MALT1 targeting suppresses CARD14-induced psoriatic dermatitis in mice.

CARD14 gain-of-function mutations cause psoriasis in humans and mice. Together with BCL10 and the protease MALT1, mutant CARD14 forms a signaling node that mediates increased NF-κB signaling and proinflammatory gene expression in keratinocytes. However, it remains unclear whether psoriasis in response to CARD14 hyperactivation is keratinocyte-intrinsic or requires CARD14 signaling in other cells. Moreover, the in vivo effect of MALT1 targeting on mutant CARD14-induced psoriasis has not yet been documented. Here, we show that inducible keratinocyte-specific expression of CARD14E138A in mice rapidly induces epidermal thickening and inflammation as well as increased expression of several genes associated with psoriasis in humans. Keratinocyte-specific MALT1 deletion as well as oral treatment of mice with a specific MALT1 protease inhibitor strongly reduces psoriatic skin disease in CARD14E138A mice. Together, these data illustrate a keratinocyte-intrinsic causal role of enhanced CARD14/MALT1 signaling in the pathogenesis of psoriasis and show the potential of MALT1 inhibition for the treatment of psoriasis.

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-κB 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.

Spatiotemporal Changes of the Phagosomal Proteome in Dendritic Cells in Response to LPS Stimulation.

Dendritic cells (DCs) are professional phagocytes that use innate sensing and phagocytosis to internalize and degrade self as well as foreign material, such as pathogenic bacteria, within phagosomes. These intracellular compartments are equipped to generate antigenic peptides that serve as source for antigen presentation to T cells initiating adaptive immune responses. The phagosomal proteome of DCs is only partially studied and is highly dynamic as it changes during phagosome maturation, when phagosomes sequentially interact with endosomes and lysosomes. In addition, the activation status of the phagocyte can modulate the phagosomal composition and is able to shape phagosomal functions.In this study, we determined spatiotemporal changes of the proteome of DC phagosomes during their maturation and compared resting and lipopolysaccharide (LPS)-stimulated bone marrow-derived DCs by label-free, quantitative mass spectrometry. Ovalbumin-coupled latex beads were used as phagocytosis model system and revealed that LPS-treated DCs show decreased recruitment of proteins involved in phagosome maturation, such as subunits of the vacuolar proton ATPase, cathepsin B, D, S, and RAB7. In contrast, those phagosomes were characterized by an increased recruitment of proteins involved in antigen cross-presentation, e.g. different subunits of MHC I molecules, the proteasome and tapasin, confirming the observed increase in cross-presentation efficacy in those cells. Further, several proteins were identified that were not previously associated with phagosomal functions. Hierarchical clustering of phagosomal proteins demonstrated that their acquisition to DC phagosomes is not only dependent on the duration of phagosome maturation but also on the activation state of DCs. Thus, our study provides a comprehensive overview of how DCs alter their phagosome composition in response to LPS, which has profound impact on the initiation of efficient immune responses.

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-κB 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-κB 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.