MALT1-deficient mice develop atopic-like dermatitis upon aging

MALT1 plays an important role in innate and adaptive immune signaling by acting as a scaffold protein that mediates NF-kappa B signaling. In addition, MALT1 is a cysteine protease that further fine tunes proinflammatory signaling by cleaving specific substrates. Deregulated MALT1 activity has been associated with immunodeficiency, autoimmunity, and cancer in mice and humans. Genetically engineered mice expressing catalytically inactive MALT1, still exerting its scaffold function, were previously shown to spontaneously develop autoimmunity due to a decrease in Tregs associated with increased effector T cell activation. In contrast, complete absence of MALT1 does not lead to autoimmunity, which has been explained by the impaired effector T cell activation due to the absence of MALT1-mediated signaling. However, here we report that MALT1-deficient mice develop atopic-like dermatitis upon aging, which is preceded by Th2 skewing, an increase in serum IgE, and a decrease in Treg frequency and surface expression of the Treg functionality marker CTLA-4

IL-33trap is a novel IL-33-neutralizing biologic that inhibits allergic airway inflammation

Background: The emergence of IL-33 as a key molecular player in the development and propagation of widespread inflammatory diseases, including asthma and atopic dermatitis, has established the need for effective IL-33 neutralizing biologics. Objective: Here we describe the development and validation of a new antagonist of IL-33, termed IL-33trap, which combines the extracellular domains of the IL-33 receptor (ST2) and its coreceptor, IL-1 receptor accessory protein, into a single fusion protein. Methods: We produced and purified recombinant IL-33trap from human cells and analyzed its IL-33 binding affinity and IL-33 antagonistic activity in cultured cells and mice. IL-33trap activity was also benchmarked with a recombinant soluble ST2 corresponding to the naturally occurring IL-33 decoy receptor. Finally, we studied the effect of IL-33trap in the Alternaria alternata mouse model of allergic airway inflammation. Results: In vitro IL-33trap binds IL-33 and inhibits IL-33 activity to a much stronger degree than soluble ST2. Furthermore, IL-33trap inhibits eosinophil infiltration, splenomegaly, and production of signature cytokines in splenic lymphocytes and lung tissue on IL-33 injection. Finally, administration of IL-33trap at the time of allergen challenge inhibits inflammatory responses in a preclinical mouse model of acute allergic airway inflammation. Conclusions: IL-33trap is a novel IL-33 antagonist that outperforms the natural IL-33 decoy receptor and shows anti-inflammatory activities in a preclinical mouse model of acute allergic airway inflammation when administered at the time of allergen challenge

Immune responses and therapeutic options in psoriasis

Psoriasis is a chronic inflammatory disease of the skin that affects about 2-3% of the population and greatly impairs the quality of life of affected individuals. Psoriatic skin is characterized by excessive proliferation and aberrant differentiation of keratinocytes, as well as redness caused by increased dilation of the dermal blood vessels and infiltration of immune cells. Although the pathogenesis of psoriasis has not yet been completely elucidated, it is generally believed to arise from a complex interplay between hyperproliferating keratinocytes and infiltrating, activated immune cells. So far, the exact triggers that elicit this disease are still enigmatic, yet, it is clear that genetic predisposition significantly contributes to the development of psoriasis. In this review, we summarize current knowledge of important cellular and molecular mechanisms driving the initiation and amplification stages of psoriasis development, with a particular focus on cytokines and emerging evidence illustrating keratinocyte-intrinsic defects as key drivers of inflammation. We also discuss mouse models that have contributed to a better understanding of psoriasis pathogenesis and the preclinical development of novel therapeutics, including monoclonal antibodies against specific cytokines or cytokine receptors that have revolutionized the treatment of psoriasis. Future perspectives that may have the potential to push basic research and open up new avenues for therapeutic intervention are provided

Psoriasis plays a wild CARD

Rare autosomal mutations in CARD14 have previously been linked to psoriasis susceptibility in humans, but their pathogenic role had not been shown. Mellett et al. generated mice harboring the patient-derived gain-of-function Card14DE138 mutation and showed that hyperactivation of CARD14 alone is sufficient to induce immunopathogenic mechanisms that are responsible for psoriasis, which is driven by the IL-17/IL-23 axis

Hemin reduces postoperative ileus in a heme oxygenase 1‐dependent manner while dimethyl fumarate does without heme oxygenase 1‐induction

Background Postoperative ileus (POI), the impairment of gastrointestinal motility after abdominal surgery, is mainly due to intestinal muscular inflammation. Carbon monoxide (CO)-releasing compounds were shown to exert an anti-inflammatory effect in murine POI partially through induction of heme oxygenase-1 (HO-1). The influence of hemin and dimethyl fumarate (DMF), currently used for multiple sclerosis (MS), was therefore tested in murine POI. Methods C57BL/6J mice were anesthetized and after laparotomy, POI was induced via intestinal manipulation (IM). Animals were treated with either 30 mg kg(-1) hemin intraperitoneally (ip), 30 mg kg(-1) DMF ip, or 100 mg kg(-1) intragastrically (ig) 24 hours before IM. Intestinal transit was assessed 24 hours postoperatively and mucosa-free muscularis or whole segments of the small intestine were stored for later analysis. Intestinal HO-1 protein expression was studied at 6, 12, and 24 hours after administration of hemin or DMF in non-manipulated mice. Key results Pretreatment with hemin and DMF, both ig and ip, prevented the delayed transit seen after IM. Concomitantly, both hemin and DMF significantly reduced the increased interleukin-6 levels and the elevated leukocyte infiltration in the muscularis. Hemin but not DMF caused a significant increase in intestinal HO-1 protein expression and co-administration of the HO-1 inhibitor chromium mesoporphyrin abolished the protective effects of hemin on POI; DMF reduced the IM-induced activation of NF-kappa B and ERK 1/2. Conclusions and Inferences Both hemin and DMF improve the delayed transit and inflammation seen in murine POI, but only hemin does so in a HO-1-dependent manner

CARD14-mediated activation of paracaspase MALT1 in keratinocytes : implications for psoriasis

Mutations in caspase recruitment domain-containing protein 14 (CARD14) have been linked to susceptibility to psoriasis. CARD14 is an intracellular scaffold protein that regulates proinflammatory gene expression. Recent studies have offered novel insights into the mechanisms of CARD14-mediated signaling in keratinocytes and the molecular impact of psoriasis-associated CARD14 mutations. CARD14 forms a signaling complex with BCL10 and the paracaspase MALT1, and this process is enhanced upon pathogenic CARD14 mutation, culminating in the activation of MALT1 protease activity and psoriasis-associated gene expression. This review summarizes the current knowledge of CARD14/MALT1-mediated signaling in keratinocytes and its therapeutic implications in psoriasis

The paracaspase MALT1 mediates CARD14-induced signaling in keratinocytes

Mutations in CARD14 have recently been linked to psoriasis susceptibility. CARD14 is an epidermal regulator of NF-jB activation. However, the ability of CARD14 to activate other signaling pathways as well as the biochemical mechanisms that mediate and regulate its function remain to be determined. Here, we report that in addition to NF-jB signaling, CARD14 activates p38 and JNK MAP kinase pathways, all of which are dependent on the paracaspase MALT1. Mechanistically, we demonstrate that CARD14 physically interacts with paracaspase MALT1 and activates MALT1 proteolytic activity and inflammatory gene expression, which are enhanced by psoriasis-associated CARD14 mutations. Moreover, we show that MALT1 deficiency or pharmacological inhibition of MALT1 catalytic activity inhibits pathogenic mutant CARD14-induced cytokine and chemokine expression in human primary keratinocytes. Collectively, our findings demonstrate a novel role for MALT1 in CARD14-induced signaling and indicate MALT1 as a valuable therapeutic target in psoriasis