Keratinocytes produce IL-6 in response to desmoglein 1 cleavage by Staphylococcus aureus exfoliative toxin A

Abstract

Many skin infections are caused by Staphylococcus aureus, a bacterial pathogen that produces virulence factors associated with these conditions such as exfoliative toxins A and B (ETA, ETB) and the leukotoxin Panton-Valentine leukocidin (PVL). Herein, we examine the potential of skin-infecting S. aureus to produce virulence factors and their impact on the local immune response. Toxin gene profiles were generated from 188 S. aureus isolated as single infecting organisms from skin lesions and demonstrated a higher potential to express ETA, ETB, and PVL than community isolates (p < 0.001). Within the study isolate group, the prevalence of genes encoding PVL was higher among methicillin-resistant S. aureus (MRSA; n = 49), while genes encoding ETs were more prevalent in methicillin-susceptible S. aureus (MSSA; n = 139). When lesion-associated white blood cell (WBC) counts were dichotomized into high- or low-WBC-count-associated bacteria, the gene for ETA was found to be associated with a low WBC count among MSSA (p = 0.001). The ETA-induced mouse model of staphylococcal scalded skin syndrome was used to investigate the link between ETA and cytokine production. Elevated IL-6 levels in the serum and increased expression of IL-6 mRNA in the skin were detected in response to ETA exposure. These findings were recapitulated in vitro using primary human keratinocytes. Thus, S. aureus may influence the local immune response via ETA cleavage of desmoglein 1 and the induction of cutaneous IL-6 expression.

The Antimicrobial Peptide Human Beta-Defensin-3 Is Induced by Platelet-Released Growth Factors in Primary Keratinocytes

“…Interleukin-6 (IL-6) is a multifunctional cytokine produced by various cell types that also influences various cell types and has multiple biological activities [ 49 ]. It regulates immune responses, hematopoiesis, acute -phase responses, and inflammation and plays a critical role in the pathogenesis of various immune processes and epithelial immune responses [ 50 – 54 ]. Since we recently demonstrated that PRGF induced the expression of IL-6 in human primary keratinocytes [ 17 ], we sought to evaluate if the observed PRGF-mediated hBD-3 induction is IL-6-dependent.…”

Platelet‐released growth factors induce the antimicrobial peptide human beta‐defensin‐2 in primary keratinocytes

“…IL‐6 is produced by various types of cells, influences various cell types and has multiple biological activities . As a response to the exfoliative toxin A of Staphylococcus aureus keratinocytes produced IL‐6 in vitro , indicating a possible role of IL‐6 in the regulation of the epidermal immune response. Increased IL‐6 levels were observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis or in the wound fluid of chronic wounds .…”

Serum cytokine modulation after Staphylococcus hyicus infection in BALB/c mice

“…Furthermore, elevated IL-6 levels in the serum and increased expression of IL-6 mRNA in the skin were detected in response to S. aureus ETA exposure (Dalrymple et al, 1996). G-CSF is a pleiotropic cytokine best known for its specific effects on the proliferation, differentiation, and activation of hematopoietic cells of the neutrophilic granulocyte lineage (Cheers et al, 1988;Rolle et al, 2013). In vitro, G-CSF stimulates growth, differentiation, and other functions in cells of the neutrophil lineage (Kawakami et al, 1990;Demetri and Griffin, 1991).…”