Staphylococcus aureus biofilm-conditioned medium impairs macrophage-mediated anti-biofilm immune response by upregulating KLF2 expression

ABSTRACT

Staphylococcus aureus (S. aureus) infections associated with the formation of biofilm onto medical implants or host tissue play a critical role in the persistence of chronic infections. One critical mechanism of biofilm infection that leads to persistent infection lies in the capacity of biofilms to evade the macrophage-mediated innate immune response. It is now increasingly apparent that microorganisms exploit the negative regulatory mechanisms of pattern recognition receptor (PRR)-mediated inflammatory response to subvert host cell functions by using various virulence factors. However, the detailed molecular mechanism, along with the identity of a target molecule, underlying the evasion of macrophage-mediated innate immune response against S. aureus infection associated with biofilm formation remains to be elucidated. Here, using an in vitro culture model of murine macrophage-like RAW 264.7 cells, we demonstrated that S. aureus biofilm-conditioned medium significantly attenuated the capacity of macrophage bactericidal and proinflammatory responses. Importantly, the responses were associated with attenuated activation of NF-κB and increased expression of Kruppel-like factor 2 (KLF2) in RAW 264.7 cells. The siRNA-mediated silencing of KLF2 in RAW 264.7 cells could restore the activation of NF-κB towards the bactericidal activity and generation of pro-inflammatory cytokines in the presence of S. aureus biofilm-conditioned medium. Collectively, our results suggest that secreted factors from S. aureus biofilm might exploit the KLF2-dependent negative regulatory mechanism to subvert macrophage-mediated innate immune defense against S. aureus biofilm.