S100A9 in inflammation
Summary, in English
In paper I, the main questions we asked were: in what condition hS100A9 could exist in cells without hS100A8? We found that the half-life of hS100A9 protein was short and degraded fast in cells, but can be stabilized by co-expressing with hS100A8 or by proteasome inhibitor. We also found that inflammatory stimuli could also stabilized hS100A9 protein and promoted the formation of proteolytically-resistant homodimer. This paper suggests that during inflammatory condition, hS100A9 protein might be able to exist as homodimer without hS100A8 and that it therefore may function as DAMP molecule after it has been released out of the cell.
In paper II, we showed that a chemical probe oxyclozanide could inhibit S100A9, S100A4 and S100A4/S100A9 binding to TLR4 and RAGE and inhibiting tumor progression in a mouse model. We also showed that hS100A4 and hS100A9 can form heterodimers. Further, we showed that S100A4 and S100A9 are differentially expressed in mouse myeloid cell populations.
In paper III, we wanted to identify co-receptor(s) involved in S100A9-mediated stimulation of TLR4. We show that CD14 is an essential co-receptor of this stimulation. Our data also suggest that some other co-receptor(s) might exist that help in S100A9 binding to cell membrane. However CD14 was crucial both for S100A9 signaling and internalization.
In summary, in this thesis we discuss the relation between S100A9 and inflammation. We show that during inflammation, the pro-inflammatory cytokine could stabilize the unstable hS100A9 by promoting it forming proteolytically-resistant homodimer. After S100A9 released out of the cell, they could function as DAMP molecule activating TLR4 in a CD14 dependent way. By blocking the interaction between the S100s with their receptors using OX, we propose a compound with clinical potential for treating inflammation and cancer.
- Immunology in the medical area
- Fredrik Ivars
- Corrado Cilio
- Tomas Leanderson
- ISBN: 978-91-7619-315-0
23 September 2016
Segerfalksalen, BMC A10, Sölvegatan 17, Lund.
- Nancy Hogg (professor)