IL-12 protects from psoriasiform skin inflammation

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis

IL-22 Is Produced by Innate Lymphoid Cells and Limits Inflammation in Allergic Airway Disease

Interleukin (IL)-22 is an effector cytokine, which acts primarily on epithelial cells in the skin, gut, liver and lung. Both pro- and anti-inflammatory properties have been reported for IL-22 depending on the tissue and disease model. In a murine model of allergic airway inflammation, we found that IL-22 is predominantly produced by innate lymphoid cells in the inflamed lungs, rather than TH cells. To determine the impact of IL-22 on airway inflammation, we used allergen-sensitized IL-22-deficient mice and found that they suffer from significantly higher airway hyperreactivity upon airway challenge. IL-22-deficiency led to increased eosinophil infiltration lymphocyte invasion and production of CCL17 (TARC), IL-5 and IL-13 in the lung. Mice treated with IL-22 before antigen challenge displayed reduced expression of CCL17 and IL-13 and significant amelioration of airway constriction and inflammation. We conclude that innate IL-22 limits airway inflammation, tissue damage and clinical decline in allergic lung disease

IL-17A mediated endothelial breach promotes metastasis formation

The role of the IL-23/IL-17A axis in tumor-immune interactions is a matter of controversy. While some suggest that IL-17A producing T cells (TH17) can suppress tumor growth, others report that IL-17A and IL-23 accelerate tumor growth. Here, we systematically assessed the impact of IL-17A-secreting lymphocytes in several murine models of tumor lung metastasis. Genetic fate-mapping revealed that IL-17A was secreted within lung metastases predominantly by γδ T cells, while TH17 cells were virtually absent. Using different tumor models, we found Il17a-/- mice to consistently develop fewer pulmonary tumor colonies. IL-17A specifically increased blood vessel permeability and the expression of E-selectin and VCAM-1 by lung endothelial cells in vivo. In transgenic mice, specific targeting of IL-17A to the endothelium increased the number of tumor foci. Moreover, the direct impact of IL-17A on lung endothelial cells resulted in impaired endothelial barrier integrity showing that IL-17A promotes the formation of lung metastases through tumor-endothelial transmigration

Th17 cells in autoimmune disease: changing the verdict

Th17 cells and their proinflammatory signature cytokine, IL-17, have recently replaced Th1 cells to be the essential Th effector population in autoimmune disease. This was based on a similar line of evidence that previously destined Th1 cells to be the sole encephalitogenic Th-cell effector type. However, as for the Th1-effector type before, an increasing amount of evidence is accumulating that questions the pivotal role of Th17 cells in autoimmunity. Recently, four high-impact articles were published that clearly show that Th1 and Th17 cells carry encephalitogenic properties, and dominance of either in an autoimmune setting can confer disease. In two mouse models for autoimmune neuroinflammation, it was suggested that Th1 and Th17 cells act in parallel, both exhibiting a different set of effector mechanisms

IL-12 protects from psoriasiform skin inflammation

Neutralization of the common p40-subunit of IL-12/23 in psoriasis patients has led to a breakthrough in the management of moderate to severe disease. Aside from neutralizing IL-23, which is thought to be responsible for the curative effect, anti-p40 therapy also interferes with IL-12 signalling and type 1 immunity. Here we dissect the individual contribution of these two cytokines to the formation of psoriatic lesions and understand the effect of therapeutic co-targeting of IL-12 and IL-23 in psoriasis. Using a preclinical model for psoriatic plaque formation we show that IL-12, in contrast to IL-23, has a regulatory function by restraining the invasion of an IL-17-committed γδT (γδT17) cell subset. We discover that IL-12 receptor signalling in keratinocytes initiates a protective transcriptional programme that limits skin inflammation, suggesting that collateral targeting of IL-12 by anti-p40 monoclonal antibodies is counterproductive in the therapy of psoriasis.ISSN:2041-172

Analysis of cytokine production and surface markers of infiltrating mononuclear cells in the lungs.

<p>Panel A shows the expression of CD25 and CD44 among IL-22 producing cells. Panel B shows the IFN-γ and IL-17A production from sensitized and challenged mouse lungs. Panel C shows the expression of Rorgt. Rorc-eYFP mice were sensitized and challenged and the lung infiltrating mononuclear cells were analyzed for the expression of YFP.</p

Intracellular cytokine staining of mononuclear cells in the lung.

<p>Cells were isolated from either challenged only (c) or sensitized and challenged (s/c) <i>Il22</i> deficient and congenic wild-type controls (IL-22^+/+). Panel A shows a representative plot of intracellular IL-5 and IFN-γ staining. Panel B shows cell counts for IL-4 positive, IFN-γ negative (IL-4⁺IFN⁻), IL-5 positive, IFN-γ negative (IL-5⁺IFN⁻), IFN-γ positive, IL-5 negative (IFN⁺IL-5⁻) and IL-17A positive, IFN-γ negative (IL-17A⁺IFN⁻) cells. Each dot represent a single mouse. Data from 2 independent experiments are given. * p<0.05 compared to all other groups.</p

Histology score and PAS-positive cells in airway epithelium.

<p>Peribronchial inflammation was graded by a semi-quantitative score (no inflammation = 0 to severe inflammation = 4). For each slide 5 randomly chosen areas were scored. Goblet cell metaplasia is expressed as number of PAS-positive cells per mm of basement membrane (BM). Mean values±SEM are given, n = 12 per group. N.D.: not detectable.</p><p>*p<0.05 compared to sens/chall PBS.</p

IL-22 expression is increased during allergic airway inflammation.

<p>Panel A: Expression of IL-22 and IL-22 R1 (IL-22 Rc) was assessed in lung tissue of challenged only (chall, n = 6) and sensitized and challenged (sens/chall, n = 6) animals. Total RNA was isolated 24 hours after the last challenge, reverse transcribed, and gene expression analyzed by PCR with specific primers for IL-22R1. Data are shown as fold induction relative to expression in naïve animals after normalization to GAPDH. Mean±SEM from 2 independent experiments are given. * p<0.05. Panel B: Levels of IL-22 in BAL fluid 48 hrs following the last challenge in challenged only (chall, n = 6) and sensitized and challenged (sens/chall, n = 6) animal. Mean±SEM from 2 independent experiments are given. * p<0.05. Panel C and D: IL-22 intracellular staining in lung cells 24 hrs following the last exposure in sensitized and challenged (top row) and challenged only (bottom row) animals and frequency of CD45⁺IL-22⁺ cells in lung tissue each dot represents a single mouse from 2 independent experiments. * p<0.05.</p

Administration of rIL-22 reduces AHR and airway inflammation.

<p>Airway responsiveness (panel A), cell counts in BAL fluid (panel B) and lung tissue inflammation and goblet cell metaplasia (panel C) were assessed in mice 48 h after the last airway challenge. Mice which were sensitized and challenged (sens/chall, n = 12) showed increased airway reactivity and numbers of eosinophils in BAL fluid compared to challenged only mice (chall, n = 5), where no eosinophils were detectable. Intranasal treatment of sensitized and challenge animals with 0.1 µg recombinant IL-22 (IL-22 0.1 µg, n = 12) showed little effects on AHR and inflammation. In contrast, mice treated with either 1 µg (IL-22 1 µg, n = 12) or 10 µg (IL-22 1 µg, n = 12) of recombinant IL-22 showed decreased AHR and number of eosinophils in BAL fluid. Means±SEM are given, *p<0.05 compared to sens/chall. <i>Panel C:</i> Tissue inflammation was evaluated 48 hrs following the last challenge using hematoxylin and eosin staining (HE) and PAS staining for goblet cells in challenged only mice (chall), non-treated sensitized and challenged mice (sens/chall) and sensitized and challenged animals treated with 10 µg of recombinant IL-22 (rIL-22). Final magnifications 100× and 400× for inserts. <i>Panels D and E:</i> Levels of IL-13 (panel D) and CCL17 (panel E) were measured in BAL fluid by ELISA 48 h after the last challenge. Means±SEM of challenged only mice (chall, <i>n</i> = 5), non-treated sensitized and challenged mice (sens/chall, n = 12), and sensitized and challenged mice treated with 0.1 µg (0.1 µg IL-22, n = 12), 1 µg (1 µg IL-22, n = 12) and 10 µg (10 µg IL-22, n = 12) of rIl-22, respectively. Mean±SEM are given. * p<0.05 compared to sens/chall and 0.1 µg IL-22.</p