The role of intracellular chloride channel 1 in immune/inflammatory responses

Download files
Access & Terms of Use
open access
Copyright: Salao, Kanin
Altmetric
Abstract
Intracellular chloride channel protein 1 (CLIC1) participates in inflammatory processes, at least in part by regulating macrophage phagosomal functions such as pH, proteolysis. Here, we sought to determine if CLIC1 can regulate immune/inflammatory responses by actions on dendritic cells (DC), the key professional antigen presenting cell. To study role of CLIC1 in immune/inflammatory responses, I first investigated immune cell phenotype changes in various tissue compartments associated with germline deletion of the gene for CLIC1 and found that both normal physiological conditions and under inflammatory responses, the immune cell composition is altered significantly in CLIC1-/- mice when compared CLIC1+/+ mice. To further investigate the role of CLIC1 in dendritic cells, I first generated bone marrow-derived DC (BMDCs) from germline CLIC1 gene deleted (CLIC1-/-) mice and examined the effect of CLIC1 gene deletion on dendritic cell migration from peripheral footpad to secondary lymph nodes of mice. I found that more CLIC1-/- BMDCs migrated from the site of injection in the footpad and homed to popliteal and to inguinal lymph nodes than CLIC1+/+BMDCs in both CLIC1+/+ and CLIC1-/- mice. Subsequently, I identified the subcellular localization of CLIC1 in BMDCs after phagocytosis and found that cytoplasmic CLIC1 translocation to the phagosomal membrane where it regulated phagosomal pH and proteolysis. Phagosomes from CLIC1-/- BMDCs displayed impaired acidification and proteolysis, which could be reproduced in wild type CLIC1+/+, but not CLIC1-/- cell were treated with IAA94, a CLIC family ion channel blocker. CLIC1-/- BMDC displayed reduced in vitro antigen processing and presentation of full-length myelin oligodendrocyte glycoprotein (MOG) reduced MOG induced experimental autoimmune encephalomyelitis. These data suggest that CLIC1 regulates immune/inflammatory responses by means of changing immune cell composition, altering dendritic cell migration, modulating dendritic cell phagosomal pH and facilitating optimal processing of antigen for presentation to antigen specific T-cells. Further, they indicate that CLIC1 is a novel therapeutic target for inflammatory diseases.
Persistent link to this record
Link to Publisher Version
Link to Open Access Version
Additional Link
Author(s)
Salao, Kanin
Supervisor(s)
Breit, Samuel
Creator(s)
Editor(s)
Translator(s)
Curator(s)
Designer(s)
Arranger(s)
Composer(s)
Recordist(s)
Conference Proceedings Editor(s)
Other Contributor(s)
Corporate/Industry Contributor(s)
Publication Year
2016
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
Files
download public version.pdf 7.55 MB Adobe Portable Document Format
Related dataset(s)