Small “doses” of inflammation initiate social sickness behavior

In their recent paper in Brain, Behavior, and Immunity, Jolink et al. (2022) remind us that subtle evolutionary forces shape social behavior outside of our awareness. The perception of threat—for our ancestors, risk of injury and infection, and in present times, psychosocial stress—activates the innate inflammatory response to protect the body from harm. The inflammatory response triggers not only changes in cell trafficking and signaling but also a constellation of ‘sickness behaviors’ believed to help conserve energy, promote recovery, and curb the spread of disease (Dantzer & Kelley, 2007). Among these are changes in social behavior (Hennessy et al., 2014). Cumulative human and animal evidence shows that experimentally-induced inflammation causes withdrawal from regular social activity, allowing for rest and reduced disease spread. However, more recent evidence supports theory that the inflammatory response also motivates approach toward close others who can provide care and protection: inflammatory challenge increases self-reported motivation and neural sensitivity to approach close others (Eisenberger et al., 2017; Muscatell & Inagaki, 2021). Jolink et al. provide the first indication that the inflammatory response relates to selective changes in automatic social behavior as well. Their findings show that relatively small increases in IL-6 following flu vaccination relate to faster approach behavior toward support figures, greater accuracy in withdrawal from strangers but not support figures, and lower accuracy in approaching strangers. This work has potential to stimulate further research: the flu vaccine’s small “dose” of inflammation approximates acute stress reactivity and appears useful for examining the automatic initiation of social sickness behaviors. As such, the flu vaccine is a promising method for advancing theory on the mechanisms and functions of sickness behaviors.

First, why would such small changes in inflammation influence social behavior? The flu vaccine produces minute changes in inflammation relative to the inflammatory response needed to fight illness and infection, whereas the theorized function of social sickness behaviors is to facilitate this recovery. At the same time, the flu vaccine produces an inflammatory response approximating acute stress reactivity; acute stress signals the body to prepare for danger. As Jolink et al. note, the brain is constantly monitoring the body’s cues to anticipate needs before they arise (Sterling, 2012). The brain monitors peripheral regulatory signals (e.g., hormones, blood pressure, thermoreceptors) and nudges behaviors to seek out or conserve resources (e.g., to increase thirst and find shade to conserve water on a hot day) before more drastic action is needed (e.g., sweating; heart rate and blood pressure changes). Likewise, small increases in peripheral inflammation—like those associated with acute stress—signal the brain to preemptively change behavior to seek care and conserve energy in case a rapid and robust inflammatory response is needed.

Varying “doses” of experimentally-induced inflammation map onto processes associated with varying degrees of systemic inflammation and likely initiate varying levels and types of sickness behaviors and symptoms. Interestingly, Jolink et al. found no association between small increases in inflammation and self-reported motivation to engage or withdraw from others; only implicit social behaviors were affected. As such, the inflammatory response associated with the flu vaccine (~0.5pg/mL increase in IL-6, similar to acute stress) may only influence social behaviors outside of awareness, with less influence on subjective feelings of social connection (Kuhlman et al., 2018). The typhoid vaccine increases IL-6 by ~1pg/mL, approximating levels of systemic inflammation associated with depression. The typhoid vaccine has not been used to study inflammation-induced social behaviors, but, like the flu vaccine, has effects on psychological and cognitive symptoms (e.g., mood, fatigue, confusion) but not physical sickness symptoms (e.g., fever, body aches) (Harrison et al., 2009). Low-dose endotoxin exposure, which increases IL-6 by over 100pg/mL, approximates acute illness. Endotoxin causes a variety of sickness symptoms, including changes in self-reported social approach and withdrawal motivation and neural sensitivity to social information, along with increases in physical sickness symptoms (Eisenberger et al., 2017). Thus, it may be that increasing levels of inflammation progressively influence neural sensitivity and automatic social behavior, followed by changes in mood that influence motivation for social approach and withdrawal, and finally physical symptoms that change intentional social behaviors (e.g., deciding to rest in bed). The brain appears to initiate behavioral adjustments at varying levels of awareness and intensity that match the degree of inflammatory response. Although acute stress may initiate changes in social behavior that help reduce risk of injury or infection, more pronounced changes in sickness behavior develop alongside acute illness and infection. Future research that compares flu, typhoid, and endotoxin exposure may be useful in clarifying this trajectory of intensifying psychological, behavioral, and physical changes that facilitate recovery.

Second, might sickness behaviors be adaptive in contexts of chronic threat and inflammation? When inflammation is chronic and systemic (as with many chronic diseases), are there ways to interrupt the trajectory toward prolonged sickness behaviors (e.g., depression, social withdrawal)? Similarly, when threat becomes chronic (e.g., loneliness, chronic stress), can a chronic inflammatory state be avoided? We recently showed that chronic stress-related inflammation predicted selective social withdrawal in a sample of mothers of a child with cancer, and that social withdrawal appeared to mitigate further increases in inflammation over time (Lindsay et al., 2022). However, in other contexts, thinning one’s social network is likely to solidify a chronic inflammatory state, as social isolation is robustly associated with poor health and mortality (Holt-Lunstad et al., 2015). Although chronic stress and inflammation each have potential to initiate a self-reinforcing state of inflammation and sickness symptoms, social behavior and inflammation may also co-regulate to urge recovery (Eisenberger et al., 2017). This cycle might also be interrupted through psychological interventions that help to reduce systemic inflammation (Bower & Irwin, 2016) or by anti-inflammatory treatments that help to reduce sickness symptoms (Miller & Raison, 2016).

Humans have a fundamental, evolutionary need for social connection. In times of threat—sickness or injury and social stress alike—survival is enhanced by drawing closer to those who care and away from others. Jolink et al. expand models of sickness behavior, showing that even a small inflammatory response begins to motivate social behaviors that promote recovery.