Acidosis differently modulates the inflammatory program in monocytes and macrophages

• Published in: Biochimica et biophysica acta 2016-01, Vol.1862 (1), p.72-81
• Main Authors: Riemann, Anne, Wußling, Hanna, Loppnow, Harald, Fu, Hang, Reime, Sarah, Thews, Oliver
• Format: Article
• Language: English
• Subjects: Acidosis; Acidosis - complications; Acidosis - immunology; Animals; Cells, Cultured; Chemokine CCL2 - immunology; Cyclooxygenase 2 - immunology; Humans; Immune cell function; Inflammation; Inflammation - complications; Inflammation - immunology; Inflammation Mediators - immunology; Macrophages; Macrophages - immunology; Mice; Monocytes - immunology; Nitric Oxide Synthase Type II - immunology; p38 Mitogen-Activated Protein Kinases - immunology; Phagocytosis; RAW 264.7 Cells; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2015.10.017

Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1ß, IL-6, TNF-α, MCP-1, COX-2 and osteopontin. In primary human monocytes MCP-1 and TNF-α were reduced but COX-2 and IL-6 were increased. In RAW264.7 macrophage cell line IL-1ß, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. For primary human monocyte-derived macrophages the regulation of inflammatory markers by acidosis depended on activation state, except for the acidosis-induced downregulation of MCP-1 and TNF-α. Acidosis affected functional immune cell behavior when looking at phagocytic activity which was increased in a time-dependent manner, but cellular motility was not changed. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells and this activation was critical for the induction of IL-1ß, COX-2 and iNOS expression. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity. [Display omitted] •Acidosis regulates inflammatory programs depending on immune cell differentiation.•In macrophages acidosis increases the expression of COX-2 and iNOS.•This increase is due to p38 activation in murine macrophages by acidosis.•In macrophages acidosis enhances functional phagocytic activity.•TNF-α and MCP-1 expression was generally reduced by acidosis.