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 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.

Therapeutic potential of a non-steroidal bifunctional anti-inflammatory and anti-cholinergic agent against skin injury induced by sulfur mustard

“…COX2 is known to play a critical role in skin inflammation. Signaling via PGE2 and its receptor induces vascular hyperpermeability and dermal edema (Rundhaug and Fischer, 2008; Zanoni et al , 2012; Morimoto et al , 2014). Our findings that inhibition of COX2 by NDH 4338 was associated with reduced edema and inflammation are consistent with a role for prostaglandins in vesicantinduced skin injury.…”

Toll-like receptor co-receptors as master regulators of the immune response

“…1). This activation of NFAT family members, in association with TLR4-dependent companion transcription factors, controls the expression of specific genes such as IL-2, Nur77 (Zanoni et al, 2009) and mPGES-1 (Zanoni et al, 2012a). The regulation of these genes affects many DC-related functions.…”

“…mPGES-1 is a key enzyme involved in PGE 2 biosynthesis. It has been demonstrated that local PGE 2 production by DCs is implicated in skin edema formation and in the control of free antigen delivery to draining lymph nodes (Zanoni et al, 2012a). The CD14-NFAT pathway controls the expression of IL-2, mPGES-1 and Nur77 (left).…”

“…Besides these non-transcriptional functions, specific http://dx.doi.org/10.1016/j.molimm.2014.05.008 0161-5890/© 2014 Elsevier Ltd. All rights reserved. TLR-co-receptors have recently been identified for their capacity to also exert transcriptional functions (Zanoni et al, 2009(Zanoni et al, , 2012a.…”

Microbe- and danger-induced inflammation

“…The TLR4 co-receptor CD14 possesses autonomous signalling capacities in DCs and it is able to induce Srcfamily kinases and phospholipase C gamma-2 (PLC␥2) activation, influx of extracellular calcium and calcineurin-dependent nuclear NFAT translocation (Zanoni et al, 2009). The activation of the NFAT pathway in DCs is required to control DC life cycle (Zanoni et al, 2009) and to regulate IL-2 and lipidic pro-inflammatory mediators production (Zanoni et al, 2012). Other PRRs such as DECTIN-1 can also trigger NFAT activation and IL-2 production (Goodridge et al, 2007).…”