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Stress primes microglia to the presence of systemic inflammation: Implications for environmental influences on the brain

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The macrophage populations of the brain have been well described and include the macrophages of the meninges, the choroid plexus, the perivascular macrophages and the microglia, the resident macrophages of the brain parenchyma. The healthy brain microenvironment has a profound and remarkable impact on microglia and they are well recognised to be a population of macrophages with the most down-regulated or switched off phenotype of all the macrophage populations in the body (Perry and Gordon, 1991). The molecular interactions that regulate the microglia phenotype are beginning to be defined and include CD200 expression on neurons binding CD200R on microglia (Hoek et al., 2000), and neuronal CD22 on neurons binding CD45 on microglia (Mott et al., 2004). The very low or undetectable levels of expression of certain macrophage antigens on microglia, for example, MHC Class II, means that small changes in the levels of expression, or de novo synthesis, are readily detected in experimental models. The rapid changes in morphology and antigen expression has led to the microglia being described as exquisite sensors of even minor pathological change (Kreutzberg, 1996).
Communication between the systemic immune system and brain also involves the microglia. Following a systemic inflammatory challenge pro-inflammatory cytokines are synthesised within the brain and there mediate aspects of sickness behaviour. The microglia play a role in the synthesis of these central cytokines (Van Dam et al., 1995). Interestingly it is not only systemic inflammation that can initiate cytokine synthesis in the brain so too can peripheral stressors and recent evidence shows that prior stress leads to an exacerbation of brain cytokine synthesis after a peripheral inflammatory challenge (Johnson et al., 2002), and microglia proliferation (Nair and Bonneau, 2006). As reported in this issue of Brain Behaviour and Immunity Frank et al. (2006) have extended these observations on the interaction between stress and systemic inflammation and show that it is the microglia that are major players in mediating the enhanced cytokine synthesis. In animals that were subjected to inescapable shock the microglia in the CA3 region of hippocampus showed significant upregulation of MHC Class II as detected by immunocytochemisty, and also the levels of CD200 mRNA were reduced. Thus, stress alone is sufficient to activate the microglia and reduce the level of control exerted by the neurons through CD200. Manipulating the degree to which the shock was or was not controlled by the animal appeared not to be an important parameter. Following the period of stress the microglia were then isolated from the hippocampus and challenged ex vivo with lipopolysaccharide (LPS). Microglia from animals that had been subjected to shock were found to synthesise greater amounts of interleukin-1? mRNA than those from control animals challenged with LPS.
These interesting studies raise a number of important issues not the least of which is the nature of the pathways and signals that lead from the stressor to the activation of the microglia. The data suggest that the downregulation of CD200 may be important but at the present time we have little idea about the regulation of CD200 expression by neurons. If stress or indeed other systemic events modulate CD200 this will significantly impact on many aspects of neuroimmune communication. Frank et al. also suggest that the astrocytes are not major players but the authors stress that it is likely premature to exclude there cells from the frame. It was notable that the microglia expression of CD11b was not modified by stress and thus any single marker, such as GFAP used to study the astrocyte population, may not be the appropriate or sensitive marker for studying a particular cell type in these conditions. The present study only examined the synthesis of interleukin-1? mRNA and there are clearly many other cytokines and other inflammatory mediators that will be of interest to study.
Whatever the mechanisms that underpin how stress leads to the activation of microglia this study adds to a growing body of evidence demonstrating that microglia that may be “primed” (Perry et al., 2003) by a number of different stimuli including neurodegeneration (Cunningham et al., 2005 C. Cunningham, D.C. Wilcockson, S. Campion, K. Lunnon and V.H. Perry, Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration, J. Neurosci. 25 (2005), pp. 9275–9284. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (40)Cunningham et al., 2005), ageing (Godbout et al., 2005) and stress (Johnson et al., 2002) such that a second systemic inflammatory stimulus, e.g., systemic inflammation, may lead to either a switch in phenotype or an exaggerated pro-inflammatory phenotype. This exaggerated cytokine response may lead to acute changes in behaviour or exacerbate pathology. Thus, the microglia are both key sensors of pathology and they also play a critical role in the communication between environmental stressors, systemic pathogens or injury, and toxins, with the brain. It is not hard to see that this will have important consequences for our understanding of environmental influences on mental health and diseases of the brain

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Perry, V.H. (2007) Stress primes microglia to the presence of systemic inflammation: Implications for environmental influences on the brain Brain, Behavior and Immunity, 21, (1), pp. 45-46. (doi:10.1016/j.bbi.2006.08.004).

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Published date: 1 January 2007


Local EPrints ID: 56527
ISSN: 0889-1591
PURE UUID: 0bbd0b91-701d-4fd0-8f62-abbaf5684053

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Date deposited: 07 Aug 2008
Last modified: 17 Jul 2017 14:30

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