Tissue protection by IL-22 during murine inflammation: the influence of gender/sex and use in combination therapy

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Release of pro-inflammatory alarmins (also called DAMPs or damage-associated molecular patterns) from dying cells is a crucial factor that amplifies pathological processes associated with infection/stress-driven inflammation. Therapeutic intervention that aims to stabilize tissue integrity may therefore be regarded as promising novel strategy for the treatment of acute and chronic inflammation. Interleukin (IL)-22 is a member of the IL-10 cytokine family displaying a pronounced tissue protective potential in models of damage-associated intestinal, pulmonary, and hepatic diseases. This function has been observed in the context of the endogenously produced cytokine and is likewise apparent for therapeutically applied recombinant IL-22. Activation of the anti-apoptotic and pro-proliferative transcription factor Signal Transducer and Activator of Transcription (STAT)-3 is supposed to be pivotal for tissue protection by IL-22. Notably, IL-22 can be applied in rodent models without immediate adverse effects. This observation is likely related to the fact that IL-22, due to selective expression of its receptor chain IL-22RI, primarily acts on cells of epithelial origin but strikingly not on leukocytes. In this research project the following aspects of tissue protective IL-22 shall be investigated in detail:1. Is there a synergism between tissue protective IL-22 and anti-inflammatory cytokines/cytokine antagonists (IL-10, IL-1 receptor antagonist, IL-18 binding protein, IL-36 binding protein) which can be employed therapeutically?2. Is there a role for newly identified IL-22-inducible proteins that may serve cytoprotective functions? Here, focus will be on bcl-3 and steap4 which we recently demonstrated to be upregulated by IL-22. 3. Do prototypic stressors (heat/cold, hyperosmolarity, nitric oxide, hypoxia, mechanical stretch) determine the release of IL-22 from leukocyte subsets and/or IL-22 action on cells of epithelial origin?4. Do type I IFN determine functional properties of IL-22 in vivo?Besides experiments on the cellular level, murine models will be utilized to investigate aforementioned matters. Specifically, in vivo models of systemic immunoactivation (administration of the viral mimetic poly (I:C)) and acute liver damage (acetaminophen-induced liver damage) will be employed in this research project. Recently, a phase I clinical trial assessing the safety profile of an IL-22 biosimilar in healthy volunteers has been initiated in Australia. Experiments outlined herein may further our understanding of IL-22 biological properties and potential therapeutic strategies based on tissue protective IL-22.