Fever and the thermal regulation of immunity: the immune system feels the heat

Abstract

Fever is a cardinal response to infection that has been conserved in warm and cold-blooded vertebrates for over 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. Here, we review our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction as well as during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. Finally, we discuss the emerging evidence that suggests the adrenergic signalling pathways associated with thermogenesis shape immune cell function.

Effect of antipyretic analgesics on immune responses to vaccination

“…A recent review by Evans et al illustrated how thermal stress stimulates and augments the innate and adaptive immune responses. 78 Given the mixed antipyretic and anti-inflammatory effects of clinically available NSAIDs and other analgesics, studies to examine this question may be difficult to perform in humans, and animal studies using novel compounds and/or in vitro studies may be needed. However, one limitation of in vitro studies is that they may artificially simplify the immune response.…”

Behavioral fever in ectothermic vertebrates

“…This process occurs through behavioral regulation, which leads the animals to migrate to warmer environment. This phenomenon is known as behavioral fever and is defined as an acute increase of the final thermal preferendum driven by pathogen infection (Evans et al, 2015;Reynolds and Casterlin, 1982).…”

“…It is a cardinal symptom of many infectious and inflammatory diseases (Evans et al, 2015). This increase of temperature is part of an integrated physiological syndrome accompanied by neuroendocrine and behavioral modifications, which aimed to increase host survival mainly but not exclusively through enhancement of immune defenses (Roth and Blatteis, 2014).…”

“…by increasing the recruitment of neutrophils with elevated respiratory burst and by enhancing the phagocytic potential of macrophages and dendritic cells) and adaptive immunity (e.g. by increasing the rate of lymphocyte trafficking through lymphoid organs) (Evans et al, 2015;Launey et al, 2011). Beside these salutary aspects, fever is also a metabolically costly defensive response: (i) a rise of core temperature of 1 C is correlated with an increase of 10e12.5% of metabolic rate (Kluger, 1979); (ii) the oxygen consumption is increased notably in the brain and heart which could be detrimental for certain illnesses (Launey et al, 2011); finally, (iii) the risk of seizures is increased in youths (Reid et al, 2009).…”

From fever to immunity: A new role for IGFBP‐6?

“…Febrile temperatures (ie, ranging from 38‐41°C; ΔT~1‐4°C above baseline) boost the effectiveness of the immune response during infections by stimulating both the innate and adaptive arms of the immune system 11. Indeed, hyperthermia elicits neutrophil functions, DC maturation and DC ability to stimulate T cells, enhance T cell trafficking through lymph nodes and effector T cell differentiation.…”