Journal of Neuroinflammation (Oct 2021)

Interleukin-6 mediates delirium-like phenotypes in a murine model of urinary tract infection

  • Mohammad Harun Rashid,
  • Nicklaus A. Sparrow,
  • Faizan Anwar,
  • Gena Guidry,
  • Ambart E. Covarrubias,
  • Haoming Pang,
  • Chandrakumar Bogguri,
  • S. Ananth Karumanchi,
  • Shouri Lahiri

DOI
https://doi.org/10.1186/s12974-021-02304-x
Journal volume & issue
Vol. 18, no. 1
pp. 1 – 16

Abstract

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Abstract Background Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. Methods C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. Results Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r 2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r 2 = 0.2653, p < 0.0001). Conclusions These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.

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