Abstract
BackgroundUrinary 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.MethodsC57/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 × 108Escherichia 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.ResultsCompared 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 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001).ConclusionsThese 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.
Highlights
Urinary tract infection (UTI) is a common condition that affects an estimated 150 million individuals worldwide per year [1]
In a mouse model of non-infectious acute lung injury, we recently demonstrated that systemic IL-6 inhibition reverses delirium-like neuronal changes in the frontal cortex and hippocampus, suggesting a key role for IL-6 in mediating delirium-like structural phenotypes [7]
No bacteria were recovered from the tissues or urine of the mice inoculated with sterile phosphate-buffered saline (PBS), while there was significantly increased formation of bacterial colonies in the mice who were transurethrally inoculated with 108 colony forming unit/mL (cfu/mL)
Summary
Urinary tract infection (UTI) is a common condition that affects an estimated 150 million individuals worldwide per year [1]. Delirium complicates recovery in approximately one-third of patients with UTI and is Rashid et al J Neuroinflammation (2021) 18:247 characterized by a constellation of symptoms that reflect dysfunction of the frontal cortex and hippocampus, including psychomotor agitation, inattentiveness, and short-term memory impairment [2,3,4,5,6]. In a mouse model of non-infectious acute lung injury, we recently demonstrated that systemic IL-6 inhibition reverses delirium-like neuronal changes in the frontal cortex and hippocampus, suggesting a key role for IL-6 in mediating delirium-like structural phenotypes [7]. 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
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