Dormant 5-lipoxygenase in inflammatory macrophages is triggered by exogenous arachidonic acid (original) (raw)

The differentiation of resident tissue macrophages from embryonic precursors and that of inflammatory macrophages from bone marrow cells leads to macrophage heterogeneity. Further plasticity is displayed through their ability to be polarized as subtypes M1 and M2 in a cell culture microenvironment. However, the detailed regulation of eicosanoid production and its involvement in macrophage biology remains unclear. Using a lipidomics approach, we demonstrated that eicosanoid production profiles between bone marrow-derived (BMDM) and peritoneal macrophages differed drastically. In polarized BMDMs, M1 and M2 phenotypes were distinguished by thromboxane B 2 , prostaglandin (PG) E 2 , and PGD 2 production, in addition to lysophospholipid acyltransferase activity. Although Alox5 expression and the presence of 5-lipoxygenase (5-LO) protein in BMDMs was observed, the absence of leukotrienes production reflected an impairment in 5-LO activity, which could be triggered by addition of exogenous arachidonic acid (AA). The BMDM 5-LO regulatory mechanism was not responsive to PGE 2 /cAMP pathway modulation; however, treatment to reduce glutathione peroxidase activity increased 5-LO metabolite production after AA stimulation. Understanding the relationship between the eicosanoids pathway and macrophage biology may offer novel strategies for macrophage-associated disease therapy. Mononuclear phagocytes such as monocytes, macrophages, dendritic cells, and their bone marrow progenitors, play a major role in inflammation by eliminating pathogens and producing soluble mediators 1. The manifold origins of macrophages are well described in mouse 2 , wherein it is postulated that the resident tissue macrophages (Res-MAs), such as from the peritoneum (PM), are not differentiated from blood monocytes but rather originate from an embryonic precursor and are maintained by self-renewal 3, 4. However, under inflammatory conditions, infiltrating monocytes from bone marrow progenitors are also found that can differentiate into inflammatory macrophages (Infl-MAs) 5. Accordingly, bone marrow-derived macrophages (BMDMs), which are derived from bone marrow cells cultured in vitro in the presence of growth factors, represent a useful system for the investigation of Infl-MA functions 6. Subsequently, the phenotype of macrophages can be polarized by the microenvironment 7. Essentially, macrophages can modify their functions between M1 macrophages (activated by interferon γ (IFN-γ), interleukin (IL)-1β, and lipopolysaccharide (LPS)) to produce inflammatory mediators; and M2 macrophages that mediate tissue repair injury and produce anti-inflammatory factors (activated by IL-4, IL-13, and the immune-complexes) 8. Previous studies on macrophage systems to define such phenotypes and their roles in immunology has been based mostly on cytokine and chemokine profiles. Instead, the eicosanoid pattern has been demonstrated on macrophage subsets, detailed biochemistry pathway relating to eicosanoid production and function may also play specific roles within the larger context of macrophage biology.