Staphylococcus δ-toxin induces allergic skin disease by activating mast cells

Nakamura, Yuumi; Oscherwitz, Jon; Cease, Kemp B.; Chan, Stephanie; Muñoz-Planillo, Raúl; Hasegawa, Mizuho; Villaruz, Amer E.; Cheung, Gordon Y. C.; McGavin, Martin J.; Travers, Jeffrey B.; Otto, Michael; Inohara, Naohiro; Núñez, Gabriel

doi:10.1038/nature12655

Cited by 468 publications

(452 citation statements)

References 35 publications

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“…5B). The large difference in G-CSF agrees with previously reported effects of one of the PSMs, ␦-toxin, on mast cell degranulation and G-CSF release (44). Differences in circulating IL-6 and IL-1␤, both of which are released from keratinocytes, were also noted (Fig.…”

Section: Discussionsupporting

confidence: 80%

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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Section: Discussionsupporting

confidence: 80%

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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“…Eight days after the start of treatment with tamoxifen or vehicle, mice were patched with OVA-DQ (Life Technologies) for 30 hours to assess OVA uptake and processing, with a protocol adapted from Geha and collaborators (83), but without tape stripping. OVAthought also to contribute to human AD (47,48,(74)(75)(76)(77), and that shares striking similarities with our Rabgef1 K-KO mice (see Figure 10), we showed that significant reductions in levels of RABGEF1 protein were observed by immunohistochemistry in HDM/SEBsensitized and challenged mouse skin, as compared with control skin. These findings clearly show that the induction of cutaneous allergic inflammation in WT mice is associated with significant reductions in levels of keratinocyte RABGEF1 in the induced skin lesions.…”

Section: Discussionsupporting

confidence: 50%

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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“…Overgrowth of and infection with S. aureus are both contributors to and consequences of the immune imbalance and poor barrier function characteristic of AD. S. aureus can directly activate allergic mast cells (8,9) and T cells (10). Treatment with antibiotics can reduce S. aureus burdens and improve symptoms but does not normalize the underlying pathology (2).…”

Section: Resultsmentioning

confidence: 99%

Transplantation of human skin microbiota in models of atopic dermatitis

Myles¹

2017

J Bacteriol Parasitol

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Staphylococcus δ-toxin induces allergic skin disease by activating mast cells

Cited by 468 publications

References 35 publications

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

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

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

Transplantation of human skin microbiota in models of atopic dermatitis

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