Induced psoriasis-like inflammation in an air pouch mouse model

Human psoriasis is a complex autoimmune skin disease, affecting a remarkable percentage of the global population. The initiation pathway comprises the differentiation and infiltration of Th17 cells into the skin and is characterized by the production of IL-17A and IL-17F cytokines among others. This results in a downstream cascade of events, including neutrophil infiltration and an exacerbated inflammatory response. In order to investigate more simplified mechanistic mouse models of psoriasis inflammation, we utilized the 6-day air pouch mouse model and aimed for the induction of a psoriasis-like inflammation by injecting a cocktail of inflammatory triggers into the air pouch cavity. The combination of anti-CD3, IL-23 with or without IL-1? resulted in significantly increased IL-17A and IL-17F intra-pouch levels, triggering a downstream production of the CXCL1 chemokine. The produced cytokines were detectable even 72 hours post-induction. In addition, TCR? was downregulated on the cell surface of CD4 and CD8 positive T cells, indicating intra-pouch T cell activation. The presence of anti-CD3 seemed to be important for the increased production of the IL-17 cytokines, even at low concentrations. Furthermore, anti-CD3 induced CD3 positive cell migration into the subcutis and the lining tissue surrounding the air pouch cavity, where in the latter a similar distribution pattern of IL17A expressing cells was also observed. In conclusion, the induced air pouch mouse model can mirror the IL-23/IL-17 axis of psoriasis-like inflammation and is to our knowledge the first published IL-23/IL-17 response established in the air pouch model.
Conclusion:
The inflammatory regiment in a moderately viscous medium, consisting of anti-CD3, IL-23 and IL-1β, induced the secretion of IL-17A and IL-17F in the murine 6-day air pouch model and this also triggered the downstream production of CXCL1. Furthermore, anti-CD3 induced T cell activation in the air pouch cavity, shown by downregulation of the TCRαβ receptor. There were no indications of Th17 and Tc17 cell differentiation and accumulation in the air pouch lavage fluid, but the source of IL-17 was speculated to be activated memory Th17 and Tc17 cells or induced γδ T cells. Eventually, more investigations are required to identify the source of the produced IL-17. In addition, the administration of anti-CD3 resulted in CD3+ immune cell infiltration into the subcutis, located underneath the parenchymal cells of dermis, towards the lining tissue of the air pouch cavity. The identity of these cells could be T cells, γδ T cells and others (i.e. iNKTs), but more markers are required to fully characterize them. To our knowledge this is the first Th17 response established in the air pouch model. In conclusion, the induced 6-day air pouch mouse model mirrors the IL-23/IL-17 axis of a psoriasis-like inflammation in regard to the cytokine secretion and the inflammatory reaction and thus this model has the potential to be used in drug discovery when targeting the Th17 inflammatory response.
Notes:
Cells from lavage fluid were characterized by flow cytometry. Visualization of TCR? expression with overlaid histograms and TCR? geometric mean fluorescent intensity (gMFI), calculated by FlowJo, of (black) control (IMDM) and (red) induced mice (2.5µg/mL anti-CD3, 500ng/mL IL-23, 10ng/mL IL-1?), terminated at 24, 48 and 72h (N=4-5 per group). Anti-CD3, IL-23 and IL-1? induced mice showed downregulation of TCR? receptor on T cell surface, indicating T cell activation. Half-solid symbols indicate samples from mice treated in the same way within the respective groups, collected from different studies. n.s.= non-significant, **p<0.01 . See gating strategy in the supporting information.