The nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide dampens lipopolysaccharideinduced transcriptomic changes in macrophages

M.C; MUÑOZ, M.D.; MARÍA CECILIA DELLAVEDOBA; BARRERAS, FS; DOUGLAS GANINI DA SILVA; MASON RP; ZILI ZHAI; DARIO C RAMIREZ; SANDRA E. GOMEZ MEJIBA

INFLAMMATION RESEARCH

BIRKHAUSER VERLAG AG

Lugar: BASEL; Año: 2018

1023-3830

M1-like inflammatory phenotype of macrophages plays a critical role in tissue damage in chronicinflammatory diseases. Previously, we found that the nitrone spin trap 5,5-dimethyl-1-pirrolineN-oxide (DMPO) dampens lipopolysaccharide (LPS)-triggered inflammatory priming ofRAW264.7 cells. Herein, we tested whether DMPO by itself can induce changes in macrophagetranscriptome, and that these effects may prevent LPS-induced activation of macrophages. To testour hypothesis, we performed a transcriptomic and bioinformatics analysis in RAW264.7 cellsincubated with or without LPS, in the presence or in the absence of DMPO. Functional dataanalysis showed 79 differentially expressed genes (DEGs) when comparing DMPO vs Control.We used DAVID databases for identifying enriched gene ontology terms and Ingenuity PathwayAnalysis for functional analysis. Our data showed that DMPO vs Control comparison DEGs arerelated to downregulation immune-system processes among others. Functional analysis indicatedthat interferon-response factor 7 and toll-like receptor were related (predicted inhibitions) to theobserved transcriptomic effects of DMPO. Functional data analyses of the DMPO+LPS vs LPSDEGs were consistent with DMPO dampening LPS-induced inflammatory transcriptomic profilein RAW 264.7. These changes were confirmed using Nanostring technology. Taking together ourdata, surprisingly, indicates that DMPO by itself affects gene expression related to regulation ofimmune system and that DMPO dampens LPS-triggered MyD88- and TRIF-dependent signalingpathways. Our research provides critical data for further studies on the possible use of DMPO asa structural platform for the design of novel mechanism-based anti-inflammatory drugs.