TSLP acts on neutrophils to drive complement-mediated killing of methicillin-resistant Staphylococcus aureus

Abstract

Abstract Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections, often presenting as serious skin infections in otherwise healthy individuals, have become a world-wide epidemic problem and warrant attention for therapeutic intervention. Accordingly, defining the mechanisms that govern the activation and regulation of the immune response to MRSA is clinically important and could lead to the discovery of much needed rational targets for therapeutic manipulation. The cytokine thymic stromal lymphopoeitin (TSLP) is most well characterized as a major contributor to Th2-type responses in which it plays a deleterious role in the promotion of allergic responses. However, while TSLP is highly expressed at barrier surfaces, including the skin, its role in host-defense against bacterial infections has not been well elucidated. Unexpectedly, we found that TSLP can play a protective role in the skin by acting directly on mouse neutrophils to increase their killing of MRSA in both an in vitro killing assay and an in vivo skin infection model. Additionally, TSLP also directly acts on purified human blood neutrophils to reduce MRSA burden. Therefore, neutrophils represent previously unrecognized potent responders to TSLP. Surprisingly, we found that TSLP mediates these effects by directly engaging the complement C5 system to modulate reactive oxygen species production by neutrophils. Thus, TSLP increases MRSA killing in a neutrophil- and complement-dependent manner, revealing an unanticipated key connection between TSLP and the innate complement system. These data demonstrate an unrecognized beneficial role for TSLP in the skin, with potentially important clinical implications.