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The aim of this study was to determine whether the severity of contact hypersensitivity reactions (CHSRs) can be observed by noninvasive in vivo optical imaging of matrix metalloproteinase (MMP) activity and whether this is an appropriate tool for monitoring an antiinflammatory effect. Acute and chronic CHSRs were elicited by application of a 1% trinitrochlorobenzene (TNCB) solution for up to five times on the right ear of TNCB-sensitized mice. N-Acetylcysteine (NAC)-treated and sham-treated mice were monitored by measuring ear swelling and optical imaging of MMP activity. In addition, we performed hematoxylin-eosin staining and CD31 immunohistochemistry for histopathologic analysis of the antiinflammatory effects of NAC. The ear thickness and the MMP activity increased in line with the increasing severity of the CHSR. MMP activity was enhanced 2.5- to 2.7-fold during acute CHSR and 3.1- to 4.1-fold during chronic CHSR. NAC suppressed ear swelling and MMP signal intensity in mice with acute and chronic CHSR. During chronic CHSR, the vessel density was significantly reduced in ear sections derived from NAC-treated compared to sham-treated mice. In vivo optical imaging of MMP activity measures acute and chronic CHSR and is useful to monitor antiinflammatory effects.

Elevated levels of High Density Lipoprotein (HDL) are correlated with decreased risk of cardiovascular disease. Much of this effect is attributed to the efflux of cellular cholesterol to HDL, reducing foam cell formation and atherosclerosis progression. HDL also has remarkable anti-inflammatory properties, for instance it can down-regulate adhesion molecule expression on endothelial cells, which may interfere with immune cell recruitment. Considering the important role of macrophages and Toll Like Receptors (TLRs) in sterile inflammatory conditions such as atherosclerosis, we directly investigated the effect of HDL on macrophage activation by TLR ligands. Here we show that HDL protects against TLR-driven, macrophage mediated liver damage in vivo and macrophage cytokine secretion in vitro. HDL does not affect upstream TLR signaling, but rather inhibits pro-inflammatory gene expression at the transcriptional level. Microarray analysis revealed that HDL strongly modulates macrophage transcription, and we identified ATF3, a transcriptional repressor of the CREB family of basic leucine zipper transcription factors, as a key mediator of HDL’s effects. HDL treatment increases ATF3 expression both in vitro and in vivo and increases occupancy of ATF3 at the promoters of its target genes. Consistent with these findings, the anti-inflammatory effects of HDL on TLR-mediated cytokine expression is lost in ATF3−/− macrophages. This work identifies a new biology for HDL as an inducer of the transcriptional modulator ATF3 and presents an opportunity to exploit endogenous molecules for therapeutic potential. [ABSTRACT FROM AUTHOR]