Investigating the role of human peroxiredoxins as damage-associated molecular patterns
(2022)
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- Authors
- Supervisors
- Knoops, Bernard
- Abstract
- Sterile inflammation occurs when endogenous molecules termed damage-associated molecular patterns (DAMPs) are released into the extracellular environment and activate immune receptors to induce the secretion of pro-inflammatory cytokines. As this phenomenon contributes to the pathogenesis of many diseases such as ischemia-reperfusion injury, understanding how DAMPs are able to induce a pro-inflammatory response is of crucial importance for the development of new therapeutic strategies. Recently, human peroxiredoxin (PRDX) family proteins have been reported to act as DAMPs. However, the molecular mechanisms allowing PRDXs to induce a pro-inflammatory response remain to be clarified, starting from the early step of PRDX recognition (i.e. binding to receptors) to the late events triggered within the cell (i.e. cytokine secretion). In this PhD thesis, we used human PRDX2 and PRDX5 to investigate the role of (i) Toll-like receptor 4 (TLR4), one of the major innate immune receptors involved in pro-inflammatory responses, (ii) TLR4 accessory molecules MD-2 and CD14, and (iii) the redox state of PRDX cysteine residues, in the PRDX pro-inflammatory activity. To this end, we used a multidisciplinary approach combining biomolecular and biophysical techniques to gain insights into the binding properties of PRDX2 and PRDX5 towards TLR4 and its accessory molecules, as well as interleukin-8 secretion from cells exposed to PRDX2 and PRDX5. Using these approaches, we confirmed the role of TLR4 in the pro-inflammatory activity of PRDX2 and PRDX5 and further demonstrated that both PRDXs are able to interact directly with TLR4. Moreover, we showed that disulfide PRDX5 triggers potent pro-inflammatory response compared to reduced or hyperoxidized forms of the protein, and that the catalytic cysteine is required for the PRDX5 pro-inflammatory activity. We next observed that MD-2 is required for the TLR4-dependent cytokine-inducing ability of PRDX2 and PRDX5. In addition, we discovered that both PRDXs are able to induce a TLR4-independent signaling pathway involving CD14. We finally reported that PRDX2 and PRDX5 are able to interact directly with both MD-2 and CD14. Altogether, our results highlight key roles of TLR4, MD-2 and CD14 as well as the importance of the redox state in the pro-inflammatory activity of human PRDXs. This work therefore provides a basis for further studies aiming at understanding the finer modulation of pro-inflammatory responses induced by human PRDXs.
- Affiliations
Citations
Poncin, M. (2022). Investigating the role of human peroxiredoxins as damage-associated molecular patterns. https://hdl.handle.net/2078.5/234752