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Integrative and Comparative Biology
Integrative and Comparative Biology, volume 54, number 3, pp. 419–426
doi:10.1093/icb/icu005
Society for Integrative and Comparative Biology
SYMPOSIUM
The Effects of Stress Hormones on Immune Function May be Vital
for the Adaptive Reconfiguration of the Immune System During
Fight-or-Flight Behavior
Shelley A. Adamo1
Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS B3H 4R2, Canada
From the symposium ‘‘Methods and Mechanisms in Ecoimmunology’’ presented at the annual meeting of the Society for
Integrative and Comparative Biology, January 3–7, 2014 at Austin, Texas.
1
E-mail: [email protected]
Synopsis Intense, short-term stress (i.e., robust activation of the fight-or-flight response) typically produces a transient
decline in resistance to disease in animals across phyla. Chemical mediators of the stress response (e.g., stress hormones)
help induce this decline, suggesting that this transient immunosuppression is an evolved response. However, determining
the function of stress hormones on immune function is difficult because of their complexity. Nevertheless, evidence
suggests that stress hormones help maintain maximal resistance to disease during the physiological changes needed to
optimize the body for intense physical activity. Work on insects demonstrates that stress hormones both shunt resources
away from the immune system during fight-or-flight responses as well as reconfigure the immune system. Reconfiguring
the immune system minimizes the impact of the loss of these resources and reduces the increased costs of some immune
functions due to the physiological changes demanded by the fight-or-flight response. For example, during the stress
response of the cricket Gryllus texensis, some molecular resources are shunted away from the immune system and toward
lipid transport, resulting in a reduction in resistance to disease. However, insects’ immune cells (hemocytes) have
receptors for octopamine (the insect stress neurohormone). Octopamine increases many hemocyte functions, such as
phagocytosis, and these changes would tend to mitigate the decline in immunity due to the loss of molecular resources.
Moreover, because the stress response generates oxidative stress, some immune responses are probably more costly when
activated during a stress response (e.g., those that produce reactive molecules). Some of these immune responses are
depressed during stress in crickets, while others, whose costs are probably not increased during a stress response, are
enhanced. Some effects of stress hormones on immune systems may be better understood as examples of reconfiguration
rather than as mediating a trade-off.
Introduction
Both short-term and long-term activation of the stress
response can have negative impacts on immune function in animals across phyla (Lacoste et al. 2001;
Glaser and Kiecolt-Glaser 2005; Martin 2009; Walsh
et al. 2011; Adamo 2012a, 2012b). The biomedical
literature is replete with information on how the
stress response impacts immune cells (e.g., via hormones) (Sapolsky et al. 2000; Webster et al. 2002).
However, the evolutionary significance of these interactions remains less well understood (e.g., Råberg
et al. 1998; Dhabhar 2002, 2009; Adamo 2008a;
Martin 2009; Boonstra et al. 2013). Nevertheless, it
is likely to be profound; in virtually every animal
the stress response interacts with the immune
system, usually to negative effect (Ottaviani and
Franceschi 1996; Humphries and Yoshino 2003;
Cohen and Kinney 2007; Adamo 2008a, 2012a).
Therefore, either these connections have been conserved over a half billion years of metazoan evolution,
or they have evolved independently in different phyla
(Adamo 2008a). Either possibility suggests that having
connections between the stress response and the
immune response is crucial for survival.
The stress response is a coordinated series of
physiological changes that optimizes an animal for
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420
fight-or-flight (Sapolsky et al. 2000; Kassahn et al.
2009). Some of the most important mediators of
these physiological changes are neuroendocrine factors (e.g., stress hormones) (Charmandari et al.
2005). In this article, the term ‘‘stress hormone’’ includes compounds released by both neurons (i.e.,
neurohormones) and endocrine glands in response
to stressful stimuli. These neuroendocrine factors
bind with receptors that induce the changes necessary to optimize the body for intense activity. Most
of these changes, such as liberation of energy compounds from storage, make good teleological sense
given the function of the stress response (Sapolsky
et al. 2000). However, the effects of stress hormones
on immune function have been more difficult to
interpret (Sapolsky 1992; Adamo 2008a; Boonstra
et al. 2013). Even under conditions of acute shortterm stress (i.e., the classic fight-or-flight response),
stress hormones often have contradictory effects on
immune cells, defying simple explanations (Walsh
et al. 2011; Matson et al. 2012). For example,
short-term exposure to norepinephrine, a compound
released by the sympathetic nervous system during
the stress response in vertebrates (Fig. 1) (Sanders
and Kavelaars 2007), can both increase TNF- production (Huang et al. 2012b) as well as decrease it
(Yano et al. 2010) in mouse macrophages, depending
on the type of adrenergic receptors the macrophage
contains (Yano et al. 2010). TNF- is an important
immune signaling molecule (i.e., cytokine) and the
amount produced will significantly influence the
magnitude of the immune response (Roitt et al.
2001). On the level of the whole organism, an increase in norepinephrine due to acute stress increases
bacterial growth (Listeria monocytogenes) in infected
organs (Cao and Lawrence 2002), but can also increase the number of some types of circulating
immune cells (Dhabhar et al. 2012). Not surprisingly,
how these changes affect resistance to disease, or
contribute to the performance of the whole organism, remain poorly understood (Sanders and
Kavaelaars 2007; Sanders 2012; but see Dhabhar
et al. 2012). Such complexity is not restricted to vertebrates. Short-term exposure to the stress hormone
octopamine has both positive and negative effects
on hemocyte function in insects (Adamo 2008a).
Hemocytes are the immune cells of the blood
(hemolymph) in insects (Beckage 2008).
Some of this complexity may be driven by the
intricacy of the systems involved. For example,
both the immune system and the stress response
can vary in their expression depending on the
nature of the inducing stimulus (e.g., Sapolsky
et al. 2000; Roitt et al. 2001; Dhabhar et al. 2012).
S. A. Adamo
Fig. 1 Simplified stress-response systems of insects and vertebrates. Both begin with the perception of threatening stimuli
(e.g., presence of a predator) by the brain. The first response, in
vertebrates, is by the sympathetic nervous system, which includes
the release of norepinephrine locally into immune organs.
Similarly, insects initially respond with the release of a biogenic
amine chemically similar to norepinephrine (octopamine). Both
systems have a second, slower hormonal response: glucocorticoids, in vertebrates, and the peptide adipokinetic hormone
(AKH) in insects (see Demas et al. 2011 for review).
To make this discussion more manageable, this article will focus on the acute stress response that occurs
in response to a fight-or-flight response. Similarly,
for the immune system, the focus will be on
immune responses that occur following injection
with heat-killed bacteria. To further simplify the
problem, this issue will be discussed using insects
rather than vertebrates as model organisms. Insects
have robust stress-response systems (Orchard et al.
1993) as well as robust immune systems (Beckage
2008). They also demonstrate extensive interactions
between the two and these interactions often are parallel to those found in vertebrates (Adamo 2008a;
2012a). However, insects have neural, endocrine,
and immune systems that, although not simple, are
simpler than those found in vertebrates, and it may
be easier to understand some of these cross-phyla
interactions in organisms with a simpler organization
(Adamo 2012a, 2012b).
Various non-mutually exclusive hypotheses have
been suggested as to why stress hormones alter
immune function (e.g., Råberg et al. 1998; Dhabhar
et al. 2012). Unfortunately, the evidence for them
tends to be equivocal with contradictory evidence
left unexplained (see Adamo 2008a, 2009, 2012b).
Moreover, some of the best-supported hypotheses,
such as the redistribution of immune resources
to enhance immune defenses against the infection
of wounds (e.g., Dhabhar et al. 2012, but see
421
Stress hormone effects on immune function
Padgett et al. 2007), do not appear to apply to insects (Adamo and Parsons 2006) or birds (Ewenson
et al. 2003), even though both insects and birds have
receptors for stress hormones on their immune cells.
Although the function of stress hormones on
immune function will vary across animals, given its
ubiquity, it might be expected that some themes
might apply across phyla. This article searches for
those themes in an insect model system, the cricket
Gryllus texensis.
Stress responses and immune responses
The stress response by insects shares a number of features with the stress-response systems of vertebrates
(Fig. 1). During, and immediately after, flying, fighting, or forced running there is a significant increase
in the stress hormone octopamine in the hemolymph
(insect blood) (Adamo et al. 1995; Adamo 2010).
Octopamine reconfigures physiological systems to
prime the body for fight-or-flight (Orchard et al.
1993; Roeder 1999, 2005; Verlinden et al. 2010).
For example, it alters anti-predator behavioral strategies towards immediate escape (e.g., Adamo et al.
2013). Such shifts in behavior and physiology increase the ability of insects to escape their predators
(Adamo et al. 2013).
Immune responses in insects resemble some innate
immune responses in vertebrates (Ferrandon et al.
2007). Given that stress and immune responses
have evolved to cope with distinctly different types
of challenges, and that both are important adaptations for survival, it might be expected that each
would be difficult to inhibit and that there would
be little interaction between the two systems.
However, the two systems are intimately connected
in insects and in other invertebrates (e.g., Adamo
2008b, 2010, 2012a).
Fig. 2 Allegorical example of reconfiguration. (A) Both cars run
best with four wheels. (B) However, wheels are limited. When
the car on the left (e.g., stress response) is needed, it takes one
of the wheels from the car on the right. This theft leaves the car
on the right seriously compromised. (C) However, stress hormones can help rebuild the car on the right so that it can run,
albeit somewhat suboptimally, on three wheels.
paradoxical changes in immune function during the
response to fight-or-flight stress.
Molecular resource trade-offs
Interactions at the network level
Figure 2 provides an allegorical example of why
stress hormones may have contradictory effects on
immune function both in vertebrates and in insects.
Stress hormones optimize the body for fightor-flight, and this may entail the reduction of
molecular resources available to the immune
system. To mitigate the negative impacts of this
physiological re-organization on the functioning of
the immune system, stress hormones also reconfigure
the immune system. Below are examples of this scenario, taken from insects. Although the biochemical
details vary across species, I use crickets to demonstrate how interactions between different physiological systems can lead to unexpected trade-offs, and to
During a stress response, some molecular resources
(e.g., one of the wheels in Fig. 2) may need to be
shifted from immune function to those processes
critical for maintaining fight-or-flight behavior
(Fig. 2B). For example, when crickets experience
fight-or-flight, the amount of lipid in their hemolymph increases (Woodring et al. 1988; Adamo
et al. 2008). A similar effect can be induced by injecting the stress hormone octopamine (Fields and
Woodring 1991; Adamo et al. 2008). As in other
animals, in insects lipids are carried in the blood
by protein molecules (apolipophorins) (Weers and
Ryan 2006). In crickets and other orthopterans
(grasshoppers, locusts, and katydids), lipid is usually ferried by high-density lipophorin (HDLp)
422
(Weers and Ryan 2006). HDLp is composed of two
proteins, apolipophorins I and II, and has limited
capacity for carrying lipids (Weers and Ryan 2006).
During the stress response, the fat body is induced to
release lipid both by octopamine, and, to an even
greater extent, by the peptide hormone adipokinetic
hormone (Fig. 1; Orchard et al. 1993). At this point
HDLp’s lipid-carrying capacity is overwhelmed and a
third protein, apolipophorin III (apoLpIII) is called
upon to combine with HDLp to form low-density
lipophorin (LDLp) (Weers and Ryan 2006). The formation of LDLp results in a reduction in uncombined apoLpIII in the hemolymph (Adamo et al.
2008). This creates a ‘‘molecular shortage’’ for the
immune system as apoLpIII is also an immunesurveillance molecule (Whitten et al. 2004). In
essence, by liberating lipid from stores in the fat
body, octopamine forces a shift in molecular resources away from immune function and toward
the needs of a fight-or-flight response (Adamo
et al. 2008). Injections of additional apoLpIII prior
to flying, decreases the decline in the resistance to
disease that usually is seen after flight (Adamo et al.
2008). This result suggests that the loss of uncombined apoLpIII is immunologically significant
(Adamo et al. 2008).
Multifunctional molecules like apoLpIII also play
important roles in the immunity of vertebrates, (e.g.,
carotenoids) (Hasselquist and Nilsson 2012). They,
too, can be shunted away from immunity under
some conditions, leading to a shortage of molecular
resources for the immune system (Hassequist and
Nilsson 2012).
Direct effects of stress hormones on
immune function
Perhaps the most puzzling aspects of stress-response
interactions with immune function are the direct
connections between the two. In insects, hemocytes
have functional octopamine receptors (Huang et al.
2012a). This information complements a body of
work using pharmacology to demonstrate that hemocytes change their function in response to a variety
of biogenic amines, hormones, and neuroactive compounds (reviewed by Adamo 2008a, 2008b, 2012a).
Interestingly, these receptors turn out to be similar
(in terms of molecular sequence) to the adrenergic
receptors found on vertebrates’ immune cells (Huang
et al. 2012a). Like adrenergic receptors, they are
G-protein coupled receptors (Huang et al. 2012a).
In insects, stress hormones tend to be immunoenhancing (Adamo 2008a; Kim et al. 2009). For example, octopamine increases both phagocytosis (Baines
S. A. Adamo
et al. 1992) and locomotion by hemocytes (e.g.,
Diehl-Jones et al. 1996). In insects, the immunoenhancing effects of octopamine and adipokinetic hormone (Goldsworthy et al. 2002) are suggested to be
part of a reconfiguration of the immune system, as
some immune responses are enhanced and thereby
mitigate the negative impact of the loss of molecular
resources to other functions such as lipid transport
(Adamo 2012a). Therefore, without the effects of
stress hormones on immune function, resistance to
disease would probably decline even more precipitously during, and immediately after, fight-or-flight
behavior. In other words, the effect of octopamine
on the immune system of the insect is like the
rebuilding of the car on the right in Fig. 2C. The
car is now able to move with three wheels, albeit
with reduced functionality.
As in vertebrates, stress hormones also can
suppress some immune functions in insects
(Adamo 2010, 2012b; Huang et al. 2012a). This complexity is not a laboratory artifact, but is built into
the response system of the immune cell. For example, the octopamine receptor of hemocytes activates
two different second messenger systems. Low concentrations of octopamine result in an increase in
intracellular calcium, whereas at high concentrations,
both intracellular calcium and cAMP concentrations
are increased (Huang et al. 2012a). Similarly, octopamine enhances hemocyte phagocytosis at low concentrations, but has the opposite effect at high
concentrations (Huang et al. 2012a). Furthermore,
the effects of octopamine on hemocytes depends on
whether or not pathogens are present (Adamo 2010).
Given that the complex effects of stress hormones on
immune cells are created by the nature of their intracellular signaling mechanisms, it seems likely that
such responses have been evolutionarily selected
(also see Råberg et al. 1998 for a similar argument).
It is these complex responses that are the most difficult to understand. The following section provides
one possible explanation.
Immune reconfiguration that
minimizes costs
To optimize the function of the whole organism
given current demands (e.g., flight in insects)
(Orchard et al. 1993), animals shift their physiological state. However, these changes in physiological
state may alter the costs/benefits of performing
other physiological functions. For example, performance of the stress response generates oxidative
stress in many animals (e.g., Costantini et al.
2013). Oxidative stress here is defined as damage
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Stress hormone effects on immune function
to molecules important for an animal’s survival (e.g.,
DNA, proteins, and cell membranes) by reactive
molecules created by some physiological processes
(Halliwell and Gutteridge 2007). In crickets, flight
increases the production of lipid peroxides in the
hemolymph (Adamo et al. manuscript in preparation); lipid peroxides are a marker of damage due
to oxidative stress (Bou et al. 2008). Therefore,
during a stress response, animals may be more sensitive to oxidative stress because it is already being
generated at levels above baseline. For example, after
a stress response, crickets are more likely to die from
a standard dose of paraquat (Adamo et al. manuscript in preparation), a compound that catalyzes
the production of reactive molecules (see Halliwell
and Gutteridge 2007). This finding suggests that
any process that results in the production of reactive
molecules is likely to become more damaging if it
occurs within the context of a stress response.
The immune response generates reactive molecules
(e.g., see Nappi and Christensen 2005) as part of its
defense against pathogens, for example, molecules
generated by phenoloxidase activity (Cerenius et al.
2008) and nitric oxide (Nappi et al. 2000). In
crickets, activating an immune response by injecting
heat-killed bacteria increases the amount of lipid
peroxides in the hemolymph, suggesting an increase
in oxidative stress (Adamo et al. manuscript in
preparation). The oxidative stress generated by
the immune response is biologically significant;
immune activation can induce self-damage in insects
(Sadd and Siva-Jothy 2006). The cost of this damage
(i.e., immunopathology) is thought to exert a major
selective force on life-history traits (Pursall and Rolff
2012). Anything that increases these costs (e.g., the
adoption of a stress-response state) may select for
changes in the configuration of the immune response
and thereby reduce them.
If animals become more sensitive to oxidative
stress during a stress response, this alters the cost/
benefit ratio for different forms of immune defense.
For example, those responses that involve reactive
molecules become more costly. Therefore, during a
stress response, other immune functions that are less
damaging, may be up-regulated, while others are depressed. There is evidence supporting this hypothesis
for crickets. After flight, or after an injection of octopamine, an immune challenge induces less expression
of the nitric oxide synthase gene than it does in
controls (Adamo et al. manuscript in preparation).
Additionally, there is a decline in the activation of
phenoloxidase (Adamo et al. manuscript in preparation). However, lysozyme-like activity, which does
not destroy pathogens by generating reactive
molecules (Van Herreweghe and Michiels 2012), is
increased in vitro when heat-killed bacteria and octopamine are both present (Adamo 2010). Lysozymelike activity and phenoloxidase activity may be
negatively correlated in many insects. Increased lysozyme activity reduces the activation of phenoloxidase
in the caterpillar Manduca sexta (Rao et al. 2010).
Whether stress hormones like octopamine play a
direct role in mediating this negative interaction
between these two immune functions remains to be
determined.
Many animals appear to make behavioral and/or
physiological changes and thereby avoid elevated
levels of oxidative stress. For example, birds tend
to avoid expressing more than one oxidative stressinducing activity at a time (Hasselquist and Nilsson
2012). Hasselquist and Nilsson (2012) suspected that
this avoidance prevents the build-up of damage that
would occur if multiple oxidative stress-generating
activities occurred simultaneously.
Implications for ecoimmunologists
Interpreting immune assays performed during stressful conditions can be difficult because of the complex
effects of stress hormones on immune function
(Adamo 2009). The magnitude of a particular
immune function is usually assumed to reflect the
relative strength of the immune system, and hence
the animal’s resistance to disease (Adamo 2004).
However, this assumption may not hold for some
immune functions during the stress response. For
example, activating the insect stress response
(e.g., by injecting octopamine) reduces the resistance
of crickets to the Gram negative bacterium Serratia
marcescens (Adamo and Parsons 2006). However,
octopamine enhances phagocytosis by hemocytes
(Baines et al. 1992). Therefore, if the phagocytic
ability of hemocytes were used to assess immune
function during stress, a researcher would erroneously conclude that stress improves resistance to disease. Host resistance tests (i.e., testing an animal’s
ability to overcome a live pathogen) may be required
to determine whether there has been a change in
resistance to disease as a result of a reconfiguration
of the immune system (Adamo 2009). More than
one type of pathogen may need to be used, as the
immune system may have different strengths and
weaknesses during stress.
Conclusions
Recent work both in vertebrates and invertebrates
has shown that stress hormones are not globally immunosuppressive, especially within the context of
424
S. A. Adamo
will be better able to understand why stress hormones alter immune function.
Funding
The Natural Science and Engineering Research
Council of Canada (NSERC); the National Science
Foundation RCN for Ecoimmunology (NSF ISO
094177).
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Fig. 3 Three reasons why stress hormones affect immune
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