Recruitment of α4β7 monocytes and neutrophils to the brain in experimental colitis is associated with elevated cytokines and anxiety-like behavior

Abstract

Background Behavioral comorbidities, such as anxiety and depression, are a prominent feature of IBD. The signals from the inflamed gut that cause changes in the brain leading to these behavioral comorbidities remain to be fully elucidated. We tested the hypothesis that enhanced leukocyte–cerebral endothelial cell interactions occur in the brain in experimental colitis, mediated by α4β7 integrin, to initiate neuroimmune activation and anxiety-like behavior. Methods Female mice treated with dextran sodium sulfate were studied at the peak of acute colitis. Circulating leukocyte populations were determined using flow cytometry. Leukocyte–cerebral endothelial cell interactions were examined using intravital microscopy in mice treated with anti-integrin antibodies. Brain cytokine and chemokines were assessed using a multiplex assay in animals treated with anti-α4β7 integrin. Anxiety-like behavior was assessed using an elevated plus maze in animals after treatment with an intracerebroventricular injection of interleukin 1 receptor antagonist. Results The proportion of classical monocytes expressing α4β7 integrin was increased in peripheral blood of mice with colitis. An increase in the number of rolling and adherent leukocytes on cerebral endothelial cells was observed, the majority of which were neutrophils. Treatment with anti-α4β7 integrin significantly reduced the number of rolling leukocytes. After anti-Ly6C treatment to deplete monocytes, the number of rolling and adhering neutrophils was significantly reduced in mice with colitis. Interleukin-1β and CCL2 levels were elevated in the brain and treatment with anti-α4β7 significantly reduced them. Enhanced anxiety-like behavior in mice with colitis was reversed by treatment with interleukin 1 receptor antagonist. Conclusions In experimental colitis, α4β7 integrin-expressing monocytes direct the recruitment of neutrophils to the cerebral vasculature, leading to elevated cytokine levels. Increased interleukin-1β mediates anxiety-like behavior.

Anxiolytic effects of Enterococcus faecalis 2001 on a mouse model of colitis

“…As mentioned above, a high rate of neuropsychiatric disorders has been reported to occur in patients with IBD 1 – 5 , but the underlying mechanisms remain unclear; other studies have reported that DSS-treated mice, commonly used in modeling UC, show UC findings, such as diarrhea and bloody stools, and exhibit anxiety-like behaviors 28 , 29 . In the present study, 2% DSS-treated mice exhibited UC-like symptoms such as diarrhea, hematochezia, and shortened colon length as well as anxiety-like behaviors in the hole-board and elevated plus-maze tests (Figs.…”

“…Dextran sulfate sodium (DSS), which causes inflammatory changes in the intestinal mucosa similar to UC, has shown to induce depression-like and anxiety-like behaviors 28 – 32 . Moreover, DSS-treated mice exhibit the disruption of gut microbiota balance, decreased intestinal barrier integrity, and elevated serum LPS, as well as elevated serum corticosterone (cortisol in humans) observed in patients with anxiety 29 , 31 , 33 – 35 .…”

Anti-inflammatory effects of β-FNA are sex-dependent in a pre-clinical model of LPS-induced inflammation

“…Others found that CXCL10 expression is increased in colonic mucosa of patients with active IBD [ 70 ]. Cluny et al, [ 71 ] recently reported that liver and gut inflammation leads to neuroinflammation as indicated by increased TNF, IL-1β, and CCL2 levels in the brain. These findings are consistent with the LPS-induced neuroinflammation coupled with inflammatory cytokine/chemokine expression in the spleen, liver, and intestines.…”

Contribution of Blood Vessel Activation, Remodeling and Barrier Function to Inflammatory Bowel Diseases

“…A strong link between the GVB and the blood–brain barrier (BBB) has been established in IBD. Manifestations of anxiety and depression have been reported in up to 40% of patients with active IBD (14), together with deterioration in cognitive functions [ 216 , 217 , 218 , 221 , 222 , 223 , 224 ]. Similar observations have been made in DSS-colitis models where mice displayed increased anxiety- and depression-like behaviors and alterations of the limbic system [ 158 , 225 , 226 , 227 ].…”