Abstract
Skin serves not only as a protective barrier to microbial entry into the body but also as an immune organ. The outer layer, the epidermis is composed predominantly of keratinocytes, which can be stimulated to produce pro-inflammatory mediators. Although some inflammation is useful to defend against infection, excessive or persistent inflammation can lead to the development of inflammatory skin diseases, such as psoriasis, a common skin disorder affecting approximately 2% of the US population. We have previously found that phosphatidylglycerol (PG) derived from soy can inhibits inflammation in a contact irritant ear edema mouse model. Here we investigated the ability of soy PG to inhibit inflammatory mediator expression in response to activators of the pattern recognition receptors, toll-like receptor-2 (TLR2) and -4 (TLR4). We found that in epidermal keratinocytes soy PG inhibited TLR2 and TLR4 activation and inflammatory mediator expression in response to a synthetic triacylated lipopeptide and lipopolysaccharide, respectively, as well as an endogenous danger-associated molecular pattern. However, at higher concentrations soy PG alone enhanced the expression of some pro-inflammatory cytokines, suggesting a narrow therapeutic window for this lipid. Dioleoylphosphatidylglycerol (DOPG), but not dioleoylphosphatidylcholine, exerted a similar inhibitory effect, completely blocking keratinocyte inflammatory mediator expression induced by TLR2 and TLR4 activators, as well as NFκB activation in a macrophage cell line (RAW264.7); however, DOPG was not itself pro-inflammatory even at high concentrations. Further, DOPG had no effect on NFκB activation in response to a TLR7/8 agonist. Our results suggest that DOPG could be used to inhibit excessive skin inflammation.
SIGNIFICANCE STATEMENT Although inflammation is beneficial for clearing an infection, in some cases the infection can be excessive and/or become chronic thereby resulting in considerable tissue damage and pathological conditions. We show here that the phospholipid, phosphatidylglycerol can inhibit the activation of toll-like receptors 2 and 4 of the innate immune system, as well as downstream inflammatory mediator expression, in response to microbial components (synthetic or natural) in the epidermal keratinocytes that form the skins physical barrier.
- The American Society for Pharmacology and Experimental Therapeutics