Thermoneutrality and Immunity: How Does Cold Stress Affect Disease?

Abstract

One of the major challenges the scientific community faces today is the lack of translational data generated from mouse trials for human health application. Housing temperature-dependent chronic cold stress in laboratory rodents is one of the key factors contributing to lack of translatability because it reveals major metabolic differences between humans and rodents. While humans tend to operate at temperatures within their thermoneutral zone, most laboratory rodents are housed at temperatures below this zone and have an increased energy demand to generate heat. This has an impact on the immune system of mice and thus affects results obtained using murine models of human diseases. A limited number of studies and reviews have shown that results obtained on mice housed at thermoneutrality were different from those obtained from mice housed in traditional housing conditions. Most of those studies, focused on obesity and cancer, found that housing mice at thermoneutrality changed the outcomes of the diseases negatively and positively, respectively. In this review, we describe how thermoneutrality impacts the immune system of rodents generally and in the context of different disease models. We show that thermoneutrality exacerbates cardiovascular and auto-immune diseases; alleviates asthma and Alzheimer's disease; and, changes gut microbiome populations. We also show that thermoneutrality can have exacerbating or alleviating effects on the outcome of infectious diseases. Thus, we join the call of others in this field to urge researchers to refine murine models of disease and increase their translational capacity by considering housing at thermoneutrality for trials involving rodents.

Keywords: body temperature; immune functions; immunity; infectious diseases; metabolism; murine model; thermoneutrality.

Figure 1

The non-shivering thermogenesis activation pathway. Cold stress is sensed by the brain (A) and signals the sympathetic nervous system to release norepinephrine (NE) (B) that interact with b-adrenergic receptor (b-AR) on brown adipocytes (C). As a result, triglycerides (TAG) are broken down to free fatty acids (FFA) (D) that interact with uncoupling protein-1 (UCP-1) (E) to induce the mitochondria to generate heat (E). The thyroid hormone (TH) plays a role in the cold stress (F) sensor region of the brain (G).

Figure 2

Changes in mouse metabolism and diseases at thermoneutral (TT) compared to suboptimal temperatures (ST). In order to maintain their core body temperatures (CBT) mice have to increase and decrease their metabolic activity to increase or decrease thermogenesis at ST compared to TT, respectively. This can decrease or increase the metabolic activity of their immune cells and have alleviating (red arrow) or exacerbating (green arrow) effects on various disease models. In the case of infectious diseases both can occur depending on the type of pathogen.