Targeting the C-terminal region of il-22ra : implication in inflammatory diseases and cancer
(2025)
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- Authors
- Supervisors
- Dumoutier, Laure
- Abstract
- Interleukin-22 (IL-22) is a cytokine that acts on diverse tissues such as the skin, gut and pancreas. In these organs, it plays various roles such as in cell proliferation, inhibition of apoptosis, chemokine and anti-microbial peptide production. These roles are essential in tissue regeneration and homeostasis as well as in defense against pathogens. Although these functions are beneficial in various contexts such as wound healing, colitis and pancreatitis, prolonged and exacerbated production of IL-22 induces tissue inflammation and immune disorders such as psoriasis and cancer. Therefore, targeting IL-22 activities to treat psoriasis or cancer bears the risk of adverse effects at other mucosal sites. In this context, we believe that finding a strategy to partially block IL-22 effects is essential. IL-22 signaling involves the activation of STAT proteins such as STAT-1,-3,-5 with a massive activation of STAT3. However, unlike most cytokines, STAT3 is preassociated with the IL-22Ra, and its activation is induced in a receptor tyrosineindependent manner. This alternative STAT3 activation relies on the coiled-coil domain of STAT3 and the C-terminal region (Cter) of the IL-22Ra, which lacks tyrosine residues. This alternative activation of STAT3 could be a good target to partially block IL-22 activities. In the first, in vivo, part of this thesis we have demonstrated that the C-terminal part of IL-22Ra is partially involved in IL-22 effects in the skin and pancreas while it only has mild effects in the gut. We also found that loss of the alternative STAT3 activation is beneficial in psoriasis while it had no impact on the protection 12 mediated by IL-22 in colitis, pancreatitis and PDAC even though in this last case further experiments are required before drawing conclusions. Given these results, inhibiting the alternative pathway in psoriasis might be beneficial with only few side effects in other epithelial organs. In this context, we pursued our investigations by trying to elucidate the mechanism of interaction linking STAT3 and the IL-22R-Cter. Even though peptide motifs on the receptor have been partially defined, more experiments are required to find a way to inhibit this interaction and use this inhibitor in the treatment of psoriasis.
- Affiliations
Citations
Puigdevall Mata, L. (2025). Targeting the C-terminal region of il-22ra : implication in inflammatory diseases and cancer. https://hdl.handle.net/2078.5/267350