Thus, the IL-1β-IL-1R signaling pathway may contribute to skin inflammation and psoriasis pathogenesis via the direct regulation of dermal IL-17-producing cells and stimulation of keratinocytes for amplifying inflammatory cascade.
To validate these findings, we investigated Treg cell adoptive transfer of skin inflammation in a murine model and found that it also resulted in a pronounced skewing away from Th1 immunity and toward IL-17 production.
We analyzed three murine models with varying severities of psoriasis-like skin disease concerning their vascular function and inflammation: (i) K14-IL-17A<sup>ind/+</sup> mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygous CD11c-IL-17A<sup>ind/ind</sup> and heterozygous CD11c-IL-17A<sup>ind/+</sup> mice overexpressing IL-17A in CD11c<sup>+</sup> cells, leading to a delayed onset of moderate psoriasis-like skin disease; and (iii) the acute model of imiquimod-induced psoriasis-like skin inflammation.
Prophylactic antibiotics, but not antibiotics after established dysbiosis, reduce IL-17A expression and skin inflammation, examined using Il17a-eGFP reporter mice.
These data demonstrate that the IL-23 MC model is a useful approach to study IL-23/IL-17-driven skin inflammation and may facilitate preclinical assessment of novel therapies.
Since neither γδ T cells nor IL-17 had been implicated in SD, our study provides novel insights into the role of MPZL3 in the pathogenesis of SD-like skin inflammation.
In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications.
First, an attenuated form of imiquimod-induced psoriasis-like skin inflammation was demonstrated in CD6-deficient mice, as deduced from lower epidermal thickness and local reduced production of pro-inflammatory cytokines, namely, interleukin-17A.
Although anti-IL-17 antibodies show marked clinical efficacy in treating psoriasis, compared with antibodies targeting IL-17A or IL-17R alone, targeting Th17 cells themselves may have a maximal benefit by affecting multiple proinflammatory cytokines, including IL-17A, IL-17F, IL-22, and granulocyte-macrophage colony-stimulating factor, which likely act synergistically to drive skin inflammation in psoriasis.
This approach successfully identified 3-cyano- N-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1 H-pyrrolo[2,3- b]pyridin-5-yl)benzamide as a potent and selective RORC2 inverse agonist, demonstrating good metabolic stability, oral bioavailability, and the ability to reduce IL-17 levels and skin inflammation in a preclinical in vivo animal model upon oral administration.
T<sub>regs</sub> that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master T<sub>H</sub>17 transcription factor, RORγt.
KC-Tie2 mice develop psoriasiform skin inflammation with increases in IL-23 and IL-17A and proinflammatory monocytosis and neutrophilia that precedes development of carotid artery thrombus formation.
These results indicate that maxacalcitol reduces psoriasiform skin inflammation by inducing Treg cells as well as downregulating IL-23 and IL-17 production.