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Banete, Andra
polarized macrophages , virus , LCMV , interleukin-4 , antiviral , R848
Macrophages (Mφ) are innate immune sentinels that can acquire highly heterogeneous phenotypes depending on their cytokine microenvironment. Mφ exhibit distinct activation patterns across a continuum from pro-inflammatory (M1), associated with the Th1 cytokine IFNγ, to anti-inflammatory (M2a), associated with the Th2 cytokine IL-4. However, emerging evidence indicates that IL-4 can play a role in promoting inflammation in certain conditions. In asthma and allergic inflammation, IL-4 mediates pro-inflammatory responses which lead to tissue damage. Consequently, other co-factors and cytokines present in the microenvironment greatly influence the effect of IL-4 on the outcome of the immune responses. As Mφ play a crucial role in regulating innate and adaptive immunity, their activation status directly influences the outcome of viral infections. However, little is known about the responses of M2a Mφ to viral infections. To this end, we first characterized the murine Mφ cell line BMA as a model for in vitro polarization. We found that that the BMA cell line can be polarized into M1/M2 phenotypes, and can therefore be used as a model for in vitro Mφ polarization reducing the need for primary Mφ isolation when investigating biological phenomena related to their polarization. Next, we characterized the signal pathways induced by different lengths of treatment with IL-4 utilizing primary spleen-derived Mφ (SpM). We report that sustained priming with IL-4 alone promotes an antiviral response in Mφ, and enhances pro-inflammatory responses to TLR7 stimulation using R848 (resiquimod). Finally, we investigated the response of activated SpM to lymphocytic choriomeningitis virus (LCMV) infection. Following infection, polarized Mφ show an increased resistance to LCMV infection. We show for the first time that the altered resistance of M1 and M2a Mφ occurs through distinct signaling mechanisms, possibly due to shifts in their immunometabolism. The results presented in this thesis highlight the need for better understanding IL-4 pro-inflammatory functions and its potential use as an immunotherapeutic. It may be used as a broad-acting antiviral in combination with R848 or other therapies to target the innate arm of immunity against emerging infections. Furthermore, understanding the mechanism through which IL-4 regulates inflammation may reveal new treatments for chronic inflammatory disorders.
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