Although it has commonly been assumed that the immune system and the processes that govern social behavior are separate, non-communicating entities, research over the past several decades suggests otherwise. Considerable evidence now shows that inflammatory processes and social behavior are actually powerful regulators of one another. This review first summarizes evidence that inflammatory processes regulate social behavior, leading to characteristic changes that may help an individual navigate the social environment during times of sickness. Specifically, this review shows that inflammation: (1) increases threat-related neural sensitivity to negative social experiences (eg, rejection, negative social feedback), presumably to enhance sensitivity to threats to well-being or safety in order to avoid them and (2) enhances reward-related neural sensitivity to positive social experiences (eg, viewing close others and receiving positive social feedback), presumably to increase approach-related motivation towards others who might provide support and care during sickness. Next, this review summarizes evidence showing that social behavior also regulates aspects of inflammatory activity, preparing the body for situations in which wounding and infection may be more likely (social isolation). Here, we review research showing: (1) that exposure to social stressors increases proinflammatory activity, (2) that individuals who are more socially isolated (ie, lonely) show increased proinflammatory activity, and (3) that individuals who are more socially isolated show increased proinflammatory activity in response to an inflammatory challenge or social stressor. The implications of the co-regulation of inflammation and social behavior are discussed.
Although inflammatory activity is known primarily for its role as the body’s first line of defense against tissue damage and microbial infection, research over the past several decades has revealed that inflammatory activity is also a powerful organizer of behavior. For instance, proinflammatory cytokines, one of the key chemical messengers of the immune system, not only orchestrate peripheral inflammatory responses to prevent infection (such as in response to a microbial antigen), but these cytokines also signal the brain to alter behavior. Specifically, through a variety of mechanisms, including activation of afferent vagal nerves (ie, proinflammatory cytokines bind to cells of the vagal paraganglia and activate the vagal nerve; Goehler et al, 1997) and transport through the blood-brain barrier (BBB; Dantzer et al, 2008; Maier and Watkins, 1998), cytokines can signal the brain to invoke a constellation of behaviors known as sickness behaviors (Hart, 1988; Dantzer, 2001; Kelley et al, 2003; Quan and Banks, 2007). These behaviors include loss of appetite, sleepiness, social withdrawal, fatigue, increased pain, and anhedonia, and are conceptualized as a coordinated motivational response thought to facilitate recuperation and recovery from illness and disease (Dantzer and Kelley, 2007; Hart, 1988).
However, more recently, research has begun to reveal that inflammation is also a particularly powerful organizer of social behavior (Eisenberger et al, 2009, 2010b; Hennessy et al, 2014; Moieni et al, 2015b; Moieni et al, 2015c). Although this is somewhat surprising, given the seeming disconnect between sickness on the one hand and social behavior on the other, the relationship between inflammation and social behavior may provide a survival advantage. Being in a ‘sick state’ or a state of heightened inflammation puts a social organism in a particularly vulnerable situation and thus sensitivity to the social world may need to be altered to navigate this more vulnerable situation. Navigating sickness for a social species may be accomplished by: (1) increasing sensitivity to threatening social experiences (Eisenberger et al, 2009; Inagaki et al, 2012; Muscatell et al, 2016) in order to better identify and avoid threats to well-being while in this vulnerable state and (2) increasing approach-related behavior towards close others (Inagaki et al, 2015) or other individuals who might be able to provide support (Muscatell et al, 2016) in order to recruit help and care in order to facilitate recovery from sickness (Figure 1, left side). Here, we review evidence from both animal and human research showing that states of heightened inflammation lead to several important changes in social behavior. We will also discuss how these inflammatory-induced alterations in social behavior may ultimately help to explain the relationship between heightened levels of inflammation and the presence of certain psychiatric disorders that involve altered social sensitivities (eg, depression).
Finally, in addition to inflammation being a powerful organizer of social behavior, social behavior may also have a powerful effect on regulating the immune system. Given the importance of social connection for human survival and the fact that social disconnection severely compromises survival—increasing risk of predation, wounding, and infection—recent theories have suggested that the immune system may respond to various forms of social disconnection by upregulating proinflammatory response genes to prepare the body for these more vulnerable situations (Cole et al, 2007; Eisenberger and Cole, 2012). For instance, to the extent that an individual is socially disconnected (ostracized and excluded), that individual faces a greater risk of wounding and infection as a function of greater vulnerability to predation or attack by hostile conspecifics without protection from others. To anticipate and protect against these possibilities, the body may respond to these potential threats by upregulating proinflammatory response genes to prepare the body for situations in which wounding is more likely. Along these lines, we review evidence showing that exposure to socially threatening situations can increase inflammatory activity, and that individuals who are lonely or socially disconnected tend to show higher levels of proinflammatory activation (Cole et al, 2007; Moieni et al, 2015a; Figure 1, right side).
Although inflammation and social behavior appear to be unlikely bedfellows, they are intricately connected. Here, we have reviewed considerable evidence: (1) that the immune system is a powerful regulator of social behavior and (2) that social behavior or features of the social environment are powerful regulators of the immune system. Indeed, this co-regulation of social behavior and immune system activity, particularly inflammatory responses, makes good sense.
When we are sick, we need to be especially sensitive to the social world in order to more carefully navigate our interactions with potentially dangerous strangers and increase our connection to those who we know will help us during this time of need. Going forward, it will be important for research in this area to more carefully delineate the effects of sickness on different types of social behaviors as there may be different effects depending on whether the social target is a stranger or a close other as well as whether the social interaction is positive or negative. To date, these differences have not been carefully examined leading to the incorrect conclusion that sickness uniformly elicits social withdrawal.
Likewise, given the powerful role that social relationships play in our survival and the fact that social isolation makes us more vulnerable to attack and wounding, the immune system may have evolved to prepare for threats to social connection by increasing efforts towards heightened proinflammatory responses in these more vulnerable situations. Future work will be necessary to: (1) identify the types of social stressors that are the most potent activators of the immune system as well as (2) investigate whether there are specialized mechanisms whereby social stressors influence the immune system or whether these are the same mechanisms that allow other non-social stressors to influence the immune system as well.
Viewing sickness as a social phenomenon, in addition to a physical phenomenon, may help us to better understand emerging relationships between inflammation and mental health problems like depression (Miller et al, 2009a). Likewise, viewing social stress or social isolation as a physiological phenomenon, as well as a psychological phenomenon, may help us to better understand the robust relationships between social ties and health (Holt-Lunstad et al, 2010). A better understanding of the co-regulation of inflammation and social behavior may bring us a step closer to these goals.
FUNDING AND DISCLOSURE
This research was funded, in part, by an R01 from NIMH to NIE (5R01MH091352). The authors declare no conflict of interest.
We acknowledge the additional support provided by a pre-doctoral NRSA individual fellowship from NIA (1F31AG048668) to MM as well as the support provided by R01AG034588; R01AG026364; R01CA160245-01; R01CA119159; R01HL095799; R01DA032922; and the Cousins Center for Psychoneuroimmunology to MRI.
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Douleur et Analgésie (2017)