CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice

作者：Zanoni Ivan; Ostuni Renato; Barresi Simona; Di Gioia Marco; Broggi Achille; Costa Barbara; Marzi Roberta; Granucci Francesca^*

来源：Journal of Clinical Investigation, 2012, 122(5): 1747-1757.

DOI：10.1172/JCI60688

Inflammation is a multistep process triggered when innate immune cells for example, DCs sense a pathogen or injured cell or tissue. Edema formation is one of the first steps in the inflammatory response; it is fundamental for the local accumulation of inflammatory mediators. Injection of LPS into the skin provides a model for studying the mechanisms of inflammation and edema formation. While it is known that innate immune recognition of LPS leads to activation of numerous transcriptional activators, including nuclear factor of activated T cells (NFAT) isoforms, the molecular pathways that lead to edema formation have not been determined. As PGE(2) regulates many proinflammatory processes, including swelling and pain, and it is induced by LPS, we hypothesized that PGE(2) mediates the local generation of edema following LPS exposure. Here, we show that tissue-resident DCs are the main source of PGE(2) and the main controllers of tissue edema formation in a mouse model of LPS-induced inflammation. LPS exposure induced expression of microsomal PGE synthase-1 (mPGES-1), a key enzyme in PGE(2) biosynthesis. mPGES-1 activation, PGE(2) production, and edema formation required CD14 (a component of the LPS receptor) and NFAT. Therefore, tissue edema formation induced by LPS is DC and CD14/NFAT dependent. Moreover, DCs can regulate free antigen arrival at the draining lymph nodes by controlling edema formation and interstitial fluid pressure in the presence of LPS. We therefore suggest that the CD14/NFAT/mPGES-1 pathway represents a possible target for antiinflammatory therapies.

• 出版日期2012-5