Abstract 472: PPARγ-agonist Rosiglitazone Modulates Macrophage Proliferation, Polarization, and Inflammatory Function

Background: Macrophages are central to the initiation, progression, and repair of inflammation. Rosiglitazone (Rosi), an antidiabetic thiazolidinedione (TZD), is a PPAR-γ agonist. Although TZDs improve certain cardiovascular risk factors and surrogate endpoints, they do not appear to reduce major cardiovascular events, and cardiovascular risk of Rosi has been a particular concern. Previously undetected effects on macrophages could provide a more nuanced understanding of how Rosi and other TZDs impact inflammation. Results: To this end, we have characterized the effects of Rosi on bone marrow-derived macrophages (BMMs) in vitro . M2-polarized BMMs express canonical mRNA markers, IL10 and Ym1. In this system, compared to polarized untreated cells and M2s treated with 1μM of the TZD Pioglitazone (Pio), M2s treated with 1μM Rosi express lower levels of anti-inflammatory M2 markers (IL10: 0.07 ± 0.01 for Rosi vs. 0.73 ± 0.04 for untreated vs. 1.00 ± 0.06 a.u. for Pio; Ym1: 0.06 ± 0.00 for Rosi vs. 0.81 ± 0.06 for untreated vs. 1 ± 0.04 a.u. for Pio). M2s polarized in the presence of Rosi express diminished protein levels of the M2 marker CD206 when compared to untreated M2s (Rosi 0.44 vs. untreated 1.00 a.u.). Culture of marrow with BMM-differentiating media in the presence of Rosi increased proliferation compared to untreated marrow and to marrow treated with Pio or the PPARγ antagonist GW9662, as measured by cell counts (Rosi 189 ± 19% relative to untreated BMM counts; Pio 115 ± 4%; GW9662 103 ± 4%; n=4, p < 0.001). There was no significant difference in monocyte-to-macrophage differentiation. Mature BMMs showed greater increase in cell counts with Rosi when compared to untreated BMMs or those treated with Pio or GW9662 (Rosi +70 ± 7%, untreated +2 ± 1%, Pio +24 ± 10%, GW9662 +8 ± 5%, n=3, p < 3 x 10 -3 ). In an in vitro system of efferocytosis, macrophages differentiated in the presence of Rosi show impaired uptake of apoptotic foam cells in comparison to untreated BMMs (Rosi 0.77 vs. untreated 1.00 a.u.). Conclusion: Overall, we find that rosiglitazone, more than pioglitazone, increases macrophage proliferation and reduces anti-inflammatory markers and effector functions. Future work will seek to delineate the mechanism of this apparent inflammatory effect on macrophages.