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Cold exposure: Human immune responses and intracellular cytokine expression

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Abstract

It is commonly believed that exposure to cold environmental temperatures depresses immune function and increases the risk for infection. This review paper will 1) present an overview of human physiological responses to cold exposure, 2) present the human studies examining the effects of cold exposure on immune responses, and 3) summarize recent experiments from our laboratories examining the effects of exercise and fatigue on immune responses during subsequent cold exposure. Based on the review of the literature, there is no support for the concept that cold exposure depresses immune function.
... All the GO terms were related to migrations of white blood cell subtypes such as leukocyte migration (Table 3); thus, molecules involved in immune functions may be activated by the cold exposure experiments. In fact, it has been reported that acute mild cold stress may affect the proliferation of several white blood cell subtypes although effects of the proliferation on host defense remain unknown [49]. Incidentally, the expression change in the CD177 molecule (CD177) gene was the most statistically significant (FDR = 6.46×10 -5 ) in the differential expression analysis. ...
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Background: Physiological thermoregulatory systems in humans have been a key factor for adaptation to local environments after their exodus from Africa, particularly, to cold environments outside Africa. Recent studies using high-throughput sequencing have identified various genes responsible for cold adaptation. However, the molecular mechanisms underlying initial thermoregulation in response to acute cold exposure remain unclear. Therefore, we investigated transcriptional profiles of six young Japanese male adults exposed to acute cold stress. Methods: In a climatic chamber, the air temperature was maintained at 28°C for 65 min and was then gradually decreased to 19°C for 70 min. Saliva samples were obtained from the subjects at 28°C before and after 19°C cold exposure and were used for RNA sequencing. Results: In the cold exposure experiment, expression levels of 14 genes were significantly changed [false discovery rate (FDR) < 0.05] although the degree of transcriptional changes was not high due to experimental conditions or blunted transcriptional reaction in saliva to cold stress. As a result, differential gene expression analyses detected the cathepsin L (CTSL) gene to be significantly upregulated, with FDR < 0.05 and log2 fold change value > 1; thus, this gene was identified as a differentially expressed gene. Given that the cathepsin L protein is related to invasion of the novel coronavirus (SARS-CoV-2), mild cold stress might alter the susceptibility to coronavirus disease-19 in humans. The gene ontology enrichment analysis for 14 genes with FDR < 0.05 suggested that immune-related molecules could be activated by mild cold stress. Conclusions: The results obtained from this study indicate that CTSL expression levels can be altered by acute mild cold stress.
... While repeated exercise in a cold climate has been shown to cause local signs of airway inflammation [27--27-29], the systemic immune effects are more uncertain [30]. Generally, short-duration, moderate-intensity exercise at room temperature has not been shown to negatively affect systemic immune function [31,32]. ...
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Exposure to a cold climate is associated with an increased morbidity and mortality, but the specific mechanisms are largely unknown. People with cardiopulmonary disease and winter endurance athletes are particularly vulnerable. This study aimed to map multiple domains of airway responses to exercise in subzero temperature in healthy individuals. Thirty-one healthy subjects underwent whole-body exposures for 50 minutes on two occasions in an environmental chamber with intermittent moderate-intensity exercise in +10 °C and -10 °C. Lung function, plasma/urine CC16 , and symptoms were investigated before and after exposures. Compared to baseline, exercise in -10 °C decreased FEV1 (p=0.002), FEV1/FVC (p<0.001), and increased R20Hz (p=0.016), with no differences between exposures. Reactance increased after +10 °C (p=0.005), which differed (p=0.042) from a blunted response after exercise in -10 °C. Plasma CC16 increased significantly within exposures, without differences between exposures. Exercise in -10 °C elicited more intense symptoms from the upper airways, compared to +10 °C. Symptoms from the lower airways were few and mild. Short-duration moderate-intensity exercise in -10 °C induces mild symptoms from the lower airways, no lung function decrements or enhanced leakage of biomarkers of airway epithelial injury, and no peripheral bronchodilatation, compared to exercise in +10 °C.
... High temperatures are known to increase respiratory morbidity, and to affect insulin therapy for type 1 diabetes patients [30]. Dry air promotes respiratory infections by reducing the action of cilia, which dry the mucosal surface and remove airway contaminants, before being absorbed by the respiratory mucosa [3,[31][32][33]. On the other hand, high-humid environment promote fungal infections, dyspnea, and allergies. ...
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IoT-based monitoring devices can transmit real-time and long-term thermal environment data, enabling innovative conversion for the evaluation and management of the indoor thermal environment. However, long-term indoor thermal measurements using IoT-based devices to investigate health effects have rarely been conducted. Using apartments in Seoul as a case study, we conducted long-term monitoring of thermal environmental using IoT-based real-time wireless sensors. We measured the temperature, relative humidity (RH), and CO2 in the kitchen, living room, and bedrooms of each household over one year. In addition, in one of the houses, velocity and globe temperatures were measured for multiple summer and autumn seasons. Results of our present study indicated that outdoor temperature is an important influencing factor of indoor thermal environment and indoor RH is a good indicator of residents’ lifestyle. Our findings highlighted the need for temperature management in summer, RH management in winter, and kitchen thermal environment management during summer and tropical nights. This study suggested that IoT devices are a potential approach for evaluating personal exposure to indoor thermal environmental risks. In addition, long-term monitoring and analysis is an efficient approach for analyzing complex indoor thermal environments and is a viable method for application in healthcare.
... In the studies of many authors, including ours, the influence of temperature exposure, both cold and warm, on various parameters of the immune system was shown (Brandt and Banet, 1984;Brenner et al., 1999;Kozyreva and Eliseeva, 2000;Castellani et al., 2002;McFarlin and Mitchell, 2003;Joseph et al., 2007;Kozyreva et al., 2012Kozyreva et al., , 2016. The mechanism of these influences is not clear and requires additional research. ...
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The effects of pharmacological stimulation of skin ion channels TRPA1, TRPM8, TRPV1 on the immune response are presented. These effects are compared with the effects of different types of temperature exposures - skin cooling, deep cooling, and deep heating. This analysis allows us to clear the differences in the influence on the immune response of thermosensitive ion channels localized in the skin; (2) whether the changes in the immune response under temperature exposures are due to these thermosensitive ion channels. Experiments were performed on Wistar rats. For stimulation of TRPM8 ion channel, an application to the skin of 1% menthol was used, for TRPA1 - 0.04% allylisotiocianate, and for TRPV1 - capsaicin in a concentration of 0.001.The antigen binding in the spleen was two-times stimulated by activation of the cold-sensitive ion channel TRPM8 and much weaker by activation of warm-sensitive TRPV1 (by 15%), and another cold-sensitive ion channel TRPA1 (by 40%). Only the stimulation of TRPA1 significantly (by 140%) increased antibody formation in the spleen, while TRPM8 had practically no effect on this process, and activation of TRPV1 significantly (by 60%) inhibited antibody formation. Stimulation of the TRPM8 ion channel significantly (by 60%) reduced the level of IgG in the blood, which is believed to control of infectious diseases.The obtained results show that pharmacological activation of the skin TRPA1, TRPM8, TRPV1 ion channels can differently affect the immune system. At the epicenter of changes there were the antigen binding and antibody formation in the spleen, as well as the level of IgG in the blood. Exactly stimulation of the TRPM8 ion channel determines the changes in the immune response when only the skin is cooling, while at deep body heating, the changes in the immune response are mostly determined by the activation of the skin TRPV1 ion channel.
... Meteorological or environmental conditions were also shown to have a direct effect on the host's susceptibility to infections (63). The role of cold weather in weakening the immune response is controversial (63,64). However, many studies indicated that cold and dry environments have an immunosuppressive effect on the host, and thereby increase the risk of acquiring infections (65)(66)(67). ...
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Respiratory viruses, including coronaviruses, are known to have a high incidence of infection during winter, especially in temperate regions. Dry and cold conditions during winter are the major drivers for increased respiratory tract infections as they increase virus stability and transmission and weaken the host immune system. The novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in China in December 2019 and swiftly spread across the globe causing substantial health and economic burdens. Several countries are battling with the second wave of the virus after a devastating first wave of spread, while some are still in the midst of their first wave. It remains unclear whether SARS-CoV-2 will eventually become seasonal or will continue to circulate year-round. In an attempt to address this question, we review the current knowledge regarding the seasonality of respiratory viruses including coronaviruses and the viral and host factors that govern their seasonal pattern. Moreover, we discuss the properties of SARS-CoV-2 and the potential impact of meteorological factors on its spread.
... In terms of systemic responses, it has been reported that low temperatures can lead to increased white blood cell counts, granulocyte counts, and plasma inflammatory cytokine, such as interleukin-6 (IL-6), concentrations. Moreover, the activity of natural killer (NK) cells is retained even after exposure to cold air [2]. ...
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Acute viral respiratory tract infections (RTIs) are commonly associated with cold weather; however, the mechanism behind this is still unclear. Secretory IgA (sIgA) mainly contributes to the immune response against pathogenic microorganisms in the respiratory tract. Certain pathogen-associated molecular patterns (PAMPs) induce the expression of B-cell activating factor (BAFF) in epithelial cells, macrophages, and dendritic cells. BAFF transforms B cells into plasma cells, which leads to the mass production of immunoglobulins, including IgA, on the mucosal epithelium. However, no studies have described the relationship between cold exposure and BAFF and/or sIgA in RTI. The aim of our study was to determine this relationship in vitro by investigating the effect of low temperature on BAFF production by BEAS-2B cells after the addition of toll-like receptor (TLR) ligands. We showed stimulation of polyinosinic:polycytidylic acid (poly I:C), which led BEAS-2B to produce interferon (IFN)-β. IFN-β itself induced BEAS-2B cells to produce BAFF. Janus kinase inhibitor I decreased the amount of BAFF produced in BEAS-2B cells upon stimulation with IFN-β and poly I:C. Significantly less BAFF was produced post-poly I:C stimulation in low-temperature conditions than in normal-temperature conditions (mean ± SD: 41.2 ± 23.3 [33 °C] vs. 138.3 ± 7.1 pg/mL [37 °C], P = 0.05). However, the low-temperature condition itself was not cytotoxic. The stimulation of poly I:C produced BAFF from BEAS2B cells via IFN-β production and the JAK/signal transducer and activator of transcription pathway played an important role in BAFF production in BEAS-2B cells. Cold exposure reduced BAFF production by BEAS2B cells after stimulation with the TLR3 ligand. Cold exposure may, therefore, suppress the production of BAFF, resulting in the inhibition of IgA secretion in the bronchial epithelium, which explains the increased frequency of RTIs in cold weather.
... It has been reported that chronic cold stimulation upregulates mRNA expression levels of IL2 and IL6, without significantly affecting IFNγ mRNA levels in chicken [38]. In human, cold stimulation was shown to increase serum IL6 levels, especially at the initial phase of stimulation [39,40]. Hangalapura et al. [28] reported that cold stimulation can enhance Th1 related cellular immunity of chickens, consequently, increase the IL2 and IFNγ mRNA levels. ...
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Appropriate cold stimulation can improve immune function and stress tolerance in broilers. In order to investigate the effect of intermittent mild cold stimulation on the intestinal immunity of broilers, 240 healthy one-day-old Ross 308 chickens were randomly divided into three groups: the control group (CC) housed in climatic chambers under usual rearing ambient temperature with a gradual 3.5 °C decrease per week; group II (C3) and group III (C6) to which cold stimulation at 3 °C below the temperature used in CC was applied every two days for 3 and 6 h, respectively, from day 15 to 35, and at the same temperature used in CC from day 35 to 43. The mRNA expression levels of immunoglobulins (IgA and IgG), cytokines (IL2, IL6, IL8, IL17, and IFNγ), and Toll-like receptors (TLR2, TLR4, TLR5, TLR7, and TLR21) were investigated in duodenum, jejunum, and ileum tissue samples on days 22, 29, 35, and 43. From day 15 to 35, mRNA expression of IL2 and IFNγ was increased in the intestine of broilers. After one week of cold stimulation on day 43, mRNA levels of immunoglobulins, cytokines, and Toll-like receptors (TLRs) stabilized. Collectively, the findings indicate that cold stimulation at 3 °C below the usual rearing temperature had a positive impact on intestinal immunity of broilers.
... The respiratory system is highly vulnerable to pollution and microorganisms. In cold weather, the relative risk of respiratory diseases increases and exposure to cold, low temperatures can impair immune mechanisms [17][18][19] . It is an established fact that respiratory infections are more frequent during cold and low humidity conditions 20 . ...
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Objective: The COVID-19 pandemic has caused a global public health crisis with social, psychological and long-lasting economical damages. Weather-related dynamics have an impact on the pattern of human health and disease. The present study aimed to investigate the impact of heat and humidity on daily basis incidence and mortality due to COVID-19 pandemic in ten of the world's hottest countries compared to ten of the coldest ones. Materials and methods: Worldwide, we selected 20 countries; 10 hottest countries with the highest temperatures and 10 coldest countries with the lowest temperature. The selection of the countries was based on the daily basis mean temperature from the date of appearance of the initial cases of COVID-19, Dec 29, 2019 to May 12, 2020. In the world's 10 hottest countries, the mean temperature was (26.31±1.51) and humidity (44.67±4.97). However, in the world's 10 coldest countries the mean temperature was (6.19±1.61) and humidity (57.26±2.35). The data on the global outbreak of COVID-19, daily new cases and deaths were recorded from World Health Organization, and daily information on temperature and humidity was obtained from metrological web "Time and Date". Results: In countries with high temperatures and low humidity, the mean daily cases incidence were (407.12±24.33); cumulative cases (9094.34±708.29); and cumulative deaths (452.84±43.30) were significantly low compared to countries with low temperatures and high humidity: daily cases (1876.72±207.37); cumulative cases (44232.38±5875.11); and cumulative deaths (2008.29±310.13). Moreover, COVID-19 cases and deaths per million population were significantly low in countries with high temperatures (cases 711.23, and deaths 16.27) compared to countries with low temperatures (cases 1685.99; and deaths 86.40). Furthermore, in hottest countries, a 1% increase in humidity reduced number of cases and deaths by (β = -5.40, p<0.001) and (β = -0.187, p=0.004) respectively. A similar trend was seen with a 1°C increase in temperature, reducing the number of deaths by (β = -1.35. p<0.001). Conclusions: The results revealed a significant decrease in incidence of daily cases and deaths in countries with high temperatures and low humidity (warmest countries), compared to those countries with low temperatures and high humidity (coldest countries). The findings could be of interest to the policymakers and the health officials on the epidemiological trends of COVID-19 pandemic and weather changes.
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White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a β3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia.
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Asthma is highly prevalent among winter endurance athletes. This “occupational disease” of cross-country skiers, among others, was acknowledged during the 1990s, with the pathogenesis attributed to repeated and prolonged exposure to cold, dry air combined with high rates of ventilation during exercise. Nevertheless, more than 25 years later, the prevalence of asthma among Scandinavian cross-country skiers is unchanged, and prevention remains a primary concern for sports physicians. Heat-and-moisture-exchanging breathing devices (HMEs) prevent exercise-induced bronchoconstriction in subjects with pre-existing disease and may have potential as a preventative intervention for healthy athletes undertaking training and competition in winter endurance sports. Herein we firstly provide an overview of the influence of temperature and humidity on airway health and the implications for athletes training and competing in sub-zero temperatures. We thereafter describe the properties and effects of HMEs, identify gaps in current understanding, and suggest avenues for future research.
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We have shown that two human monocyte subsets can be isolated from the peripheral blood of healthy donors; these subsets possess different morphological, cytochemical, functional, and in vivo trafficking properties [1]. In this report, these two subsets were further characterized. One subset (intermediate monocytes, IM) has been shown to have significantly lower acid phosphatase activity and total cellular protein content as well as lower peroxidase activity when compared with another subset (regular monocytes, RM). The overall activation status of the two subsets (as determined by their alkaline phosphodiesterase activity) was identical. We also examined the capacity of these subsets to release various cytokines with or without polyriboinosinic and polyribocytidylic acid (Poly I:C) stimulation. There was no appreciable difference in their ability to release interferon (IFN), interleukin 1 (IL-1), and prostaglandin E (PGE) without stimulation, while IM produced slightly, but significantly, higher amounts of colony-stimulating factor (CSF) than RM. The amount of IFN released by IM in response to poly I:C was approximately three times higher than the amount of IFN released by RM. IL-1 was also released in higher amounts by IM than by RM in response to poly I:C. IM were also found to release more CSF than RM in response to poly I:C. In contrast, it was noted that IM secrete significantly less PGE response to poly I:C than do RM. These findings indicate that two purified human monocyte subsets, distinguishable by maturation markers, differ significantly in their ability to release various cytokines after stimulation; this difference may be relevant to potential in vivo roles of these immunoregulatory cells.