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 threatrelated 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 social withdrawal is a prominent symptom of sickness, the mechanisms associated with this behavioral change remain unclear. In animals, the amygdala is a key neural region involved in sickness-induced social withdrawal. Consistent with this, in humans, heightened amygdala activity to negative social cues is associated with social avoidance tendencies. Based on these findings, we investigated whether an experimental inflammatory challenge selectively increased amygdala activity to socially threatening images as well as whether this activity related to feelings of social disconnection. Thirty-nine participants were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammatory activity. Pro-inflammatory cytokines were assessed at 7 hourly time points via blood draws; self-reported feelings of social disconnection and physical sickness symptoms were assessed hourly as well. Two hours post-injection, participants underwent an fMRI procedure to assess amygdala reactivity during the presentation of socially threatening images (fear faces) as well as non-socially threatening images (guns), socially non-threatening images (happy faces), and non-social, non-threatening images (household objects). Endotoxin led to greater amygdala activity in response to socially threatening vs. all other types of images. No such differences were found for placebo participants. Additionally, increased amygdala activity in endotoxin participants during the viewing of socially vs. non-socially threatening images was associated with increased feelings of social disconnection. These findings highlight the amygdala as a neural region that may be important for sickness-induced social withdrawal. The implications of amygdalar involvement in sickness-induced social withdrawal are discussed.

On the basis of the importance of social connection for survival, humans may have evolved a "sociometer"-a mechanism that translates perceptions of rejection or acceptance into state self-esteem. Here, we explored the neural underpinnings of the sociometer by examining whether neural regions responsive to rejection or acceptance were associated with state self-esteem. Participants underwent fMRI while viewing feedback words ("interesting," "boring") ostensibly chosen by another individual (confederate) to describe the participant's previously recorded interview. Participants rated their state self-esteem in response to each feedback word. Results demonstrated that greater activity in rejection-related neural regions (dorsal ACC, anterior insula) and mentalizing regions was associated with lower-state self-esteem. Additionally, participants whose self-esteem decreased from prescan to postscan versus those whose self-esteem did not showed greater medial prefrontal cortical activity, previously associated with self-referential processing, in response to negative feedback. Together, the results inform our understanding of the origin and nature of our feelings about ourselves.

The current research explored the neural mechanisms linking social status to perceptions of the social world. Two fMRI studies provide converging evidence that individuals lower in social status are more likely to engage neural circuitry often involved in ‘mentalizing’ or thinking about others' thoughts and feelings. Study 1 found that college students' perception of their social status in the university community was related to neural activity in the mentalizing network (e.g., DMPFC, MPFC, precuneus/PCC) while encoding social information, with lower social status predicting greater neural activity in this network. Study 2 demonstrated that socioeconomic status, an objective indicator of global standing, predicted adolescents' neural activity during the processing of threatening faces, with individuals lower in social status displaying greater activity in the DMPFC, previously associated with mentalizing, and the amygdala, previously associated with emotion/salience processing. These studies demonstrate that social status is fundamentally and neurocognitively linked to how people process and navigate their social worlds.

Psychological stress is implicated in the etiology of many common chronic diseases and mental health disorders. Recent research suggests that inflammation may be a key biological mediator linking stress and health. Nevertheless, the neurocognitive pathways underlying stress-related increases in inflammatory activity are largely unknown. The present study thus examined associations between neural and inflammatory responses to an acute laboratory-based social stressor. Healthy female participants (n = 31) were exposed to a brief episode of stress while they underwent an fMRI scan. Blood samples were taken before and after the stressor, and plasma was assayed for markers of inflammatory activity. Exposure to the stressor was associated with significant increases in feelings of social evaluation and rejection, and with increases in levels of inflammation. Analyses linking the neural and inflammatory data revealed that heightened neural activity in the amygdala in response to the stressor was associated with greater increases in inflammation. Functional connectivity analyses indicated that individuals who showed stronger coupling between the amygdala and the dorsomedial prefrontal cortex (DMPFC) also showed a heightened inflammatory response to the stressor. Interestingly, activity in a different set of neural regions was related to increases in feelings of social rejection. These data show that greater amygdala activity in response to a stressor, as well as tighter coupling between the amygdala and the DMPFC, are associated with greater increases in inflammatory activity. Results from this study begin to identify neural mechanisms that might link stress with increased risk for inflammation-related disorders such as cardiovascular disease and depression.

Although considerable research has shown that inflammation leads to social withdrawal more generally, it is also possible that inflammation leads to social approach when it comes to close others. Whereas it may be adaptive to withdraw from strangers when sick, it may be beneficial to seek out close others for assistance, protection, or care when sick. However, this possibility has never been explored in humans nor have the neural substrates of these behavioral changes. Based on the role of the ventral striatum (VS) in responding to: (1) the anticipation of and motivation to approach rewarding outcomes and (2) viewing social support figures, the VS may also be involved in sickness-induced approach toward support figures. Thus, the goal of the present study was to examine whether inflammation leads to a greater desire to approach support figures and greater VS activity to viewing support figures. To examine this, 63 participants received either placebo or low-dose endotoxin, which safely triggers an inflammatory response. Participants reported how much they desired to be around a self-identified support figure, and viewed pictures of that support figure while undergoing an fMRI scan to assess reward-related neural activity. In line with hypotheses, endotoxin (vs. placebo) led participants to report a greater desire to be around their support figure. In addition, endotoxin (vs. placebo) led to greater VS activity to images of support figures (vs. strangers) and greater increases in inflammation (IL-6 levels) were associated with greater increases in VS activity. Together, these results reveal a possible neural mechanism important for sickness-induced social approach and highlight the need for a more nuanced view of changes in social behavior during sickness.

Inflammation, part of the body’s innate immune response, can lead to “sickness behaviors,” as well as alterations in social and affective experiences. Elevated levels of pro-inflammatory cytokines have been associated with increased neural sensitivity to social rejection and social threat, but also decreased neural sensitivity to rewards. However, recent evidence suggests that inflammation may actually enhance sensitivity to certain social rewards, such as those that signal support and care. Despite a growing interest in how inflammation influences neural reactivity to positive and negative social experiences, no known studies have investigated these processes in the same participants, using a similar task. To examine this issue, 107 participants were randomly assigned to receive either placebo or low-dose endotoxin, which safely triggers an inflammatory response. When levels of pro-inflammatory cytokines were at their peak, participants were scanned using fMRI while they received positive, negative, and neutral feedback from an “evaluator” (actually a confederate) about how they came across in an audio-recorded interview. In response to negative feedback (vs. neutral), participants in the endotoxin condition showed heightened neural activity in a number of threat-related neural regions (i.e., bilateral amygdala, dorsal anterior cingulate cortex) and a key mentalizing-related region (i.e., dorsomedial PFC), compared to placebo participants. Interestingly, when receiving positive feedback (vs. neutral), endotoxin led to greater neural activity in the ventral striatum and ventromedial PFC, regions often implicated in processing reward, compared to placebo. Together, these results reveal that individuals exposed to an inflammatory challenge are more “neurally sensitive” to both negative and positive social feedback, suggesting that inflammation may lead to a greater vigilance for both social threats and social rewards.

Socioeconomic status (SES), often conceptualized as income, education, or occupation, is associated with risk for disease morbidity and psychopathology. Recent research has focused on the potential biological mechanisms linking lower SES and poor outcomes; much of this work has examined the relationship between SES and markers of systemic inflammation. The strength of the estimated association between SES and inflammatory markers varies widely across individual studies. Thus, we used meta-analytic techniques to quantify the magnitude of this relationship. To accomplish this, PubMed and PsycINFO were searched for papers that reported on SES and two commonly measured systemic inflammatory markers, C-reactive protein (CRP) and interleukin-6 (IL-6). Peer-reviewed, empirical papers conducted in non-patient populations were included. Data from 43 papers (N = 111,156) reporting a total of 63 relevant effect sizes were included in analyses. SES, broadly defined, was significantly associated with both levels of CRP (Z = 0.12; 95% CI, 0.09-0.16) and IL-6 (Z = 0.15; 95% CI,0.12-0.18); individuals with lower SES showed higher levels of systemic inflammation. Subanalyses demonstrated that studies operationalizing SES as either levels of income or educational attainment also found significant associations with both CRP and IL-6. Moderator analyses revealed that effect sizes varied based on sample characteristics and analysis approaches. Lower SES is associated with significantly elevated levels of inflammatory markers of disease risk. Thus, proinflammatory pathways are likely an important mechanism translating socioeconomic inequalities into mental and physical health disparities.