Abstract
BackgroundCognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits.MethodsSepsis was induced in adult male C57BL/6 J and CXCR5−/− mice by cecal ligation and puncture (CLP). At 14–18 days after surgery, animals were tested in a Morris water maze, followed by a fear conditioning test. Transmission electron microscopy of hippocampal sections was used to assess levels of autophagy. Primary microglial cultures challenged with lipopolysaccharide (LPS) were used to examine the effects of short interfering RNA targeting CXCR5, and to investigate the possible involvement of the p38MAPK/NF-κB/STAT3 signaling pathway.ResultsCLP impaired learning and memory and up-regulated CXCR5 in hippocampal microglia. CLP activated hippocampal autophagy, as reflected by increases in numbers of autophagic vacuoles, conversion of microtubule-associated protein 1 light chain 3 (LC3) from form I to form II, accumulation of beclin-1 and autophagy-related gene-5, and a decrease in p62 expression. CLP also shifted microglial polarization to the M1 phenotype, and increased levels of IL-1β, IL-6 and phosphorylated p38MAPK. CXCR5 knockout further enhanced autophagy but partially reversed all the other CLP-induced effects, including cognitive deficits. Similar effects on autophagy and cytokine expression were observed after knocking down CXCR5 in LPS-challenged primary microglial cultures; this knockdown also partially reversed LPS-induced up-regulation of phosphorylated NF-κB and STAT3. The p38MAPK agonist P79350 partially reversed the effects of CXCR5 knockdown in microglial cultures.ConclusionsCXCR5 may act via p38MAPK/NF-κB/STAT3 signaling to inhibit hippocampal autophagy during sepsis and thereby contribute to cognitive dysfunction. Down-regulating CXCR5 can restore autophagy and mitigate the proinflammatory microenvironment in the hippocampus.
Highlights
Cognitive deficits are common in patients with sepsis
Considering previous studies that linked C-X-C motif chemokine receptor 5 (CXCR5) to p38MAPK activation [23], and p38MAPK to autophagy and neuroinflammation [24], the mechanistic investigation in the current study focused on the p38MAPK/Nuclear factor kappa-B (NF-κB)/Signal transducer and activator of transcription (STAT3) pathway
Results from the present study suggest that CXCR5 contributes to cognitive impairment by enhancing p38MAPK/NF-κB/STAT3 signaling
Summary
Cognitive deficits are common in patients with sepsis. Previous studies in sepsis-associated encephalopathy (SAE) implicated the C-X-C chemokine receptor type (CXCR) 5. The present study used a mouse model of SAE to examine whether CXCR5 down-regulation could attenuate cognitive deficits. The major resident immune cells in the CNS are activated upon sepsis, and shift from a “surveillance” phenotype to a proinflammatory M1 phenotype to release inflammatory signals [9, 10]. In this way, microglial activation exacerbates neuronal injury and impairs learning and memory [11]. SAE could be alleviated by blocking microglial activation via inhibiting the IL-17A/IL-17R inflammatory pathway [12], injecting attractylone to polarize microglia toward the M2 phenotype [13], or injecting minocycline [14] or the ginsenoside Rg1 [15] to inhibit neuroinflammation
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