Thesis etd-05292015-161228 |
Link copiato negli appunti
Thesis type
Tesi di specializzazione (5 anni)
Author
RAGGI, FEDERICA
URN
etd-05292015-161228
Thesis title
The hypoxic environment differentially reprograms DCs depending on their maturation stage. Identification of TREM-1 as a common hypoxia marker.
Department
RICERCA TRASLAZIONALE E DELLE NUOVE TECNOLOGIE IN MEDICINA E CHIRURGIA
Course of study
PATOLOGIA CLINICA
Supervisors
relatore Mingari, Maria Cristina
relatore Bosco, Maria Carla
relatore Bosco, Maria Carla
Keywords
- Dendritic cells
- Hypoxia
- Trem-1
Graduation session start date
22/06/2015
Availability
Full
Summary
DCs are central to the orchestration of immunity and the maintainance of self-tolerance. DC development and functions are regulated by signals generated in the local microenvironment, and deregulated DC responses may result in amplification of inflammation, loss of tolerance, or immune escape. DC generation from monocytic precursors recruited at sites of inflammation, tissue damage, or neoplasia occurs under condition of hypoxia Understanding DC biology in low O2 environment may open new therapeutic opportunities for inflammation and cancer. We defined the hypoxic transcriptome of immature (i) and mature (m)DCs generated from human monocytes. We present data pointing to a role for hypoxia in differentially reprogramming DCs depending on their maturation stage. Specifically, hypoxia promotes the onset of a migratory phenotype in iDCs through the upregulation of chemokine receptors and an inflammatory state in mDCs by increasing production of proinflammatory, Th1-priming chemokines/cytokines. Interestingly, hypoxia induces profound changes in the expression of a significant cluster of genes coding for immune-related cell surface receptors in both cell subsets. Among them, TREM-1, a member of the Ig receptor family, was commonly inducible by hypoxia in iDCs and mDCs in vitro and expressed in vivo in DCs infiltrating the inflamed hypoxic joints of Juvenile Idiopathic Arthritis patients. TREM-1 inducibility was mediated by HIF-1 alpha and reversed by cell reoxygenation, and its engagement elicited DAP12-linked signaling resulting in the production of proinflammatory cytokines/chemokines and upregulation of T cell costimulatory molecules and chemokine homing receptors.The relevance of these findings for leukocyte trafficking and T cell activation in diseased tissues and their potential implications for the persistence and amplification of inflammation will be discussed
File
Nome file | Dimensione |
---|---|
Tesi_Fin...Raggi.pdf | 1.33 Mb |
Contatta l’autore |