CD14 and NFAT mediate lipopolysaccharide-induced skin edema formation in mice
Ivan Zanoni, Renato Ostuni, Simona Barresi, Marco Di Gioia, Achille Broggi, Barbara Costa, Roberta Marzi, Francesca Granucci
Ivan Zanoni, Renato Ostuni, Simona Barresi, Marco Di Gioia, Achille Broggi, Barbara Costa, Roberta Marzi, Francesca Granucci
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Research Article Immunology

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

Abstract

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.

Authors

Ivan Zanoni, Renato Ostuni, Simona Barresi, Marco Di Gioia, Achille Broggi, Barbara Costa, Roberta Marzi, Francesca Granucci

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Figure 4

DCs regulate LPS-induced tissue edema formation through CD14-dependent and NFAT-dependent mPGES-1 expression.

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DCs regulate LPS-induced tissue edema formation through CD14-dependent a...
(A) Inflammatory swelling in the footpads of WT and Cd14–/– mice at the indicated time points after s.c. injection of LPS (20 μg/footpad). (B) Inflammatory swelling in the footpads of WT mice treated with LPS and pretreated or not with FK-506. (C) Inflammatory swelling in the footpads of CD14-deficient mice induced by LPS, LPS plus thapsigargin, or PGE2 alone (10 nM). (D) Inflammatory footpad swelling induced by LPS in mice pretreated or not with the COX-2 inhibitor. Data represent 2 independent experiments with 5 mice per group. Means and SEM are shown. *P < 0.05; **P < 0.005; ***P < 0.0005; ****P < 0.00005.