC also increase the expression of GLUT1 and PHD3 transcripts, which are well-described HIF1α target genes indicating HIF1α functional activity in these cells. VSMC modify its transcriptome when HIF1α is stabilized affecting important pathways in GCA pathogenesis. In these cells the migratory capacity is reduced, angiogenic factors are increased (VEGFA, IL6, CXCL8), chemokine expression is imbalanced (CCL2 and CCL5 decreased and CXCL8 increased) and inflammation-relation transcripts were increased (IL6, IL1B, TNFA and CSF2). Inhibiting TNFα, IL1 and GM-CSF in an inflammatory microenvironment was able to reduce HIF1α protein levels in VSMC. GM-CSF and its receptor (GM-CSFRα) are present in GCA lesions, and its downstream pathway (JAK2/STAT5) is activated. Inhibiting GM-CSF effects with mavrilimumab, a monoclonal antibody against GM-CSF receptor alpha chain , in an ex-vivo model of the disease induced the following effects: reduction of lymphocyte and myeloid cell markers; reduction in T cell activation related molecules and Th1 differentiation pathway; decrease of pro-inflammatory cytokines; decrease of mediators of vascular injury; and reduction in tissue angiogenesis. Blocking GM-CSF receptor with mavrilimumab reduces some HIF1α targets (IL6, IL1β, and TNFα) which, including IFNγ, are also identified as stimuli for HIF1α that accumulated in VSMC, supporting the relationship between HIF1α and GM-CSF pathways in the pathogenesis of GCA. |
|---|