Macrophage Innate Training Induced by IL-4 and IL-13 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

Abstract

Macrophages are key innate immune cells for determining the outcome of Mycobacterium tuberculosis infection. Polarization with IFNγ and LPS into the “classically activated” M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating the bacterium. By contrast, “alternatively activated” M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 counterintuitively induces protective innate memory against mycobacterial challenge. This was associated with enhanced pro-inflammatory cytokine responses and killing capacity. Moreover, despite this switch towards a phenotype that is more akin to classical activation, IL-4 trained macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4 trained macrophages. Lastly, this work identifies that IL-10 negatively regulates protective IL-4 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

Resveratrol inhibits cytokine production in LPS-stimulated RAW264.7 cells potentially through TLR4/MyD88/NF-κB pathway

“…Resveratrol (Res) is a polyphenolic compound found naturally in many common food sources. This substance has been proposed to have a variety of therapeutic properties, including antioxidant, cardioprotective, antiviral, anti-aging, and anti-inflammatory effects (Holthoff et al, 2010).Many studies have indicated that Res can inhibit molecules related to the TLR4 signaling pathway, decrease proinflammatory cytokines and prevent inflammatory responses (Lundahl et al, 2022;Ma et al, 2017;Tong et al, 2019;Youn et al, 2005). NF-κB activation is strongly associated with inflammatory responses and other chronic diseases (Hayden & Ghosh, 2004).…”