Elevation in Body Temperature to Fever Range Enhances and Prolongs Subsequent Responsiveness of Macrophages to Endotoxin Challenge

Chen-Ting Lee,Thomas A. Mace,Lingwen Zhong,Elizabeth A. Repasky,Edward Harhaj

doi:10.1371/journal.pone.0030077

Abstract

Macrophages are often considered the sentries in innate immunity, sounding early immunological alarms, a function which speeds the response to infection. Compared to the large volume of studies on regulation of macrophage function by pathogens or cytokines, relatively little attention has been devoted to the role of physical parameters such as temperature. Given that temperature is elevated during fever, a long-recognized cardinal feature of inflammation, it is possible that macrophage function is responsive to thermal signals. To explore this idea, we used LPS to model an aseptic endotoxin-induced inflammatory response in BALB/c mice and found that raising mouse body temperature by mild external heat treatment significantly enhances subsequent LPS-induced release of TNF-α into the peritoneal fluid. It also reprograms macrophages, resulting in sustained subsequent responsiveness to LPS, i.e., this treatment reduces “endotoxin tolerance” in vitro and in vivo. At the molecular level, elevating body temperature of mice results in a increase in LPS-induced downstream signaling including enhanced phosphorylation of IKK and IκB, NF-κB nuclear translocation and binding to the TNF-α promoter in macrophages upon secondary stimulation. Mild heat treatment also induces expression of HSP70 and use of HSP70 inhibitors (KNK437 or Pifithrin-µ) largely abrogates the ability of the thermal treatment to enhance TNF-α, suggesting that the induction of HSP70 is important for mediation of thermal effects on macrophage function. Collectively, these results support the idea that there has been integration between the evolution of body temperature regulation and macrophage function that could help to explain the known survival benefits of fever in organisms following infection.

Highlights

A primary function of macrophages is to remove cellular debris generated during normal tissue function while following tissue injury or infection, macrophages can respond rapidly to various ‘‘alarm’’ signals generated from inflamed sites and become activated to release pro-inflammatory mediators [1,2,3]
To identify the cellular source of cytokine production in vivo, we injected LPS intraperitoneally into BALB/c mice which received heat treatment (HT) to help increase their body temperature or into mice which were maintained under standard room temperature conditions (RT,22–24uC) for 2 hours
We used a mouse model of LPS-induced inflammation to dissect the role of elevated body temperature in regulation of macrophage cytokine production

Summary

Introduction

A primary function of macrophages is to remove cellular debris generated during normal tissue function while following tissue injury or infection, macrophages can respond rapidly to various ‘‘alarm’’ signals generated from inflamed sites and become activated to release pro-inflammatory mediators [1,2,3]. Production of pro-inflammatory cytokines by resident macrophages in turn promotes the recruitment of neutrophils and inflammatory monocytes/macrophages to the inflamed region [6] Integrated actions among these immune phagocytes help to eliminate pathogens, repair damaged tissues, initiate an adaptive immune response, and most importantly, restore tissue homeostasis [6,7,8]. While the biological significance of fever is a topic of long-lasting debate, it is important to note that many studies have revealed a significantly positive relationship between elevated temperatures and improved survival rate following infection [9,14,15,16]. It is clear from these earlier studies that the improved survival seen following fever is not due to thermal suppression of bacterial growth [16]

Methods

Results

Conclusion