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Benso, Lia

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Benso

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Benso, Lia

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    Differential Function of in Vitro Generated Macrophages From Systemic Lupus Erythematosus and Non-Diseased Peripheral Blood Mononuclear Cells
    (2016-05-02) Benso, Lia; Alves, Stephen; Denkin, Steven
    Macrophages are a major type of tissue resident phagocytic cell that help orchestrate the innate immune response (through recognition to highly conserved pathogens) as well as facilitate the adaptive immune response (through antigen presentation and chemokine/cytokine secretion) at the site of inflammation or insult. Macrophages are derived from circulating monocytes, and migrate into tissues via chemokine signaling. They are characterized by two major subtypes; M1 macrophages secrete IL-6, TNFα, and IFNγ in a pro-inflammatory Th1 mediated response. In the context of a Th2 anti-inflammatory response, M2 macrophages are characterized by secretion of IL-10. The phagocytizing capability of these cells has been found to vary between the polarization states, with M2 macrophages characterized as having increased phagocytizing ability compared to M1. In systemic lupus erythematosus (SLE), there is evidence of ineffective or dysfunctional clearance of apoptotic cells by monocytes which contributes to tissue damage and inflammation, yet macrophages in particular have not been a cellular target for therapies as of yet. Recent studies have compared various in vitro macrophage differentiation protocols in normal healthy donors (NHD) in order to characterize the phenotypes and recapitulate what is known about macrophage function in vivo (Mia et al., 2014)(Vogel at al., 2014). To our knowledge, a comparison of macrophage polarization conditions, either long or short term has not been performed in SLE patient macrophages, and may help to inform and understand the pathologic role of macrophages as a target cell for the treatment of SLE. In this series of studies, we tested and characterized several macrophage differentiation protocols in NHD samples to establish a robust phenotype based on cell marker expression and functional response to toll-like receptor (TLR) ligands. We compared NHD to SLE macrophages based on gene expression and TLR response. We then tested soluble effects of SLE serum on macrophage polarization as well as downstream effects on T cells. We find that despite a traditional, long differentiation protocol, SLE macrophages did not behave comparably to NHD macrophages based on gene expression analysis and response to TLR ligands, as the SLE M1 macrophages had a dampened proinflammatory response in the assay system tested. Perhaps more interestingly, the SLE M2 macrophages had decreased characteristic M2 markers as well. NHD T cell gene expression indicated functional differences when co-cultured with autologous M1 or M2 macrophages in the presence of NHD or SLE serum as well. We conclude that within the sample population assayed, there are differential functional characteristics of SLE macrophages that remain despite the addition of exogenous growth factors and that the relationship between macrophages and T cells is altered in a diseased state.