Commensal bacteria regulate Toll-like receptor 3–dependent inflammation after skin injury

Abstract

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 (TLR) 3. The significance of this is seen by observations 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. 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.

Regulation of immunity and disease resistance by commensal microbes and chromatin modifications during zebrafish development

“…Notably we observed that C3, like the other genes encoding antimicrobial effectors, showed similar expression levels in CONR and GF animals. This result was not unexpected, because fish surfaces comprise a large area of delicate epithelium, the major route of entry for pathogenic microorganisms; thus, healthy fish, as well as mammals, are capable of limiting infection effectively through the release of systemically expressed antimicrobial effectors that neutralize a broad range of microbes (64)(65)(66)(67). Indeed we speculate that these mechanisms are shared features among several phyla and constitute a primitive immune defense mechanism among a wide range of eukaryotic organisms.…”

Intradermal Delivery of TLR Agonists in a Human Explant Skin Model: Preferential Activation of Migratory Dendritic Cells by Polyribosinic-Polyribocytidylic Acid and Peptidoglycans

“…It is not clear if the effect of Poly I:C on DCs is solely caused by direct activation through TLR3/MDA5, as CD1a + DDCs express low levels of TLR3 but higher levels of MDA5, or indirectly. TLR3 and MDA5/RIG-I are also functionally expressed by keratinocytes and as such may have triggered the release of DC-activating cytokines that subsequently can induce DC maturation (20,21). Generalized increases in p-ERK expression in both LC and CD14 + DDC as well as in CD1a + DDC may argue in favor of the latter option.…”

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

“…Furthermore, absence of TLR2 may result in attenuated downstream signaling through MyD88, and consequent inflammation. [31][32][33]45 Taken together, these findings are best valued when recognizing that diabetes-induced TLR2 activation, signaling, and inflammation is undesirable in wounds and that genetic deficiency of TLR2 significantly abrogates the hyperinflammatory state of diabetic wounds. Future studies will focus on examining the role of the TLR2 on the increased inflammation in diabetic wounds on NOD and db/db genetic backgrounds, and will address the status of TLR2-mediated inflammation at intermediate time points (days 4 and 7 after wounding) to see the effects when granulation is maximal.…”