Thermal regulation of macrophage function during the inflammatory response and its impact on the progression of arthritis
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Macrophages respond to the danger signals following injury or infection and upon activation, release pro-inflammatory cytokines which help to generate an increase in body temperature, or fever. Macrophages are often exposed to elevated temperatures during inflammation. However, whether macrophages sense and respond to temperature change in a way that specifically regulates their function has not yet been clarified. In this study, we generated an aseptic endotoxin (LPS)-induced inflammatory response in BALB/c mice to study thermal effects on the functions of peritoneal macrophages at early (2-hour post LPS challenge) or late (3-day post LPS challenge) activation stages. These two stages are representative of the initiation and resolution phases of inflammation. Macrophages representing the early stage of activation were isolated from mice treated with mild heat treatment (HT, 39.5°C) and it was observed that they produce increased levels of TNF-α, IL-6 and IL-1β after in vitro LPS/IFN-γ re-stimulation compared to those cells isolated from mice maintained at room temperature. We also found that HT increased LPS-induced NF-κB activation. Importantly, HT-induced extracellular heat shock protein (HSP) 70 synergized with LPS to induce macrophage TNF-α production. These data suggest that in the initiation phase of inflammation, fever-range temperature can act as a stimulus to enhance macrophage functions. On the other hand, in macrophages representative of a late stage of activation, HT consistently resulted in lower levels of TNF-α and IL-6 after IFN-γ/LPS stimulation compared to cells maintained at 37oC. To explore the potential mechanisms underlying this negative regulation, we found that HT inhibited binding of NF-κB to the TNF-α promoter region. In addition, HT significantly suppressed IFN-γ receptor-mediated signaling pathway by inhibiting LPS/IFN-γ-induced IFN-γ receptor up-regulation and downstream STAT1 phosphorylation. We also observed an increase of heat shock factor 1 and HSP70 expression in the heat-treated cells in a time-dependent manner, and inhibition of HSP70 abrogated the thermal effects on cytokine production. These data suggest that for previously activated macrophages, fever-range temperature provides a negative signal to suppress their functions, especially cytokine production. Finally, this understanding of the effect of temperature on late stage macrophage function led us test if there is any beneficial effect of HT in reducing chronic inflammatory disease which is known to be driven by inappropriate macrophage activity. Using a murine collagen-induced arthritis (CIA) model, we found that administration of mild, HT significantly reduced arthritis disease severity. Surprisingly, HT is as effective as a well characterized pharmacological treatment, methotrexate. Overall, our results increase our understanding of the role of elevated temperature in regulation of the activation-stage specific functions of macrophages. They also provide additional information which contributes to the rationale for using heat treatment as a therapy for chronic inflammatory diseases.