Saturday, March 27, 2010

bacteria regulate inflammation after skin injury


Scotty and the Haggis.

PubMed | The normal microflora of the skin includes staphylococcal species that will induce inflammation when present below the dermis but are tolerated on the epidermal surface without initiating inflammation. Here we reveal a previously unknown mechanism by which a product of staphylococci inhibits skin inflammation. This inhibition is mediated by staphylococcal lipoteichoic acid (LTA) and acts selectively on keratinocytes triggered through Toll-like receptor 3(TLR3). We show that TLR3 activation is required for normal inflammation after injury and that keratinocytes require TLR3 to respond to RNA from damaged cells with the release of inflammatory cytokines. Staphylococcal LTA inhibits both inflammatory cytokine release from keratinocytes and inflammation triggered by injury through a TLR2-dependent mechanism. To our knowledge, these findings show for the first time that the skin epithelium requires TLR3 for normal inflammation after wounding and that the microflora can modulate specific cutaneous inflammatory responses.


What is riveting here is their elucidation of not only the importance of host cellular responses to self-RNA in the context of wound repair but also the intriguing overlay of signals to influence this process from the colonizing microbiota that normally inhabit the skin.

Novel findings of this study have revealed the ability of keratinocytes to readily detect RNA released from dying cells during injury via Toll-like receptor 3 (TLR3), which triggers an acute inflammatory response contributing to wound repair. I find the second theme of the investigation by Lai et al. especially intriguing. Lipoteichoic acid produced by Staphylococcus epidermidis, bacteria that commonly inhabit the skin, can substantially attenuate this keratinocyte response through a TLR2-dependent inhibition of the TLR3 signaling via TNF receptor-associated factor 1 (TRAF1). Given that innate immunity mediates a delicate balancing act, this study should serve as a cornerstone to our emerging understanding of the multiple ways the mammalian host utilizes signals from colonizing microbiota to maintain homeostatic balance at surface epithelia. On the one hand, the multifaceted defense mechanisms of innate immunity must be ever ready to effectively deal with assault by noxious pathogens. On the other hand, the extent (or trigger point) for these proinflammatory responses may require attenuation to maintain homeostasis and avoid chronic inflammation. This investigation elucidates multiple molecular mechanisms that contribute to maintaining this balance, and finds that the dialogue between host cells and a prominent member of the colonizing microbiota is key to creating a measured response. From a different angle, the ability of several, but not all, lipoteichoic acid isoforms to inhibit keratinocyte responses, as shown here, might provide some pathogenic bacteria with a mechanism to subvert homeostatic pathways. The implications of the new findings established in this investigation will likely have relevance not only for understanding cutaneous wound repair, infection and chronic inflammatory disease but also for the biology of other mucosal surfaces.