Inflammatory macrophages in patients with fatigue

Abstract

Background: Hyperinflammatory, so-called M1 macrophages play a major role in chronic inflammatory diseases often linked to impaired well-being as well as fatigue and sarkopenia. Cytokines such as IL-1, IL-6 play a role in polarizing the differentiation into M1 macrophages and simultanously inhibit the differentiation of anti-inflammatory M2 macrophages. Methods: We enriched blood derived macrophages from peripheral blood and characterized their phenotypes by flow cytometry. The purinergic receptor P2 × 7 was tested by patch clamping and ion flux measurement. Microparticle and exosome release was induced by exogenous ATP-stimulation and qualified by trans-electorn microscopy as well as by nanosizer measurements. Results: M1 macrophages typically lacked surface CD163 and P2 × 7, but M2 macrophages expressed both markers. ATP stimulation induced cell death in M1 but microparticle and exosome release in M2 macrophages. Ion channel measurement confirmed the hypersensitivity of M1 and impaired ion flux by ATP. These result imply that chronic inflammatory diseases linked to highly elevated M1 type macrophages are highly sensitive to exogenous ATP, the most important danger signal in physical and psychiatric trauma. By contrast, anti-inflammatory, M2 macrophages mediate Calcium-signaling and exosome release upon ATP stimulation. MiRNA expression analysis further demonstrated that Let7b-5p discriminates between M1 and M2 macrophage polarization. Conclusion: M1 macrophage and microglia polarization may explain the detrimental response against ATP related trauma in a number of inflammatory conditions which may fuel into fatigue and sarkopenia.