Formation of eicosanoids and other oxylipins in human macrophages

In this review it is attempted to summarize current studies about formation of eicosanoids and other oxylipins in different human macrophages. There are several reports on M1 and M2 cells, also other phenotypes have been described. The eicosanoids formed in the largest amounts are the COX products TxB₂ and PGE₂. Thus shortlived bioactive TxA₂ is a dominating product both in M1- and in M2-lineages, one exception seems to be M_{GM-CSF, TGFβ} cells. 5-LOX products are produced in both M1 and M2 macrophages, as well as in not fully polarized cells of both lineages. M_M-CSF as well as M2 macrophages produced LTC₄ more readily compared to M1 lineage cells. In M_{GM-CSF, TGFβ} cells LTB₄ is a major eicosanoid, in line with high expression of LTA₄ hydrolase. Recent reports described increased formation of leukotrienes in macrophages subjected to trained immunity with inflammatory transcriptional reprogramming. Also in macrophages derived from monocytes collected from post-COVID-19 patients. 15-LOX-1 is strongly upregulated in CD206⁺ M2 cells (M2a), differentiated in presence of IL-4. These macrophages also express 15-LOX-2. In incubations with pathogenic E. coli as well as other stimuli 15(S)-HETE and 17(S)-HDHA were major oxylipins formed. Also, the SPM precursor 5,15-diHETE and the SPM RvD5 were produced in considerable amounts, while other SPMs were less abundant. In M2 macrophages incubated with E. coli or S. aureus the cytosolic 15-LOX-1 enzyme accumulated to punctuate structures in a Ca²⁺ dependent manner with a relatively slow time course, leading to formation of mediators from endogenous substrate. Chalcones, flavone-like anti-inflammatory natural products, induced translocation of 15-LOX-1 in M2 cells, with high formation of 15-LOX derived oxylipins.