Chronic hypoxia stimulates an enhanced response to immune challenge without evidence of an energetic tradeoff

Abstract

SUMMARYThere is broad interest in whether there is a tradeoff between energy metabolism and immune function, and how stress affects immune function. Under hypoxic stress, maximal aerobic metabolism is limited, and other aspects of energy metabolism of animals may be altered as well. Although acute hypoxia appears to enhance certain immune responses, the effects of chronic hypoxia on immune function are largely unstudied. We tested: (1) whether chronic hypoxia affects immune function and (2) whether hypoxia affects the metabolic cost of immune function. First, flow cytometry was used to monitor the peripheral blood immunophenotype of mice over the course of 36days of hypoxic exposure. Second, hypoxic and normoxic mice were subjected to an adaptive immune challenge via keyhole limpet hemocyanin (KLH) or to an innate immune challenge via lipopolysaccharide (LPS). The resting metabolic rates of mice in all immune challenge treatments were also measured. Although hypoxia had little effect on the peripheral blood immunophenotype, hypoxic mice challenged with KLH or LPS had enhanced immunological responses in the form of higher antibody titers or increased TNF- production, respectively. Initially, mice exposed to hypoxia had lower metabolic rates, but this response was transitory and resting metabolic rates were normal by the end of the experiment. There was no effect of either immune challenge on resting metabolic rate, suggesting that mounting either the acute phase response or a humoral response is not as energetically expensive as previously thought. In addition, our results suggest that immune responses to chronic and acute hypoxia are concordant. Both forms of hypoxia appear to stimulate both innate and adaptive immune responses.

Metabolic Cost of the Activation of Immune Response in the Fish-Eating Myotis (Myotis vivesi): The Effects of Inflammation and the Acute Phase Response

“…Although our study is not strictly comparable to previous studies in vertebrates because mass-specific doses differ, this increase in metabolic rate was much higher than in wild and model vertebrates. RMR increased by ~33–40% in Pekin ducks ( Anas platyrhynchos ; 0.1 mg kg -1 ) and house sparrows (5 mg kg -1 ) after an LPS challenge [22, 23], and the increase was modest (~10%) in lab rats ( Rattus norvegicus ; 0.05 mg kg -1 ) [25] and null in lab mice ( Mus musculus ; 0.5 mg kg -1 ) [27]. Therefore, with the exception of house sparrows [23], higher increments of RMR in our study compared to other studies [22, 25, 27] might be the result of our use of a relatively higher LPS dose.…”

“…RMR increased by ~33–40% in Pekin ducks ( Anas platyrhynchos ; 0.1 mg kg -1 ) and house sparrows (5 mg kg -1 ) after an LPS challenge [22, 23], and the increase was modest (~10%) in lab rats ( Rattus norvegicus ; 0.05 mg kg -1 ) [25] and null in lab mice ( Mus musculus ; 0.5 mg kg -1 ) [27]. Therefore, with the exception of house sparrows [23], higher increments of RMR in our study compared to other studies [22, 25, 27] might be the result of our use of a relatively higher LPS dose. The increase in RMR after the LPS injection amounted to an average total increased energy cost of 6.50 kJ, but daily energy requirements have not been measured for fish-eating Myotis, making interpretation of the significance of this additional energy burden more difficult.…”

“…For example, PHA administration has been shown to induce large (30%) [15] or small increases in resting metabolic rate (RMR) in some organisms (~5%) [16], no increases in RMR [17–21], and even decreases in RMR in others (-20‒-25%) [18]. Similarly, the effect of LPS administration on vertebrate RMR varies from large (~33‒40%) [22, 23] to small (~10%) [24–26] or null [27, 28]. In theory, LPS administration should evoke a more metabolically expensive response than PHA because it often induces an increase in body temperature (T b ).…”

Selection for increased mass-independent maximal metabolic rate suppresses innate but not adaptive immune function

“…Second, both traits may compete for limited resources, such as energy or other nutrients [17,19]. Some studies report that immune function is energetically costly [20][21][22][23], but others fail to find a significant energetic cost [24][25][26]. The ambiguity of these findings might be explained, at least in part, by the complexity of the immune system, and because some immune functions may be more costly than others [27][28][29].…”

Immunologic Consequences of Hypoxia during Critical Illness

“…This concept is supported by the observation that endotoxin tolerance, which bears similarities to sepsis-induced immunoparalysis, was partially reversed by chronic mild hypoxia in mice 78 . However, this single animal study does not fully reflect the complex dynamics of HIF-1α during human sepsis.…”