Stressor-Induced Increases in Circulating, but Not Colonic, Cytokines Are Related to Anxiety-like Behavior and Hippocampal Inflammation in a Murine Colitis Model

Abstract

Stressor exposure increases colonic inflammation. Because inflammation leads to anxiety-like behavior, we tested whether stressor exposure in mice recovering from dextran-sulfate-sodium (DSS)-induced colitis enhances anxiety-like behavior. Mice received 2% DSS for five consecutive days prior to being exposed to a social-disruption (SDR) stressor (or being left undisturbed). After stressor exposure, their behavior was tested and colitis was assessed via histopathology and via inflammatory-cytokine measurement in the serum and colon. Cytokine and chemokine mRNA levels in the colon, mesenteric lymph nodes (MLNs), hippocampus, and amygdala were measured with RT-PCR. SDR increased anxiety-like behaviors, which correlated with serum and hippocampal IL-17A. The stressor also reduced IL-1β, CCL2, and iNOS in the colonic tissue, but increased iNOS, IFNγ, IL-17A, and TNFα in the MLNs. A network analysis indicated that reductions in colonic iNOS were related to elevated MLN iNOS and IFNγ. These inflammatory markers were related to serum and hippocampal IL-17A and associated with anxiety-like behavior. Our data suggest that iNOS may protect against extra-colonic inflammation, and when suppressed during stress it is associated with elevated MLN IFNγ, which may coordinate gut-to-brain inflammation. Our data point to hippocampal IL-17A as a key correlate of anxiety-like behavior.

Connecting the dots from east to west

“… Maltz et al (2022) studied the role of social disruption in mice following recovery from colitis. The social disruption stressor did not exacerbate recovery from colitis but did increase anxiety-like behaviors and these correlated with an increase in interleukin (IL)-17A in both blood and brain.…”

“…These contributions include pre-clinical studies focusing on the molecular mechanisms by which social stress and immune activation alter behaviors relevant to depression such as reward motivation and social interaction ( Cuomo-Haymour et al, 2022 ; DiSabato et al, 2022 ). Additionally, the role of stress, circadian rhythms, and microbiome–gut–immune–brain interactions were explored in the context of medical illnesses that have strong PNI components including high rates of comorbid depression and anxiety ( Amoroso et al, 2021 ; Su et al, 2022 ; Maltz et al, 2022 ). Clinical studies in this Special Issue also reflect a growing focus on personalized and/or nuanced approaches in PNI including consideration of specific depressive symptoms, neural circuit dysfunction, and EEG-defined microstates associated with inflammatory dysregulation, as well as moderation of the association between inflammation and depression by race and ethnicity ( Wijaya et al, 2022 ; Zhao et al, 2022 ; Toussaint et al, 2022 ).…”