Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-of-function mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14ΔE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.
0 5 5Recognition of pathogen-associated molecules in microbes by TLRs leads to activation of transcription factors such as NF-κB that promote increased transcription of proinflammatory cytokines and interferons 1 . All mammalian TLRs, with the exception of TLR3, use the adaptor MyD88 as the receptor-proximal signaling molecule to trigger downstream activation of NF-κB 2 . The association of MyD88 with TLRs facilitates recruitment of members of the IRAK family of kinases that in turn activate the E3 ubiquitin ligase TRAF6 (refs. 3-5). The formation of polyubiquitin chains by TRAF6 serves to bring TAK1 into close proximity with its substrates, including IκB kinases (IKKs). The TAK1-induced phosphorylation and activation of IKKα and IKKβ promotes IKK-induced phosphorylation of IκB proteins 6 that normally sequester NF-κB in an inactive form in the cytoplasm. Phosphorylated forms of IκB are subject to polyubiquitination and subsequently proteasome-dependent degradation, thus liberating NF-κB to translocate to the nucleus and transcriptionally upregulate the expression of a plethora of genes 7 . Most TLRs use this MyD88-dependent pathway to activate NF-κB, but TLR4 can additionally deploy another adaptor protein, TRIF, to trigger a MyD88-independent pathway that also activates NF-κB 8 . Among TLRs, TLR3 uses TRIF as its exclusive receptor-proximal adaptor protein. TRIF interacts with RIP1 kinase to trigger downstream IKK-mediated activation of NF-κB 9,10 . TRAF6 has been reported to associate with TRIF and mediate activation of NF-κB 11-13 , but other studies had concluded that TRAF6 is dispensable for TLR3 signaling 14,15 . Such discrepancies in relation to the role of TRAF6 in TRIF signaling may be due to cell-specific roles for TRAF6 and/or functional redundancy of TRAF6 with other members of the TRAF family 11 . In addition to activation of NF-κB, TRIF can also trigger activation of interferon-regulatory factor (IRF) transcription factors. Thus, TRIF forms a complex with the kinases TBK1 and IKKi (also known as IKKε) and both kinases can catalyze phosphorylation and activation of IRF3 and IRF7, leading to their nuclear translocation and induction of type I interferons 1,16 . The latter are key antiviral molecules that block viral replication 17,18 .It is clear from the above that ubiquitination is important in TLR signal transduction. Additionally, there is an emerging appreciation of the roles of the E3 ubiquitin ligase family of Pellino proteins in TLR signaling. The mammalian Pellino family consists of four members: Pellino1, Pellino2 and splice variants of Pellino3 termed Pellino3 long (Pellino3L; also known as Pellino3a) and Pellino3 short (Pellino3S; also known as Pellino3b) 19,20 . Each Pellino family member contains an N-terminal forkhead-associated (FHA) domain that recognizes phosphothreonine residues and mediates association with IRAKs 21 , and a C-terminal RING-like domain that confers E3 ubiquitin ligase activity and an ability to catalyze lysine 63 (Lys63)-linked polyubiquitination of IRAKs [22][23]...
The CARD: BCL10: MALT1 (CBM) complex is an essential signaling node for maintaining both innate and adaptive immune responses. CBM complex components have gained considerable interest due to the dramatic effects of associated mutations in causing severe lymphomas, immunodeficiencies, carcinomas and inflammatory disease. While MALT1 and BCL10 are ubiquitous proteins, the CARD-containing proteins differ in their tissue expression. CARD14 is primarily expressed in keratinocytes. The CARD14-BCL10-MALT1 complex is activated by upstream pathogen-associated molecular pattern-recognition in vitro, highlighting a potentially crucial role in innate immune defense at the epidermal barrier. Recent findings have demonstrated how CARD14 orchestrates activation of the NF-κB and MAPK signaling pathways via recruitment of BCL10 and MALT1, leading to the upregulation of pro-inflammatory genes encoding IL-36γ, IL-8, Ccl20 and anti-microbial peptides. Following the identification of CARD14 gain-of function mutations as responsible for the psoriasis susceptibility locus PSORS2, the past years have witnessed a large volume of case reports and association studies describing CARD14 variants as causal or predisposing to a wide range of inflammatory skin disorders. Recent publications of mouse models also helped to better understand the physiological contribution of CARD14 to psoriasis pathogenesis. In this review, we summarize the clinical, genetic and functional aspects of human and murine CARD14 mutations and their contribution to psoriatic disease pathogenesis.
Interleukin-17A, the prototypical member of the interleukin-17 cytokine family, coordinates local tissue inflammation by recruiting neutrophils to sites of infection. Dysregulation of interleukin-17 signalling has been linked to the pathogenesis of inflammatory diseases and autoimmunity. The interleukin-17 receptor family members (A-E) have a broad range of functional effects in immune signalling yet no known role has been described for the remaining orphan receptor, interleukin-17 receptor D, in regulating interleukin-17A-induced signalling pathways. Here we demonstrate that interleukin-17 receptor D can differentially regulate the various pathways employed by interleukin-17A. neutrophil recruitment, in response to in vivo administration of interleukin-17A, is abolished in interleukin-17 receptor D-deficient mice, correlating with reduced interleukin-17A-induced activation of p38 mitogen-activated protein kinase and expression of the neutrophil chemokine mIP-2. In contrast, interleukin-17 receptor D deficiency results in enhanced interleukin-17A-induced activation of nuclear factor-kappa B and interleukin-6 and keratinocyte chemoattractant expression. Interleukin-17 receptor D disrupts the interaction of Act1 and TRAF6 causing differential regulation of nuclear factorkappa B and p38 mitogen-activated protein kinase signalling pathways.
Neutrophils constitute essential players in inflammatory responses and are the first line of defence against harmful stimuli. However, dysregulation of neutrophil homeostasis can result in excessive inflammation and subsequent tissue damage. Neutrophilic dermatoses are a spectrum of inflammatory disorders characterized by skin lesions resulting from a neutrophil-rich inflammatory infiltrate in the absence of infection. The exact molecular pathophysiology of neutrophilic dermatoses has long been poorly understood. Interestingly, neutrophil-rich cutaneous inflammation is also a cardinal feature of several autoinflammatory diseases with skin involvement, the latter being caused by aberrant innate immune responses. Overactivation of the innate immune system leading to increased production of interleukin-1 family members and 'sterile' neutrophil-rich cutaneous inflammation are features of both inherited autoinflammatory syndromes with skin involvement and an increasing number of neutrophilic dermatoses. Therefore, we propose that autoinflammation may be a cause of neutrophilic dermatoses.
TLRs initiate immune responses by direct detection of molecular motifs that distinguish invading microbes from host cells. Five intracellular adaptor proteins, each containing a Toll/IL-1R (TIR) domain, are used by TLRs and play key roles in dictating gene expression patterns that are tailored to the invader. Such gene expression is mediated by transcription factors, and although TIR adaptor-induced activation of NF-κB and the IFN regulatory factors have been intensively studied, there is a dearth of information on the role of TIR adaptors in regulating CREB. In this paper, we describe a role for the TIR adaptor Mal in enhancing activation of CREB. Mal-deficient murine bone marrow-derived macrophages show a loss in responsiveness to TLR2 and TLR4 ligands with respect to activation of CREB. Mal-deficient cells also fail to express the CREB-responsive genes IL-10 and cyclooxygenase 2 in response to Pam2Cys-Ser-(Lys)4 and LPS. We reveal that Mal-mediated activation of CREB is dependent on Pellino3 and TNFR-associated factor 6, because CREB activation is greatly diminished in Pellino3 knockdown cells and TNFR-associated factor 6-deficient cells. We also demonstrate the importance of p38 MAPK in this pathway with the p38 inhibitor SB203580 abolishing activation of CREB in murine macrophages. MAPK-activated protein kinase 2 (MK2), a substrate for p38 MAPK, is the likely downstream mediator of p38 MAPK in this pathway, because Mal is shown to activate MK2 and inhibition of MK2 decreases TLR4-induced activation of CREB. Overall, these studies demonstrate a new role for Mal as a key upstream regulator of CREB and as a contributor to the expression of both pro- and anti-inflammatory genes.
Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36g, are highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36g. Such an IL-36g overexpression was not observed in patients with drug-induced maculopapular rash. In vitro, the causative drug specifically induced IL-36g release either directly by the patient's peripheral blood monocytes or indirectly by keratinocytes in the presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36g secretion in vitro was specific for AGEP and involved toll-like receptor 4 sensing the drug/albumin complex as a danger signal. Our results suggest that IL-36g secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.
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