Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes

Dai, Xiuju; Sayama, Koji; Tohyama, Mikiko; Shirakata, Yuji; Hanakawa, Yasushi; Tokumaru, Sho; Yang, Lüjun; Hirakawa, Satoshi; Hashimoto, Koji

doi:10.1016/j.jaci.2010.12.006

Cited by 140 publications

(119 citation statements)

References 61 publications

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“…No differences were detected at baseline between the two groups; however, increased IL-8 and KC-like secretion levels were seen in atopic compared with healthy keratinocytes after stimulation. These data are in agreement with previous studies showing an increased production of proinflammatory cytokines by HDM (7,(22)(23)(24)(25). The different behaviours between the two keratinocyte populations suggest that atopic keratinocytes could respond excessively to environmental stimuli and that intrinsic alterations present in atopic keratinocytes, and not the presence of external proteases, may contribute to the excessive inflammatory response in AD.…”

Section: Discussionsupporting

confidence: 94%

Evaluation of antimicrobial peptides and cytokine production in primary keratinocyte cell culture from healthy and atopic beagles

Santoro

Ahrens

Marsella

et al. 2015

Experimental Dermatology

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Increased secretion of antimicrobial peptides and cytokines is present in atopic skin. The purpose of this study was to compare the production of b-defensin (cBD)3-like, cathelicidin (cCath) and cytokines in atopic and healthy canine keratinocytes. Seven atopic house dust mites (HDMs) sensitive and five healthy age-matched beagles were used. Keratinocytes were stimulated for 24 h, and the supernatant was collected. A significantly higher production of cBD3-like was present at baseline in atopic compared with healthy keratinocytes, but cBD3-like did not increase after stimulation. IL-17 and lipopolysaccharide increased cBD3-like in healthy compared with atopic keratinocytes. cCath increased in both groups after stimulation. Atopic keratinocytes exposed to HDM produced more IL-8 and keratinocyte-derived chemokine-like than healthy keratinocytes. Exposure to HDM induced an increased IL-8 in atopic keratinocytes and a decreased IFN-c in healthy keratinocytes. These results may suggest an over sensitization of atopic keratinocytes and a possible impairment of the cutaneous defense against micro-organisms.

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Section: Discussionsupporting

confidence: 94%

Evaluation of antimicrobial peptides and cytokine production in primary keratinocyte cell culture from healthy and atopic beagles

Santoro

Ahrens

Marsella

et al. 2015

Experimental Dermatology

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“…Keratinocyte activation and release of IL-18 and IL-1␤ by caspase 1 as part of an active inflammasome have been reported (37). Additionally, an inflammasome-independent role for caspase 1 in apoptosis of keratinocytes has been described (38).…”

Section: Discussionmentioning

confidence: 99%

Staphlyococcus aureus Phenol-Soluble Modulins Stimulate the Release of Proinflammatory Cytokines from Keratinocytes and Are Required for Induction of Skin Inflammation

et al. 2015

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Staphylococcus aureus is a human commensal that colonizes the skin. While it is normally innocuous, it has strong associations with atopic dermatitis pathogenesis and has become the leading cause of skin and soft tissue infections in the United States. The factors that dictate the role of S. aureus in disease are still being determined. In this work, we utilized primary keratinocyte culture and an epidermal murine colonization model to investigate the role of S. aureus phenol-soluble modulins (PSMs) in proinflammatory cytokine release and inflammation induction. We demonstrated that many species of Staphylococcus are capable of causing release of interleukin 18 (IL-18) from keratinocytes and that S. aureus PSMs are necessary and sufficient to stimulate IL-18 release from keratinocytes independently of caspase 1. Further, after 7 days of epicutaneous exposure to wild-type S. aureus, but not S. aureus ⌬psm, we saw dramatic changes in gross pathology, as well as systemic release of proinflammatory cytokines. This work demonstrates the importance of PSM peptides in S. aureus-mediated inflammatory cytokine release from keratinocytes in vitro and in vivo and further implicates PSMs as important contributors to pathogenesis. Staphylococcus aureus is a human commensal that lives in the nose, skin, and throat in approximately 30% of the human population (1, 2). While S. aureus is usually harmless, it is an opportunistic pathogen that has become a leading cause of nosocomial infections in the United States (3) and can manifest as skin and soft tissue infections, infective endocarditis, osteomyelitis, and sepsis (1). Further, it has a role in exacerbation of atopic dermatitis (AD), a chronic inflammatory disease of the skin that affects up to 20% of children and up to 3% of adults (4, 5). Chronic cutaneous inflammation during AD results in increased production of extracellular matrix components that permit attachment of S. aureus (6). Subsequently, S. aureus promotes AD by stimulating a strong proinflammatory response (7). S. aureus proteins, such as hemolysin ␣ (HLA), staphylococcal protein A (SPA), and lipoteichoic acids (LTA), promote proinflammatory cytokine production from keratinocytes (7-11). However, this stimulation requires the concurrent presence of a surfactant, such as SDS (11).Keratinocytes serve as the first line of defense against cutaneous pathogens and are able to stimulate an immune response by releasing cytokines, defensins, and antimicrobial cationic peptides, such as LL-37, to fight off pathogens (12). One cytokine that is produced by keratinocytes and has a role in promoting AD is interleukin 18 (IL-18) (13,14). IL-18 is a proinflammatory cytokine that is cleaved and activated primarily by caspase 1 (15). Caspase 1 activation occurs following exposure to danger-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), which stimulate the activation of the inflammasome (16). Caspase 1 activation can also result in the activation of the proinflammatory cytokine IL-1␤ (17)...

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“…LCs, positioned covertly under the TJs, are polarized to send their dendrites outside of the TJ barrier when activated by danger signals such as TSLP, TNF-α, and IL-1β, presumably secreted from keratinocytes that somehow detect SC damages (Figure 2 and refs. 47,[53][54][55][56]. The SG1 layer allows LCs to sample for foreign materials that have violated the SC barrier (13).…”

Section: The Three Musketeers Of the Epidermal Barriermentioning

confidence: 99%

“…Interestingly, tape-stripping mouse ear skin activates LCs and induces penetration of the TJ barrier by LC dendrites, suggesting that causing physical stress to the SC induces danger signals in epidermis that directly or indirectly activate LCs ( Figure 2 and refs. 13,47,50,[53][54][55][56]. Thus, perturbation of the SC barrier not only allows allergen penetration throughout this barrier, but also triggers LC activation and facilitates subsequent uptake of antigens by LCs across the epidermal TJ barrier.…”

Section: Figurementioning

confidence: 99%

“…After antigen acquisition, LCs presumably migrate to draining lymph nodes and activate antigen-specific T cells. Although danger signals similar to those observed in simple epithelium models, such as the lungs, may also occur in skin, as shown in Figure 2 (7,53,(111)(112)(113)(114), it is not yet clear how LCs sense danger signals caused by SC damage, and the specific signals that are delivered across the TJ barrier remain to be investigated.…”

Section: Figurementioning

confidence: 99%

See 1 more Smart Citation

Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases

Kubo¹,

Nagao²,

Amagai³

2012

J. Clin. Invest.

318

289

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Classic atopic dermatitis is complicated by asthma, allergic rhinitis, and food allergies, cumulatively referred to as atopic diseases. Recent discoveries of mutations in the filaggrin gene as predisposing factors for atopic diseases have refocused investigators' attention on epidermal barrier dysfunction as a causative mechanism. The skin's barrier function has three elements: the stratum corneum (air-liquid barrier), tight junctions (liquid-liquid barrier), and the Langerhans cell network (immunological barrier). Clarification of the molecular events underpinning epidermal barrier function and dysfunction should lead to a better understanding of the pathophysiological mechanisms of atopic diseases. IntroductionAtopic dermatitis (AD) is a chronic relapsing eczematous skin disorder that is frequently associated with elevated serum IgE levels and a family history of AD, allergic rhinitis, and/or asthma. Clinical manifestations of classic AD are dry skin and relapsing eczema, which usually start during early infancy or childhood and become complicated by food allergies, asthma, and/or allergic rhinitis during the first several years of life, in a process called "atopic march" (1). AD is highly prevalent in industrialized countries, where it affects approximately 15%-30% of children and 2%-10% of adults (2). The various observations of the disease indicate that AD has a complex etiology with genetic, immunological, and environmental aspects.Living organisms rely critically on surface barriers to isolate themselves from the external environment and to maintain homeostasis. While unicellular organisms are enclosed by cell membranes and cell walls, epithelial barrier structures, in several forms, cover the surfaces of multicellular organisms (3). In mammals, the airway and gastrointestinal tract are lined by simple epithelia covered with mucus. In contrast, the outer surface of the body is covered by a stratified epithelial cellular sheet called the epidermis, the outermost layer of which is cornified. Recent findings have shown that disruption of epithelial barrier systems are involved in the pathogenesis of immune disorders such as inflammatory bowel disease, asthma, and AD (4-12). In this review, we describe the barrier system of the epidermis, which is far more sophisticated than previously thought (13,14), and attempt to discuss its function with special focus on antigen penetration through these barriers and antigen capture by dendritic cells in the context of AD.

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Mite allergen is a danger signal for the skin via activation of inflammasome in keratinocytes

Cited by 140 publications

References 61 publications

Evaluation of antimicrobial peptides and cytokine production in primary keratinocyte cell culture from healthy and atopic beagles

Evaluation of antimicrobial peptides and cytokine production in primary keratinocyte cell culture from healthy and atopic beagles

Staphlyococcus aureus Phenol-Soluble Modulins Stimulate the Release of Proinflammatory Cytokines from Keratinocytes and Are Required for Induction of Skin Inflammation

Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases

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