Elsevier

Brain Research

Volume 1446, 29 March 2012, Pages 144-155
Brain Research

Review
Central nervous system inflammation in disease related conditions: Mechanistic prospects

https://doi.org/10.1016/j.brainres.2012.01.061Get rights and content

Abstract

Inflammation is part of the innate immune response following insults to the body. This inflammatory reaction can spread throughout the systemic circulation and also into the central nervous system (CNS). CNS involvement has been demonstrated following acute peripheral insults including sepsis, surgery, burns and organ injury. It has also been observed in chronic conditions including obesity, diabetes and rheumatoid arthritis. Inflammation within the CNS is part of the pathogenesis of neurodegenerative diseases, in particular Alzheimer's disease, multiple sclerosis and Parkinson's disease. These diseases are prone to exacerbation as a result of increased inflammation within the CNS following peripheral insult. The effect of inflammation within the CNS can also be modulated by other factors including age and also oestrogen, although how pro-inflammatory cytokines within the CNS cause clinical changes remains to be elucidated. The mechanism underlying the passage of inflammation from the periphery into the CNS also remains unclear. Evidence has led to the suggestion of two main pathways: blood brain barrier (BBB) dependent and BBB independent. This uncertainty has led to an increasing body of work exploring the processes involved in both the passage of inflammation into, and the effect of cytokines on, the CNS.

Introduction

Inflammation is part of the innate immune response triggered by infection or injury. The reaction has two main aims: tissue homeostasis and tissue protection. These aims are met through numerous different processes including: activation of cell death mechanisms (apoptosis), the removal of dead cells and the promotion of wound healing. The body achieves this by stimulating the release of chemokines and cytokines that trigger the recruitment of specific immune cell populations and coordinate the local and systemic immune response (Carson et al., 2006).

In the central nervous system (CNS), inflammation can occur either as a result of local insult or as part of the systemic immune response. The involvement of the CNS in systemic inflammatory responses has opposed the traditional view of the blood brain barrier (BBB) as an impermeable membrane (Barker and Billingham, 1977, Medawar, 1948). CNS involvement has been demonstrated in response to both acute and chronic peripheral disease states. In this manuscript we aim to explore the acute disease states of infection (Dantzer, 2004), surgery (Wan et al., 2007), burns (Reyes et al., 2006) and organ injury (D'Mello et al., 2009, Liu et al., 2008), and the chronic diseased state of rheumatoid arthritis (RA) (Emmer et al., 2009) and depression (Loftis et al., 2010). We also explore the role of high fat consumption in triggering CNS inflammation (Thirumangalakudi et al., 2008). Inflammation within the CNS has also been associated with chronic neurodegenerative disease including: Alzheimer's diseases (AD) (Akiyama et al., 2000), multiple sclerosis (MS) (Prat et al., 2002) and Parkinson's disease (PD) (Hirsch and Hunot, 2009). The CNS inflammatory reaction is considered an integral part of the reaction to the primary cause of the disease and can be exacerbated by peripheral insults that cause inflammation (Perry et al., 2003). Herein in this review, we have discussed the following aspects: the CNS inflammation in disease and/or disease related conditions; the pathway linking peripheral and central inflammation; mechanism of action of cytokines in mediating changes in behaviour, including cognition, food intake and sleep; the effect of age and oestrogens on the central inflammatory response to peripheral insults and the relationship of these responses to neurodegenerative disorders.

Section snippets

Infection

Infections, such as the common cold, are able to cause changes in behavioural and physiological functions leading to what is known as ‘sickness behaviour’ (Dantzer et al., 2008). ‘Sickness behaviour’ is the collection of changes associated with infection including: lethargy, changes in sleep and changes in appetite (Dantzer et al., 2008). This central response to infection has been explored since the 1940s when experiments demonstrated that serum containing ‘endogenous factor’ after endotoxin

Obesity

Obesity is a disease like condition of great importance due to its increasing incidence and associated co-morbidities. In the UK, the percentage of adult population classified as obese has increased from 14.9% to 23% from 1993 to 2009 (Tabassum, 2009). Co-morbidities associated with obesity, including type 2 diabetes mellitus (T2DM) (Wannamethee and Shaper, 1999), cardiovascular disease (Hubert et al., 1983), high blood pressure (Garrison et al., 1987) and cognitive change (Elias et al., 2003),

Alzheimer's disease (AD)

An association between AD and neuroinflammation was established by post-mortem examination of Alzheimer's affected brain tissue (Uchihara et al., 1997), magnetic resonance imaging (MRI) and positron emission tomography (PET) (Cagnin et al., 2001). These studies all demonstrate microglial infiltration into the brain (Cagnin et al., 2001, Uchihara et al., 1997). Using the in vivo marker [11C](R)-PK11195 to identify activated microglia, reactive cells were found in the inferior and middle temporal

Mechanism of spread from peripheral source to the CNS

The CNS is surrounded by the BBB, which consists of endothelial cells connected by tight junctions (Reese and Karnovsky, 1967). These capillaries are surrounded by astrocytes, pericytes and neurones which come together forming the neurovascular unit (Hawkins and Davis, 2005). The BBB acts as an effective barrier between the periphery and the CNS (Lorton et al., 2008). Inflammation must either pass through or bypass the BBB in order to enter the CNS. Current evidence suggests three possible

Mechanisms underlying behaviour changes

Cytokines act on a variety of brain structures to stimulate the behavioural and cognitive changes associated with central inflammation. IL-1β at supra-physiological levels has been previously described to cause cognitive change (Terrando et al., 2010b, Yirmiya et al., 2002), reduced food intake (Kent et al., 1996) and weight loss (Kent et al., 1996). Its role in cognitive change, and in memory in particular, is complicated by its role, at physiological levels, in the process of long-term

Age as a risk factor in an exaggerated CNS inflammatory response

Age is an extremely important risk factor for exaggerated inflammatory response following peripheral insult (Godbout et al., 2005, Moller et al., 1998). This is reflected by an increased inflammatory reaction within the CNS of older animals after an inflammatory insult (Cao et al., 2010, Godbout et al., 2005, Rosczyk et al., 2008). This inflammatory reaction is characterised by increased glial activation and IL-1β expression following surgery (Cao et al., 2010, Rosczyk et al., 2008). Animal

Gender as a risk factor in exaggerated CNS inflammatory response

The drop in oestrogen levels at menopause has been associated with a large increase in the frequency of inflammatory diseases in women affecting the brain and other organs (Pozzi et al., 2006). Oestrogen has been demonstrated to suppress the microglial and pro-inflammatory cytokine response to LPS by inhibition of the NF-κB pathway (Galea et al., 2002, Gatson et al., 2009, Vegeto et al., 2001). The mechanism underlying this was shown to be through inhibition of p-65 subunit translocation (

Conclusion

The presence of CNS inflammation, a complication of the body's acute and chronic stress response, is increasingly being recognised in the clinical changes associated with ‘sickness behaviours’, ‘post-operative cognitive dysfunction’ and other disease conditions. Acute and chronic peripheral inflammation can stimulate and exacerbate CNS inflammation, potentially leading to exacerbation of pre-existing neurodegenerative disease. The pathway linking the peripheral inflammatory reaction to the CNS

Authors' contributions

All authors approve and participated in the writing of this manuscript.

Acknowledgments

This work was supported by the Research Fund from Alzheimer's Society/BUPA Foundation, London, UK.

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