Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide

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Abstract

Interleukin (IL)-10 is important for regulating inflammation but whether it protects against infection-related deficits in cognitive function is unknown. Therefore, the current study evaluated sickness behavior, hippocampal-dependent matching-to-place performance and several inflammatory cytokines and neurotrophins in wild-type (IL-10+/+) and IL-10-deficient (IL-10−/−) mice after i.p. injection of lipopolysaccharide (LPS). Additionally, morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus was assessed. Treatment with LPS increased IL-1β, IL-6, and tumor necrosis factor α (TNFα) mRNA in all brain areas examined including the hippocampus, in both IL-10+/+ and IL-10−/− mice but the increase was largest in IL-10−/− mice. Plasma IL-1β, IL-6 and TNFα were also higher in IL-10−/− mice compared to IL-10+/+ mice after LPS. Consistent with increased inflammatory cytokines in IL-10−/− mice after LPS treatment, were a more lengthy sickness behavior syndrome and a more prominent reduction in hippocampal levels of nerve growth factor mRNA; brain-derived neurotrophic factor mRNA was reduced similarly in both genotypes after LPS. In a test of hippocampal-dependent learning and memory that required mice to integrate new information with previously learned information and switch strategies to master a task, IL-10−/− mice were found to be less efficient after LPS than were similarly treated wild-type mice. LPS did not affect morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus in either genotype. Taken together the results are interpreted to suggest that during peripheral infection IL-10 inhibits sickness behavior and tribulations in hippocampal-dependent working memory via its propensity to mitigate inflammation. We conclude that IL-10 is critical for maintaining normal neuro-immune communication during infection.

Introduction

Interleukin (IL)-10 is a prototypical anti-inflammatory cytokine in that it inhibits production of inflammatory cytokines such as IL-1β, IL-6, and tumor necrosis factor alpha (TNFα) (Moore et al., 2001, Strle et al., 2001) and promotes the release of other anti-inflammatory cytokines including IL-1 receptor antagonist (IL-1ra) (Howard et al., 1992). In the brain of rats IL-10 has been shown to reduce IL-1β and TNFα after traumatic brain injury and improve neurological recovery (Knoblach and Faden, 1998). Furthermore, infarct volume produced by middle cerebral artery occlusion was exacerbated in IL-10 knockout (IL-10−/−) mice compared to wild-types (Grilli et al., 2000), and addition of recombinant murine IL-10 to primary cortical or cerebellar granular neuron cultures from IL-10−/− mice prevented neuronal damage induced by excitotoxicity (Grilli et al., 2000). In the brain IL-10 also appears to inhibit the development and progression of chronic neurodegenerative diseases. For example, the onset of neuroinflammation and progression of prion disease was accelerated in mice deficient in IL-10 (Thackray et al., 2004). Interestingly, individuals with a polymorphism in the IL-10 promoter that results in lower levels of IL-10 have a higher likelihood of developing multiple sclerosis (de Jong et al., 2000) and Alzheimer’s disease (McGeer and McGeer, 1996). Collectively, these findings on brain injury and neurodegenerative disease indicate that IL-10 in the brain is an important counterbalance to the inflammatory response, which is injurious if unchecked.

During a peripheral infection, the immune system conveys a message to the brain and microglial cells respond and produce inflammatory cytokines that induce a behavioral response that is ordinarily adaptive. Excessive production of inflammatory cytokines in the brain, however, can cause behavioral pathology (Dantzer et al., 2008, Sparkman and Johnson, 2008). When lipopolysaccharide (LPS) was administered to mimic a peripheral infection, old mice experienced an exaggerated inflammatory cytokine response in the brain and exhibited signs of behavioral pathology, including prolonged anorexia (Godbout et al., 2005), depressive-like behavior (Godbout et al., 2008), and cognitive disturbances (Chen et al., 2008) that were not seen in younger cohorts. Architectural changes to dorsal CA1 hippocampal neurons have also been reported in young mice given LPS intracerebroventricularly (ICV) (Milatovic et al., 2003) and in older mice given LPS i.p. (Richwine et al., 2008). Other studies provide compelling evidence for a linkage between inflammatory cytokine expression in the brain and learning and memory deficits (Ben Menachem-Zidon et al., 2008) as well as depression (O’Connor et al., 2008). And the expression pattern of genes known to be involved in neuroplasticity, including brain-derived neurotrophic factor (BDNF), Arc, and ephrin receptor, is influenced by inflammatory stimuli (Bonow et al., 2008, Richwine et al., 2008, Rosi et al., 2005). All told, regulating inflammatory cytokines in the brain in the context of a peripheral infection appears important for preserving neuroplasticity and protecting against behavioral disorders.

Whereas the effects of IL-10 in brain injury and some neurodegenerative diseases has received considerable attention, less is known about the role of IL-10 in mediating communication between the peripheral immune system and brain during infection and it is not known if IL-10 has a role in preventing cognitive disorders that are associated with inflammation. In support of an important role for IL-10, results from one study suggested that IL-10 functions as an endogenous antipyretic following peripheral injection of LPS (Leon et al., 1999), and another study found several inflammatory cytokines to be higher in whole brain of IL-10-deficient mice compared to wild-type mice after ICV injection of LPS (Agnello et al., 2000). Moreover, ICV injection of IL-10 inhibited the depression in social behavior caused by a peripheral injection of LPS (Bluthe et al., 1999), and recently LPS-induced fatigue and deficits in psychomotor coordination were found to be exacerbated in mice deficient in IL-10 (Krzyszton et al., 2008).

Given the relationship between inflammatory cytokines and cognitive function, the present study was conducted to determine if IL-10 protects against infection-related neurobehavioral complications including cognitive deficits. Specifically, we evaluated sickness behavior, matching-to-place performance and several inflammatory cytokines and neurotrophins in wild-type and IL-10-deficient mice after i.p. injection of LPS. Additionally, morphology of dendrites of pyramidal neurons in the dorsal CA1 hippocampus was assessed. Our hypothesis was that inflammatory cytokines in the brain and neurobehavioral deficits in mice challenged with LPS would be increased in the absence of IL-10. It was further hypothesized that increased inflammation would be associated with reduced neurotrophic support and dendritic atrophy of CA1 pyramidal neurons.

Section snippets

Animals

Two month old male congenic IL-10 knockout (IL-10−/−) (C.129P2(B6)-Il10tm1Cgn/J) mice and wild-type C57BL/6 (IL-10+/+) controls were purchased from The Jackson Laboratory (Ben Harbor, Maine). Because The Jackson Laboratory maintains the IL-10−/− strain homozygously, the standard inbred background strain must be used as controls. The congenic IL-10−/− strain, which was produced by backcrossing 10 generations, is estimated to be 99.9% similar to the background inbred strain at all unlinked gene

Sickness behavior

In the first experiment, we sought to determine if IL-10 inhibits LPS-induced deficits in locomotor activity and food intake. Analysis of locomotor behavior revealed both LPS-treated IL-10+/+ and IL-10−/− mice showed significant reductions in distance traveled at the 4 h time point. However, by 24 h IL-10+/+ mice treated with LPS had recovered to approximately 72% of the activity levels expressed by saline-treated IL-10+/+ mice and LPS-treated IL-10−/− mice were still reduced to 35% of their

Discussion

We recently reported that infection-related fatigue and deficits in psychomotor coordination were exacerbated in mice deficient in IL-10 (Krzyszton et al., 2008). The fatigue and psychomotor deficits in IL-10−/− mice were associated with higher plasma inflammatory cytokine levels and increased expression of inflammatory cytokine genes in brain areas important for skilled motor behaviors. The results of the present study are consistent with this earlier report but extend it by showing that

Acknowledgments

This research was funded by National Institutes of Health Grants AG016710 and AG023580.

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