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

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

Body temperature regulation determines immune reactions and species longevity

Temperature variations in various species have marked changes in body metabolism with higher temperatures associated with increased ageing. The observation that diets with calorie restriction are associated with species longevity are now related to the heat shock genes and body temperature regulation. Temperature increases that induce temperature dysregulation are connected to non alcoholic fatty liver disease (NAFLD) and the induction of diabetes and neurodegenerative diseases. Specific microRNAs are associated with heat shock gene regulation and override body temperature regulation relevant to adipose tissue-liver defects and insulin resistance. In geriatrics and diabetics complete heat shock gene inactivation is associated with mitochondrial apoptosis relevant to defective hepatic dietary fat and drug metabolism. The connections between core body temperature defects and autoimmune disease have now become important to determine programmed cell death in many cells and tissues with relevance to the global chronic disease epidemic and species survival

Stress-induced rise in body temperature is repeatable in free-ranging Eastern chipmunks (Tamias striatus)

In response to handling or other acute stressors, most mammals, including humans, experience a temporary rise in body temperature (T b). Although this stress-induced rise in T b has been extensively studied on model organisms under controlled environments, individual variation in this interesting phenomenon has not been examined in the field. We investigated the stress-induced rise in T b in free-ranging eastern chipmunks (Tamias striatus) to determine first if it is repeatable. We predicted that the stress-induced rise in T b should be positively correlated to factors affecting heat production and heat dissipation, including ambient temperature (T a), body mass (M b), and field metabolic rate (FMR). Over two summers, we recorded both T b within the first minute of handling time (T b1) and after 5 min of handling time (T b5) 294 times on 140 individuals. The mean ∆T b (T b5 – T b1) during this short interval was 0.30 ± 0.02°C, confirming that the stress-induced rise in T b occurs in chipmunks. Consistent differences among individuals accounted for 40% of the total variation in ∆T b (i.e. the stress-induced rise in T b is significantly repeatable). We also found that the stress-induced rise in T b was positively correlated to T a, M b, and mass-adjusted FMR. These results confirm that individuals consistently differ in their expression of the stress-induced rise in T b and that the extent of its expression is affected by factors related to heat production and dissipation. We highlight some research constraints and opportunities related to the integration of this laboratory paradigm into physiological and evolutionary ecology