Role of Interleukin 1 in Atopic Dermatitis

Abramovits, William; Bejarano, Joaquin J. Rivas; Valdecantos, Wendell C.

doi:10.1016/j.det.2013.04.008

Cited by 41 publications

(44 citation statements)

References 23 publications

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“…to be involved in the pathogenesis of skin inflammation (24), our data support the hypothesis that in mice whose keratinocytes lack RABGEF1, activation of keratinocyte IL-1R may favor aberrant MYD88-dependent signaling and the associated development of skin barrier dysfunction and skin lesions. This idea is further tion of MYD88/NF-κB-dependent signaling pathways in their basal state.…”

Section: Resultssupporting

confidence: 73%

“…Defects in filaggrin, including loss-of-function mutations of the FLG gene (3,17,18), represent a well-characterized predisposing factor for AD (3,19) and ACD (17,20). Keratinocyte activation and secretion of proinflammatory cytokines, such as thymic stromal lymphopoietin (TSLP) (21)(22)(23) or cytokines from the IL-1 family (24)(25)(26), also play a central role in the initiation and maintenance of aberrant immune responses associated with allergic skin disorders (25,26). There is evidence that the aberrant barrier function and modified skin microenvironment observed in such settings endow dendritic cells Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Marichal¹,

Gaudenzio²,

Abbas³

et al. 2016

Journal of Clinical Investigation

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, 2-way ANOVA with Bonferroni's test for multiple comparisons (G and K), or Mann-Whitney test (L). *P < 0.05; **P < 0.01; ***P < 0.001. Scale bars: 50 μm; original magnification in B and I, ×20; NS, not significant. The Journal of Clinical Investigation R E S E A R C H A R T I C L E4 4 9 9 jci.org Volume 126 Number 12 December 2016 some expression of keratin 14 (K14) in epithelial cells. However, these organs did not exhibit histological abnormalities (Supplemental Figure 3). These results indicate that the cause of death in such mice is more likely related to the skin abnormalities. Because of the accelerated mortality in Rabgef1 K-KO mice, and to assess the function of keratinocyte-intrinsic RABGEF1 in adult mice that would exhibit no potential developmental effects of constitutive Rabgef1 deletion, we generated mice in which Rabgef1 can be depleted in keratinocytes by tamoxifen treatment, i.e., K14-Cre-ERT2 + Rabgef1 fl/fl mice (called Rabgef1 KERT2-KO mice). Topical tamoxifen treatment on the back skin of adult Rabgef1 KERT2-KO mice, but not adult Rabgef1 fl/fl mice, promoted the development of skin lesions that were similar to those in Rabgef1 K-KO mice and were associated with RABGEF1 deletion in keratinocytes (Figure 1, H-K). Such skin lesions were associated with a modest, albeit statistically significant, increase in the number of bacteria that could be cultured from the affected skin ( Figure 1L), but not with evidence of associated systemic bacterial infection (Supplemental Figure 4).RABGEF1 deletion in keratinocytes results in epidermal barrier dysfunction, features of type 2 skin inflammation, and elevated levels of IgE antibodies. Histological and immunohistological analyses of back skin from newborn mice did not reveal obvious differences between Rabgef1 K-KO and control mice (Supplemental Figure 5). By contrast, back skin lesions of postnatal day 7-9 as well as day 49-56 (i.e., adult) Rabgef1 K-KO mice exhibited marked epidermal hyperplasia (Figure 1, F and G) and spongiosis ( Figure 2A These observations prompted us to investigate whether keratinocyte-intrinsic RABGEF1 deficiency resulted in epidermal barrier dysfunction. We used our model of inducible keratinocyte Rabgef1 deletion by topical tamoxifen treatment of Rabgef1 KERT2-KO mice and assessed barrier function by measuring transepidermal water loss (TEWL) (ref. 36 and Figure 2F). As shown in Figure 2G, TEWL was significantly increased in the back skin of tamoxifen-treated Rab gef1 KERT2-KO mice versus tamoxifen-treated control mice. Consistent with the increased permeability of the skin, the transepidermal passage of a harmless antigen, ovalbumin (OVA), patched on the skin was also potentiated when RABGEF1 was defective in keratinocytes. Indeed, dermal DC uptake and endosomal digestion of OVA was also substantially induced in tamoxifen-treated Rabgef1 KERT2-KO mice, whereas OVA was less accessible to DCs in vehicle-treated Rab gef1 KERT2-KO mice or tamoxifen-treated littermate control mice ( Figure 2H).(DCs) with the capacity to induce a ...

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Section: Resultssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis

Marichal¹,

Gaudenzio²,

Abbas³

et al. 2016

Journal of Clinical Investigation

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“…It is believed that the activation of inflammasomes by allergens or pathogens can lead to an exacerbation of the disease. 93,94 However, Niebuhr et al reported lower NALP3 and caspase-1 expressions in atopic dermatitis lesions, when compared to normal skin and to psoriasis lesions, and suggest that this lesser function of the inflammasome may well explain, at least in part, the role of S. aureus as an aggravating factor in atopic patients. 95 Evaluating NLRP1, NLRP3, and CARD8 single nucleotide polymorphisms, Bivik et al found no association between atopic dermatitis and NLRP3 or CARD8.…”

Section: Dermatological Diseases Associated With Inflammasomesmentioning

confidence: 99%

Inflammasomes and dermatology

Sá

Neto

2016

An. Bras. Dermatol.

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Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

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“…At the systemic level, IL-1 mediates the development of pain reactions, fever, vasodilation, and hypotension (Abramovits et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Interleukin (IL)-1␤, one of the key pro-inflammatory cytokines playing an important role in the innate immune response, participates in the inflammatory reactions involved both in the acute and chronic phases of AD (Abramovits et al, 2013).…”

Section: Introductionmentioning

confidence: 99%