Why does acute stressinduced immunosuppression exist

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Increased susceptibility to disease during flight-or-fight should reduce survival. As Dhabhar (2002) has pointed out, during fighting or fleeing, animals run a real risk of injury and, therefore, exposure to pathogens. Although it might make good adaptive sense to delay copulation, digestion, and egg-laying until the predator has passed, the immune response may not be dispensable during flight-or-fight behaviours, because of the increased risk of injury (Dhabhar, 2002).

Nevertheless, animals from three different phyla exhibit this pattern, suggesting that immunosup-pression provides some benefit, despite its costs. Below I review some of the hypotheses about why animals display acute stress-induced immunosup-pression. I assess which of these hypotheses fit the available data on insects. The hypotheses are not mutually exclusive. The energy crisis hypothesis

One common hypothesis for the existence of acute stress-induced immunosuppression is that it allows animals to channel more energy into flight-or-fight behaviour (e.g. see Raberg et al, 1998; Segerstrom, 2007). The increased energy is hypothesized to raise the odds of escaping a predator successfully, or of winning a fight. These benefits are thought to outweigh the increased risk of developing wound infections. However, if the suppression of energetically expensive physiological processes enhances the success of flight-or-fight, then other phenomena, such as red-blood-cell production in mammals, should also be suppressed. Red blood cells have a half-life of approximately 120 days in humans and take 7 days to form from precursor cells (Ganong, 1983, p. 422). Therefore, suppressing their production for a few hours would probably be less costly in terms of reduced survival than depressing immune function during flight-or-fight. Nevertheless, stress hormones such as glucocorticoids appear to increase erythropoiesis under some conditions (e.g. Kolbus et al., 2003).

Furthermore, it is unclear whether stress-induced immunosuppression saves energy over the short term. For example, some mechanisms of stress-induced immunosuppression in vertebrates (e.g. apoptosis of precursor lymphoid cells leading to reduced lymphopoiesis; see Trottier et al., 2008) require an initial increase in energy expenditure (Dhabhar, 2002). The need to suppress entire physiological systems to decrease energy demand may be more important for longer-term changes in energy expenditure (e.g. egg production) than for short-term flight-or-fight demands. Over the short term (e.g. minutes) insects do not seem to be energy-limited, even during intense activities such as flight (Chapman, 1998, p.220).

At present, there is little direct evidence supporting the energy-crisis hypothesis in insects. The over-excitation hypothesis

Acute stress-induced immunosuppression may be beneficial because it prevents the immune system from becoming too active and harming the animal during flight-or-fight. In vertebrates, intense exercise produces minor damage to tissues such as muscle, increasing the risk of an autoimmune reaction (Raberg et al., 1998). Therefore, the vertebrate immune system shifts towards a less inflammatory state (Elenkov and Chrousos, 2006). This shift leads to a decrease in inflammation, but also leads to an increased susceptibility to bacterial and viral pathogens. The increased risk of infection is thought to be less than that of an autoimmune reaction. However, this key assumption remains untested.

Animals also run the risk of having an over-active immune response during an immune challenge. As would be predicted by the over-excitation hypothesis, an immune challenge also activates the acute stress response in vertebrates (Elenkov and Chrousos, 2006).

Like vertebrates, insects show some aspects of the acute stress response when they respond to an immune challenge. For example, some larval lepidotopterans (i.e. caterpillars) release octopa-mine when challenged with bacteria (Dunphy and Downer, 1994), although the source of this octopamine is uncertain (Adamo, 2005). However, in insects immune cell activity appears to be upregulated during acute stress (Table 11.2). Such upregulation does not support the over-excitation hypothesis. The shift-in-focus hypothesis This hypothesis suggests that during flight-or-fight behaviours animals are not immunosuppressed per se, but that they shift the focus of their immune effort from protection against systemic invaders to protection against opportunistic organisms that might gain entry through a wound (Dhabhar, 2002; Trottier et al., 2008). However, the shift-in-focus hypothesis may not apply to insects. Octopamine does enhance haemolymph clotting in some arthropods (e.g. Battelle and Kravitz, 1978), although this effect has yet to be demonstrated in insects. Regardless of the effects of octopamine on haemo-lymph clotting in insects, flight-or-fight behaviour results in an increase in the risk of infection after wounding (Adamo and Parsons, 2006). With their stiff exoskeletons, insects may have less need of increased peripheral defence during flight-or-fight than do vertebrates. However, more studies on this issue are required to determine definitively whether insects express a shift in focus. The resource crunch hypothesis A number of physiological changes are needed to make flight-or-fight possible (Orchard et al., 1993; Charmandari et al., 2005). The resource crunch hypothesis suggests that some of these changes will result in a shift in resources away from the immune system, in order to optimize the flight-or-fight response. This hypothesis differs from the energy crisis hypothesis because it is not energy per se that is limiting, but specific molecules that are required for both immunity and some other physiological function.

The resource crunch hypothesis explains, at least in part, acute stress-induced immunosuppression in insects. In crickets, conflicts between immune function and lipid transport can lead to acute stress-induced immunosuppression (Adamo et al., 2008). Crickets release octopamine during flight-or-fight behaviours (Adamo et al, 1995). Octopamine, directly and/or indirectly, induces the mobilization of lipid from the fat body in order to fuel flight-or-fight behaviours (Orchard et al., 1993). As lipid levels in the haemolymph increase, the protein apolipo-phorin III (apoLpIII) changes its conformation and combines with high-density lipophorin (HDLp) to form low-density lipophorin (LDLp), which has an increased lipid-carrying capacity (Figure 11.4; see Weers and Ryan, 2006 for review). However, in the unlipidated form, apoLpIII acts as an immune-surveillance molecule (Weers and Ryan, 2006). Once apoLplll becomes part of LDLp, it appears to lose that ability. This loss results in a decline in immune surveillance (Adamo et al, 2008). The decline in immune surveillance probably explains the increase in disease susceptibility that occurs immediately after flying and fighting (Adamo et al, 2008). In crickets, intense activity leads to transient immunosuppression because apoLpIII is co-opted into lipid transport and becomes unavailable as an immune-surveillance molecule (Adamo et al, 2008). Therefore, crickets become immunosuppressed during flight-or-fight, even if they have abundant energy stores (Adamo et al., 2008).


^ ApoLp III

^ ApoLp III

Figure 11.4 Lipid transport in Orthoptera. (a) Under normal conditions (e.g. when the insect is at rest), high-density lipophorin (HDLp) transports lipid (diacylglycerol, DAG) from the fat body and gut to the muscle. Apoliphorin III (apoLpIII) remains in the unlipidated form. (b) Under flight-or-fight conditions, apoLpIII undergoes a conformational change and combines with HDLp to form low-density liphophorin (LDLp). The amount of free apoLpIII in the haemolymph declines. Adapted from Weers and Ryan (2003).

Figure 11.4 Lipid transport in Orthoptera. (a) Under normal conditions (e.g. when the insect is at rest), high-density lipophorin (HDLp) transports lipid (diacylglycerol, DAG) from the fat body and gut to the muscle. Apoliphorin III (apoLpIII) remains in the unlipidated form. (b) Under flight-or-fight conditions, apoLpIII undergoes a conformational change and combines with HDLp to form low-density liphophorin (LDLp). The amount of free apoLpIII in the haemolymph declines. Adapted from Weers and Ryan (2003).

The ability of octopamine to mobilize lipid probably explains why octopamine produces immuno-suppression when it is injected into crickets. The injection of octopamine results in the release of lipid (Woodring et al., 1989), which would lead to a decrease in immune surveillance as the amount of free apoLpIII in the haemolymph declines. However, octopamine also enhances the ability of haemocytes to respond to pathogens (Table 11.2). I hypothesize that octopamine helps maintain immune system function as some of the components of the immune system are being siphoned off into lipid transport. In other words, octopamine helps to liberate lipid stores (needed to fuel flight-or-fight behaviour) while simultaneously reconfiguring the immune system to maintain maximal function under the new physiological conditions. I predict that without the effects of octopamine on immune function, disease resistance would decline even more precipitously during flying or fighting. This hypothesis, if correct, would explain why octopamine can have both immunosuppres-sive and immunoenhancing effects.

Why do crickets not make enough apoLpIII to support both immune surveillance and increased lipid transport? First, it would be energetically expensive to do so. ApoLpIII is already a very abundant protein in the haemolymph of many adult insects (Weers and Ryan, 2006). To produce more of this protein would decrease the energy available for reproduction and other activities. Second, as the concentration of apoLpIII increases, it may begin to bind more promiscuously, initiating inappropriate immune responses. Such auto-immunity could be costly (e.g. Sadd and Siva-Jothy, 2006). Therefore, the most adaptive response may be to shuttle apoLpIII between immune surveillance and lipid transport, even though it results in transient immunosuppression during flying or fighting.

However, this particular resource crunch may not exist in all insects, because not all species use lipid to fuel flight-or-fight. For example, stressed cockroaches exhibit hypertrehalosaemia, not hyper-lipidaemia, and injections of octopamine increase trehalose, not lipid, in the haemolymph (Downer, 1980). Therefore, I predict that cockroaches will not show a decline in apoLpIII during acute stress. Whether an immune response during flight-or-fight behaviours leads to other physiological conflicts in cockroaches remains unexplored.

Determining whether acute stress-induced immunosuppression in crickets is the result of a lack of energy or a lack of resources might seem superficially unimportant to evolutionary considerations about immune function (i.e. ecological immunology). However, an understanding of the physiological mechanisms responsible for a change in immune function is often critical for the design and the interpretation of experiments in ecological immunology. For example, if a researcher did not know that acute stress-induced immunosuppression is mediated by a conflict between lipid transport and immune function, it might be assumed that this immunosuppression was caused by insufficient 'energy' to fuel both flying and mounting an immune response. This false assumption would lead to the prediction that increased energy intake will decrease stress-induced immunosuppression. However, feeding a bolus of high-lipid (i.e. high-energy) food to crickets leads to increased immunosuppression (S.A. Adamo, unpublished results). The increased immunosuppression probably occurs because eating high-lipid foods increases the amount of lipid in the haemolymph (S.A. Adamo, unpublished results). The increased lipid, in turn, reduces the amount of free apoLpIII in the haemolymph, resulting in reduced immune surveillance and resistance to bacterial infection. Conversely, food deprivation would be expected to increase stress-induced immunosuppression. But the effects of food deprivation are likely to depend on whether it raises haemolymph lipid levels (e.g. by inducing the breakdown of fat stores) or lowers them. Therefore, whether a researcher finds evidence of an energetic constraint on immune function can depend on the experimental details (e.g. type of food used, duration of food deprivation), resulting in confusion in the literature.

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