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Objective Systemic Lupus Erythematosus (SLE) is a systemic autoimmune syndrome associated with organ damage and an elevated risk of cardiovascular disease (CVD) resulting from activation of both innate and adaptive immune pathways. Recently, increased activation of the inflammasome machinery in SLE has been described. This study explores if caspase-1, the central enzyme of the inflammasome, plays a role in the development of SLE and its associated vascular dysfunction, using the pristane model of lupus. Methods Eight-week old wild-type or caspase-1 −/− mice were exposed to PBS or pristane via intraperitoneal injection. Six months post injection, mice were euthanized and the development of a lupus phenotype and vascular dysfunction was assessed. Results While wild-type mice exposed to pristane develop autoantibodies and a strong type I IFN response, mice lacking caspase-1 are significantly protected from these features, including pristane-induced vascular dysfunction. Further, the development of immune-complex glomerulonephritis, prominent after pristane exposure in wild-type mice, is significantly abrogated in caspase-1 −/− mice. Conclusion These results indicate that caspase-1 is an essential component in the development of lupus and its associated vascular dysfunction and may play an important role in the cross-talk between environmental exposures and autoimmunity development, thus identifying a novel pathway for therapeutic targeting.

Cutaneous lupus erythematosus (CLE) is a disfiguring and common manifestation in systemic lupus erythematosus (SLE), and the etiology of this predisposition for cutaneous inflammation is unknown. Here, we sought to examine the keratinocyte as an important source of IL-6 and define the mechanism for its increased production in CLE. Evaluation of discoid and subacute cutaneous lupus erythematosus lesions revealed significant epidermal upregulation of IL-6 when compared with control via real-time PCR and immunohistochemistry. Keratinocytes from unaffected skin of lupus patients produced significantly more IL-6 compared with healthy controls following exposure to TLR2, 3, or 4 agonists, or exposure to UVB radiation. Importantly, pretreatment with type I interferons (IFNα and IFNκ) increased IL-6 production by control keratinocytes, and type I IFN blockade decreased IL-6 secretion by lupus keratinocytes. Secretion of keratinocyte-specific IFNκ was significantly increased after TLR2 and UVB treatment in lupus keratinocytes and neutralization of IFNκ decreased IL-6 production by lupus keratinocytes. Thus, lupus keratinocytes are primed for IL-6 hyper-production in a type I IFN-dependent manner. Increased production of IFNκ by lupus keratinocytes drives this response, indicating that IFNκ may play a pathogenic role in CLE and serve as a novel target for treatment.

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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)...