Microglial Activation

From: Traumatic Brain Injury Rehabilitation, Treatment, and Case Management, Fourth Edition <a href="http://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdfhttp://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdf">http://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdfhttp://gynecology.sbmu.ac.ir/uploads/4_5902284924500574896.pdf</a>

The microglia surround and protect the neurons in our brains and spinal cord. As the main immune defenders in the brain, they spew out an array of inflammatory and neurotoxic substances when activated. When we have a cold these substances cause the symptoms associated with ‘sickness behavior’ such as fatigue, pain, and mental fogginess.

Some researchers speculate that stress, infections, repeated insults and/or  genetic factors can prime the microglia to over-respond to substances called alarmins generated by cellular stress. They believe that this microglial hypersensitivity is causing neuroinflammation in many diseases.

A small 2014 study using a PET scan to measure microglial activation suggested the microglia were indeed activated in large parts of the brains of people with ME/CFS. Dr. Jarred Younger’s small study at Stanford suggests microglial sensitization to leptin could be causing the fatigue in ME/CFS. He believes low dose naltrexone’s (LDN’s) success in small Fibromyalgia trials derives from LDN’s ability to reduce microglial activation.

While microglial activation clearly plays a role in neuropathic pain, direct evidence of microglial activation in ME/CFS or FM is still scanty. The potential microglial inhibitors listed below are not intended as a treatment prescription for ME/CFS or FM, but to illustrate treatment possibilities that future research may indicate are helpful.

Cytokine Inflamation
From: 'Part 2: Brain Cells Making us Sick? Messed up microglia could be driving symptoms' <a href="http://phoenixrising.me/archives/25310">http://phoenixrising.me/archives/25310</a>
Interferon-gamma, a proinflammatory cytokine <a href="http://www.nature.com/gene/journal/v6/n8/full/6364246a.html" target="blank">that can activate microglia</a>, seemed to play a particularly important role. Patients with two copies of the most active interferon-gamma gene version were likely to be sicker initially and <a href="http://www.ncbi.nlm.nih.gov/pubmed/18937577" target="blank">about three times more likely to develop CFS at six months</a>.
This hypothesis got some support from a <a href="http://phoenixrising.me/archives/24936" target="blank">recent small study</a> which found that microglia in the brains of ME/CFS patients were activated — exactly what the Dubbo hypothesis predicts.
A second way that microglia could cause a continuing sickness response is by becoming over-reactive. <a href="http://www.southampton.ac.uk/biosci/about/staff/vhp.page" target="blank">Hugh Perry, Professor of experimental neuropathology</a> from the University of Southampton, and Dr. Jarred Younger of Stanford University have independently proposed that the problem starts with “priming” of microglia by a variety of factors, including previous infections, obesity, chronic stress, and age.
Primed microglia are hypersensitive — a bit like a primed or armed bomb — so they react too easily and/or too aggressively, which could lead to long-term sickness response. So an infection or other trigger that would lead to no long-term problems in someone with “normal” microglia could lead to ME/CFS or fibromyalgia in someone with primed microglia.
Primed microglia are <a href="http://www.nature.com/nrneurol/journal/v10/n4/full/nrneurol.2014.38.html" target="blank">measurably different from patrolling ones</a>, with very different receptors on their cell surface. Fewer of the receptors that respond to “keep calm” signals from healthy neurons and more receptors that respond to any “shoot now” signals. The result is an excitable, trigger-happy microglial cell.
Much of the work on priming has been done on animals, since the only sure way to detect priming is to physically examine them. However, studies looking at brains of people who have died of neurodegenerative disease also reveal primed microglia.
Perry believes that priming is an important factor in these illnesses because it could lead to an overly-aggressive immune response, damaging tissue instead of helping it heal.
At the recent International Symposium for CFS/ME in Australia Perry suggested that <a href="http://www.twitlonger.com/show/n_1rt43lk" target="blank">priming of microglia could be behind this illness as well</a> (though he doesn’t think neurones degenerate in ME/CFS the way they do in the other illnesses he studies). Once primed, Perry argues, an infection could send the microglia into a permanently activated state, triggering a long-term sickness response.

Dr. Jarred Younger

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Younger, a <a href="https://med.stanford.edu/profiles/jarred-younger" target="blank">pain researcher at Stanford</a>, independently developed a very similar theory, which he described at the <a href="http://phoenixrising.me/archives/24323" target="blank">Stanford Symposium</a>and IACFS/ME conference in March. He primarily focused on fibromyalgia in the IACFS/ME talk, but believes the same mechanism could be behind ME/CFS. Priming could lead to the ME/CFS and fibromyalgia in two possible ways, says Younger:

<ul>

<li>Similar to Perry’s view, microglia might get “stuck” in the activated state: “they fail to revert to their former patrolling state and are therefore constantly producing chemicals that cause ME/CFS symptoms. Microglia are long-lived cells (many, many years), so microglia stuck in [an activated] state can cause problems for a long period of time.”</li>

</ul>

<ul>

<li>Or, primed microglia may react when they shouldn’t, producing the flares characteristic of ME/CFS and FM as they become fully activated and pump out the chemicals that cause sickness.</li>

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From: 'Cytokines across the Night in Chronic Fatigue Syndrome with and without Fibromyalgia' <a href="http://cvi.asm.org/content/17/4/582.full">http://cvi.asm.org/content/17/4/582.full</a>

"These data provide additional experimental evidence against the hypothesis that CFS is a manifestation of an upregulated proinflammatory state and leave open the role for anti-inflammatory cytokines in the genesis of CF"
A major hypothesis for the cause of CFS is an immune dysfunction characterized by a general upregulation of proinflammatory cytokines. This hypothesis is based, in part, on clinical reports that administration of proinflammatory cytokines in the treatment of disease in humans produces a flu-like syndrome resembling that of CFS (<a id="xref-ref-26-2" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-26">26</a>). However, there have been few empirical data supporting this hypothesized link between proinflammatory cytokines and CFS, and our own prior studies in CFS patients did not find any cytokine abnormalities (<a id="xref-ref-15-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-15">15</a>, <a id="xref-ref-38-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-38">38</a>). The results of this study using nocturnal samples also do not support the hypothesis of an upregulated inflammatory immune system mediated by cytokines in the genesis of CFS. A similar conclusion has been reached in a study of a sample of patients with postinfectious fatigue (<a id="xref-ref-32-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-32">32</a>).
Experimental evidence exists to support the notion of a cytokine/sleep network in which proinflammatory cytokines induce sleep and anti-inflammatory cytokines disturb sleep (<a id="xref-ref-13-2" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-13">13</a>, <a id="xref-ref-14-2" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-14">14</a>). The existence of this immunological homeostatic system controlling sleep led us to generate an alternative hypothesis to the proinflammatory one as a cause of CFS, namely, that disturbances in this cytokine/sleep network could lead to disturbed sleep with resulting fatigue. Our own earlier study looking at cytokine secretory patterns in plasma across a 24-h day supported that hypothesis. We found elevated levels of IL-10 in the blood of FM patients occurring during the nighttime (<a id="xref-ref-28-5" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-28">28</a>). The data collected here support that result for the CFS-only group and not for the CFS plus FM group, as might have been expected. But the magnitude of this difference was small, less than 1 pg/ml, and thus may be of only limited biological significance. Moreover, our analyses covered multiple cytokines and multiple methods, and so this one significant finding could reflect a type 1 error.
However, plasma levels of IL-10 in our patients did correlate inversely with their total sleep period, and our own earlier work using neural nets (<a id="xref-ref-12-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-12">12</a>) as well as that of other groups studying cytokines in CFS also reported a shift of the cytokine network away from a proinflammatory and toward an anti-inflammatory balance (<a id="xref-ref-25-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-25">25</a>, <a id="xref-ref-27-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-27">27</a>). Thus, the modest change in IL-10 reported here is consistent with the suggestion that patients with CFS show a shift toward Th2-type cytokines.
The argument that CFS is caused by immune dysregulation has also been extended to patients with FM (<a id="xref-ref-33-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-33">33</a>). In FM, the best evidence is for elevations in IL-8, a chemokine involved in the early stages of the genesis of an inflammatory response (<a id="xref-ref-10-2" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-10">10</a>, <a id="xref-ref-33-2" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-33">33</a>, <a id="xref-ref-34-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-34">34</a>). Those results were based on single daytime samples of either serum or supernatants of stimulated or unstimulated PBMCs. We did not find this result in our sample of CFS patients with FM, despite our sampling repeatedly during the nighttime. We cannot explain this discrepancy except to suggest that the differences found previously may reflect an altered circadian pattern of IL-8, with increases just during the waking period. Another group reported no decrease in either serum level or gene expression of mRNA for IL-8 in patients with chronic widespread pain who were taking various medicines for their pain (<a id="xref-ref-31-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-31">31</a>). However, those researchers did find that the chronic pain patients had both reduced gene expression and reduced serum levels of the anti-inflammatory cytokines IL-4 and IL-10 compared to healthy controls, a different result from that found in the current study. It is also possible that differences in medication usage among patients in these different studies might have been responsible for this discrepant result.
The fact that both CFS and FM patients have some alterations in the balance of Th1 and Th2 cytokines toward a Th2 or sleep-disrupting response suggests a possible role for cytokine-induced, disturbed sleep in the pathogenesis of both syndromes. We have recently studied the sleep of subgroups of patients with CFS alone or with CFS plus FM after excluding patients with diagnosable sleep pathology (<a id="xref-ref-29-2" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-29">29</a>). We found that both subgroups had evidence of disrupted sleep as manifested by shorter bouts of sleep than healthy controls (<a id="xref-ref-29-3" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-29">29</a>). In a subsequent study, we sleep deprived some of these patients for an entire night and found that one-third of them showed delays in falling asleep the next morning compared to healthy control subjects (unpublished data). Sleep deprivation is an obvious cause of severe fatigue, and several studies have shown that disrupted sleep can also lead to reduced pain thresholds in healthy volunteers (<a id="xref-ref-11-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-11">11</a>, <a id="xref-ref-16-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-16">16</a>, <a id="xref-ref-19-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-19">19</a>). Combined, these data suggest that sleep disturbances, perhaps related to an altered sleep/cytokine network favoring a Th2 response, may lead to the symptoms consistent with the diagnoses of CFS and FM.
Because the literature did not indicate which of the several methodologies available to assay cytokines would be the best in identifying abnormalities in CFS and FM, we used a comprehensive approach and measured cytokine protein concentrations in plasma, constitutive and stimulated protein release from PBMCs, and cytokine mRNA expression in whole blood cells. Importantly, our findings indicate that cytokine data using each of the assay methods did not correlate well with cytokine data generated by the other methods, suggesting that each method captures different aspects of cytokine properties or function. The relatively poor correlation between assay methods has been noted previously (<a id="xref-ref-21-1" class="xref-bibr" href="http://cvi.asm.org/content/17/4/582.full#ref-21">21</a>).
The only method that revealed a significant result between patients and controls was measurement of cytokines in plasma using the Luminex technology. The fact that more basic measures of cytokine secretion and release did not reveal significant differences between patients and controls may mean that the increases in IL-10 observed here and in our previous work may reflect systemic factors influencing cytokine levels in blood from CFS patients rather than frank increases in anti-inflammatory cytokine manufacture.
In summary, we designed this study to examine two alternative hypotheses: one, that CFS and FM are caused by increases in proinflammatory cytokines, and two, that CFS and FM are caused by disrupted sleep produced by increases in anti-inflammatory cytokines. Since disparate results have come from studies sampling the blood once during the daytime, we decided to sample blood several times during the nighttime while subjects slept. We reduced variability by studying women with CFS alone or with CFS plus FM, at the same menstrual phase, and after excluding any subjects with current major depression. Despite using these “pure” patient groups, we found evidence for a rather small elevation of one anti-inflammatory cytokine, IL-10, only in those patients with CFS alone, and in only one of three assays, the one quantifying cytokines in plasma. Obvious limitations of this study are the relatively small sample size and our focus on female patients only. These data provide additional experimental evidence against the hypothesis that CFS is a manifestation of an upregulated proinflammatory state and leave open the role for anti-inflammatory cytokines in the genesis of CFS.