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

J Clin Invest. 2012 May;122(5):1747-57. doi: 10.1172/JCI60688. Epub 2012 Apr 2.


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 PGE2 regulates many proinflammatory processes, including swelling and pain, and it is induced by LPS, we hypothesized that PGE2 mediates the local generation of edema following LPS exposure. Here, we show that tissue-resident DCs are the main source of PGE2 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 PGE2 biosynthesis. mPGES-1 activation, PGE2 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology
  • Antigens / metabolism
  • Biological Transport / immunology
  • Cells, Cultured
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Dinoprostone / biosynthesis
  • Edema / immunology
  • Edema / metabolism*
  • Edema / pathology
  • Enzyme Induction
  • Gene Expression Profiling
  • Gene Expression Regulation, Enzymologic
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharide Receptors / physiology*
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / metabolism
  • Lymph Nodes / immunology
  • Lymph Nodes / metabolism
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NFATC Transcription Factors / metabolism
  • NFATC Transcription Factors / physiology*
  • Prostaglandin-E Synthases
  • Real-Time Polymerase Chain Reaction
  • Skin / immunology
  • Skin / metabolism
  • Skin / pathology*
  • Transcription, Genetic


  • Antigens
  • Lipopolysaccharide Receptors
  • Lipopolysaccharides
  • NFATC Transcription Factors
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone