Extracellular Adherence Protein of Staphylococcus aureus Suppresses Disease by Inhibiting T-Cell Recruitment in a Mouse Model of Psoriasis

Abstract

Psoriasis is a T-cell-mediated inflammatory disease. Previous studies focused on lymphocyte function-associated antigen 1 (LFA-1)-expressing T cells as a molecular target for therapeutic intervention. By contrast, information on therapeutic effects and the underlying mechanism of blocking the LFA-1 counter receptor, ICAM-1 is scarce. Here, we used the CD18 (beta2-integrin) hypomorphic (CD18hypo) mouse model of psoriasis to investigate the therapeutic role of extracellular adherence protein (Eap) of Staphylococcus aureus, which exerts antiinflammatory activities by interacting with the ICAM-1 function. We show that ICAM-1 is predominantly upregulated on endothelial cells in lesional skin of CD18hypo mice. In vitro Eap was found to disrupt cell-cell contacts between T cells and dendritic cells, and inhibit T-cell proliferation. By contrast, in vivo Eap rather blocked transmigration of T cells from vessels to inflamed skin of CD18hypo mice, but did not inhibit their proliferation and activation. Most importantly, Eap successfully suppressed the disease by blocking T-cell extravasation into the inflamed skin. Together, these data indicate that interaction between LFA-1 and ICAM-1 is causally involved in the pathogenesis of psoriasiform skin inflammation, and targeting ICAM-1 to selectively block T-cell extravasation by Eap without immune suppression may represent a potential therapeutic strategy for psoriasis.

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

“…Epidermal deletion of JunB and c-Jun (26), the absence of endogenous MHC class II (27) in inbred mice, or reduced expression of the common chain of β2 integrin in CD18 hypomorphic PL/J mice (28) led to PsA-like disease symptoms. On the other hand, TLR7 ligation in innate immune cells by imiquimod, triggered Ps symptoms (29), while targeting of intracellular adhesion molecule-1 ameliorated the disease (30).…”

A play in four acts: Staphylococcus aureus abscess formation

“…Structural studies showed that Eap and the C-terminal half of TSST1 (toxic shock syndrome toxin 1) as well as SEB (staphylococcal enterotoxin B) display homology, and Eap was thus shown to have superantigenic activity and to induce pro-inflammatory (IL6, TNFα) cytokine production by monocytes73. However, Eap has also been shown to exert numerous anti-inflammatory effects by inhibiting neutrophil adherence to the endothelium74, leukocyte recruitment in a murine bacterial peritonitis model75, T cell activation and recruitment to the dermis76.…”

A battle for iron: host sequestration and Staphylococcus aureus acquisition

“…Eap and Emp non-covalently associate with the cell wall and promote staphylococcal adhesion to host proteins fibronectin, fibrinogen, vitronectin, and collagen [23]. Interestingly, Eap was found to decrease neutrophil and T-cell recruitment by binding to endothelial ICAM-1, preventing its interaction with leukocyte LFA-1 [24–25]. The expression of Eap and Emp is not only dependent on Fur but also on the global regulators Agr, SarA and Sae underscoring the diverse signals that direct biofilm formation [26].…”