Journal Article

Cigarette Smoking Decreases Global MicroRNA Expression in Human Alveolar Macrophages

Gross, Thomas J., Kim, Jongkwang, Wilson, Mary E., Hassan, Ihab H., Kremens, Karol, Reisetter, Anna C., Powers, Linda S., Monick, Martha M., Dickson, Anne M., Graff, Joel W.

2012

Overview

Human alveolar macrophages are critical components of the innate immune system. Cigarette smoking-induced changes in alveolar macrophage gene expression are linked to reduced resistance to pulmonary infections and to the development of emphysema/COPD. We hypothesized that microRNAs (miRNAs) could control, in part, the unique messenger RNA (mRNA) expression profiles found in alveolar macrophages of cigarette smokers. Activation of macrophages with different stimuli in vitro leads to a diverse range of M1 (inflammatory) and M2 (anti-inflammatory) polarized phenotypes that are thought to mimic activated macrophages in distinct tissue environments. Microarray mRNA data indicated that smoking promoted an \"inverse\" M1 mRNA expression program, defined by decreased expression of M1-induced transcripts and increased expression of M1-repressed transcripts with few changes in M2-regulated transcripts. RT-PCR arrays identified altered expression of many miRNAs in alveolar macrophages of smokers and a decrease in global miRNA abundance. Stratification of human subjects suggested that the magnitude of the global decrease in miRNA abundance was associated with smoking history. We found that many of the miRNAs with reduced expression in alveolar macrophages of smokers were predicted to target mRNAs upregulated in alveolar macrophages of smokers. For example, miR-452 is predicted to target the transcript encoding MMP12, an important effector of smoking-related diseases. Experimental antagonism of miR-452 in differentiated monocytic cells resulted in increased expression of MMP12. The comprehensive mRNA and miRNA expression profiles described here provide insight into gene expression regulation that may underlie the adverse effects cigarette smoking has on alveolar macrophages.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Abundance / Adult / Alveoli / Biology / Cancer / Cell activation / Chronic obstructive pulmonary disease / Cigarette smoking / Cigarettes / Critical components / Databases, Genetic / Development and progression / DNA microarrays / Down-Regulation - genetics / Emphysema / Female / Gene expression / Gene Expression Profiling / Gene Expression Regulation / Gene regulation / Genetic aspects / Health aspects / Humans / Immune system / Immunology / Inflammation / Innate immunity / Lung diseases / Macrophages / Macrophages, Alveolar - metabolism / Male / Matrix Metalloproteinase 12 - genetics / Matrix Metalloproteinase 12 - metabolism / Medicine / MicroRNA / MicroRNAs / MicroRNAs - genetics / MicroRNAs - metabolism / Middle Aged / miRNA / Monocytes / Pathogens / Physiological aspects / Polymerase chain reaction / Reproducibility of Results / Respiratory diseases / Ribonucleic acid / RNA / RNA, Messenger - genetics / RNA, Messenger - metabolism / Smoking / Smoking - adverse effects / Smoking - genetics / Tissue Donors / Transcription / Up-Regulation - genetics / Wilson, Martha