T cell tolerance to the skin: a central role for central tolerance

T cell tolerance to self-antigens is believed to be achieved in a two-step process. The first step, called central tolerance, takes place in the thymus. The second step takes place outside the thymus in secondary lymphoid organs. One may ask why two mechanisms are needed to insure T cell tolerance. These two mechanisms share redundant functions and dysfunctions, leading to T cell-mediated autoimmune syndromes. By reviewing the literature on relevant animal models for T cell tolerance and our own recent findings, we are providing evidences that only central tolerance is acting for the ski

CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule, Caspase Recruitment Domain-Containing Protein 14 (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 Th17 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 Th17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and pro-inflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives Th17-mediated psoriasis skin disease in vivo

The Nlrp3 inflammasome regulates acute graft-versus-host disease

The success of allogeneic hematopoietic cell transplantation is limited by acute graft-versus-host disease (GvHD), a severe complication accompanied by high mortality rates. Yet, the molecular mechanisms initiating this disease remain poorly defined. In this study, we show that, after conditioning therapy, intestinal commensal bacteria and the damage-associated molecular pattern uric acid contribute to Nlrp3 inflammasome-mediated IL-1β production and that gastrointestinal decontamination and uric acid depletion reduced GvHD severity. Early blockade of IL-1β or genetic deficiency of the IL-1 receptor in dendritic cells (DCs) and T cells improved survival. The Nlrp3 inflammasome components Nlrp3 and Asc, which are required for pro-IL-1β cleavage, were critical for the full manifestation of GvHD. In transplanted mice, IL-1β originated from multiple intestinal cell compartments and exerted its effects on DCs and T cells, the latter being preferentially skewed toward Th17. Compatible with these mouse data, increased levels of active caspase-1 and IL-1β were found in circulating leukocytes and intestinal GvHD lesions of patients. Thus, the identification of a crucial role for the Nlrp3 inflammasome sheds new light on the pathogenesis of GvHD and opens a potential new avenue for the targeted therapy of this severe complication

The role of type I interferons (IFNs) in the regulation of chicken macrophage inflammatory response to bacterial challenge

International audienceMammalian type I interferons (IFNα/β) are known to modulate inflammatory processes in addition to their antiviral properties. Indeed, virus-induced type I interferons regulate the mammalian phagocyte immune response to bacteria during superinfections. However, it remains unresolved whether type I IFNs similarly impact the chicken macrophage immune response. We first evidenced that IFNα and IFNβ act differently in terms of gene expression stimulation and activation of intracellular signaling pathways in chicken macrophages. Next, we showed that priming of chicken macrophages with IFNα increased bacteria uptake, boosted bacterial-induced ROS/NO production and led to an increased transcriptional expression or production of NOS2/NO, IL1B/IL-1β and notably IFNB/IFNβ. Neutralization of IFNβ during bacterial challenge limited IFNα-induced augmentation of the pro-inflammatory response. In conclusion, we demonstrated that type I IFNs differently regulate chicken macrophage functions and drive a pro-inflammatory response to bacterial challenge. These findings shed light on the diverse functions of type I IFNs in chicken macrophages

New insights into acne pathogenesis: Propionibacterium acnes activates the inflammasome

The precise contribution of the commensal bacterium Propionibacterium acnes (P. acnes) in the inflammatory response associated with acne vulgaris remains controversial. In this issue Qin et al. show that P. acnes induces robust IL-1β secretion in monocytic cells by triggering the activation of the NLRP3 inflammasome. In vivo, the encounter of P. acnes and macrophages in the peri-follicular dermis could locally result in the release of substantial amounts of IL-1β and therefore exacerbate inflammation. Such findings suggest that molecules targeting IL-1β and/or the NLRP3 inflammasome may constitute new treatment possibilities for acne vulgaris

Propionibacterium acnes Strains Differentially Regulate the Fate of Th17 Responses in the Skin

Agak et al. demonstrate that different strains of Propionibacterium acnes, a bacterium colonizing pilosebaceous units in healthy skin and acne, have the ability to induce T helper type 17 cells secreting either IFN-γ or IL-10 and exhibiting either pathogenic or protective properties, respectively. This work contributes to growing evidence indicating that the phenotype of T helper type 17 cells is largely dependent on their microbiological environment

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases

In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1β-induced neutrophil recruitment to the skin. IL-1β blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1α monoclonal antibody MABp1 and anti-IL-1β Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases

The inflammasomes in autoinflammatory diseases with skin involvement

During the past years, significant progress in the understanding of the complexity, regulation, and relevance of innate immune responses underlying several inflammatory conditions with neutrophilic skin involvement has been made. These diseases belong to the novel class of autoinflammatory diseases, and several are caused by mutations in genes regulating the function of innate immune complexes, termed inflammasomes, leading to enhanced secretion of the proinflammatory cytokine IL-1β. Consequently, targeting of IL-1β has proven successful in the treatment of these diseases, and the identification of related pathogenic mechanisms in other more common skin diseases characterized by autoinflammation and neutrophilic tissue damage also provides extended opportunities for therapy by interfering with IL-1 signaling