Do differentiated macrophages display profoundly different metabolic profiles, reflecting their different functions?

Macrophages have a wide range of immunological and non-immunological functions in the host, ranging from clearance of apoptotic cells, tissue remodelling, and release of pro and anti-inflammatory mediators at site of tissue damage or infection. Within these wide-ranging functions however, subsets of macrophages show unique phenotypic adaptations to their role. Studies on monocyte-derived cell lines have shown that these phenotypic differences are matched by underlying metabolic signatures, with the potential to have profound effects on cell capabilities. In order to determine whether differentiated macrophages displayed similar profound metabolic profiles, and whether these differences affect function, we differentiated primary blood monocytes under a range of culture oxygenation conditions. Initial results show significant differences in the metabolic profiles of M1 vs. M2 macrophages undergoing differentiation, with M1s displaying much reduced lactate levels, and corresponding increases in glucose suggestive of gluconeogenesis via putative PFKFB3 (fructose-1,6-bisphosphatase) activity. M1s were demonstrated to be constitutively active under reperfusion conditions, with no corresponding metabolic changes following LPS stimulation. M2s, in contrast, showed an expected hypoxia profile of increased lactate levels under differentiation, and remained inactive in reperfusion conditions, however production of IL-10 following LPS stimulation was shown to be significantly reduced in hypoxic conditions. A model of permissive inflammation during M1 infiltration and under hypoxia is suggested, with reperfusion and reduced recruitment driving resolution in normal tissues. However, in persistently hypoxic tissues or regions of aberrant recruitment and proliferation, the potential exists for differentiating macrophages to drive and maintain a chronic inflammatory state.


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