Sterile inflammation is a key component of a variety of diseases including, gout, arthritis, type 1 diabetes, Alzheimer’s disease and multiple sclerosis (MS). Sterile inflammation induces the recruitment of immune cells via chemokines, such as CCL5 and CXCL10. Expression of these chemokines is dependent on IRF-1. Recently the FDA has approved the use of a pro-drug, FTY720 that after phosphorylation becomes a S1P mimetic for the treatment of MS. This report describes two novel and opposing mechanisms of S1P action in sterile inflammation. First, intracellular S1P acts as a cofactor of cIAP2 that inducesIL-1-dependent K63-polyubiquitination of IRF-1, which leads to the recruitment of immune cells to the site of inflammation. Conversely, extracellular S1P provides a feedback loop that inhibits CXCL10 and CCL5 expression through S1PR2 signaling. Accordingly, immune cell infiltration to sites of sterile inflammation is increased in S1PR2-/- production via calcium-dependent, but cAMP- and PKA-independent mechanisms that likely involve c-Fos expression and unconventional PKC activation. Elevated c-Fos could competitively inhibit CCL5 expression directly or indirectly via blocking IFN production. These two novel pathways highlight unexpected aspects of S1P signaling, and provide potential mechanisms that can be exploited for the improvement of therapeutics for the treatment of MS.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-4244 |
| Date | 15 August 2013 |
| Creators | Yester, Jessie |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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