PerspectiveNeuroscience

Microglia: The Enemy Within?

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Science  05 Dec 2003:
Vol. 302, Issue 5651, pp. 1689-1690
DOI: 10.1126/science.1092864

Unlike most other structures in the adult brain, the hippocampus is able to produce new neurons (neurogenesis) throughout adult life as it contains a population of neural stem cells. It is believed that neurogenesis contributes to the primary task of the hippocampus, that of coordinating learning and memory. On page 1760 of this issue, Monje, Toda, and Palmer report that in a rat model of brain inflammation, the ability of hippocampal neural stem cells to generate new neurons is severely reduced. Intriguingly, the authors were able to restore hippocampal neurogenesis by blocking inflammation with indomethacin, a common nonsteroidal anti-inflammatory drug (1).

The myriad cognitive functions computed by the brain have been credited in large part to neurons, called those “noble elements” by the father of neuroscience, Ramón y Cajal. Yet brain neurons are vastly outnumbered by other brain cells called glia, which include astrocytes, oligodendrocytes, and microglia. The brain is an immuno-privileged tissue that exhibits dampened adaptive immunity in response to injury, infection, or tumor formation. However, the brain does exhibit a robust innate immune response thanks to its microglia, which defend against invading microorganisms and clean up by engulfing the debris of dying cells. In addition, the inflammatory mediators released by microglia during an innate immune response strongly influence neurons and their ability to process information (2).

In a previous study, Monje, Palmer, and co-workers investigated whether the cognitive decline observed in brain cancer patients undergoing irradiation treatment could be due to a reduction in hippocampal neurogenesis (3). They found that irradiation blocked differentiation of neural stem cells in vivo but not in vitro. They then went on to show that irradiation perturbed the structural microenvironment of the “stem cell niche” in the hippocampus, disrupting close interactions between stem cells and blood vessels. Adult neurogenesis then decreased as a result of alterations to the neural stem cell microenvironment. Monje et al. speculated that a strong inflammatory response induced by irradiation might be the underlying cause of perturbations to the stem cell microenvironment (3).

In their new work, these investigators follow up on these observations with their demonstration that much of the irradiation-induced damage in brain tissue is “homemade” due to local inflammation. Working in rats, they show that blocking inflammation elicited by either irradiation or injection of bacterial lipopolysaccharide (LPS) with indomethacin restores hippocampal neurogenesis (1). In an independent recent report, Ekdahl, Lindvall, and co-workers showed that LPS-induced inflammation in the brains of adult rats impaired hippocampal neurogenesis. The investigators then demonstrated that neurogenesis could be boosted after experimentally induced seizures if the rats were given minocycline, which blocks activation of microglia (4). This study implicates microglia as pivotal players in the inflammation-induced impairment of hippocampal neurogenesis. The next challenge will be to identify the exact stem cell microenvironment targets of microglia and of other components of the inflammatory response. From a research perspective, irradiation of brain tissue in animal models is a frequently used tool for studying hippocampal neurogenesis in the adult. The Monje et al. study clearly underscores the need to reconsider the consequences of irradiation not only experimentally, but also clinically.

Earlier this year, Santarelli et al. (5) demonstrated that irradiation of the hippocampus in a mouse model blocks the effectiveness of antidepressant drugs in promoting neurogenesis and in alleviating anxious behavior. This work suggested that the effects of antidepressant drugs on performance in an anxiety task depend on the integrity of the stem cell niche in the hippocampus. The new Monje et al. study (1) places the Santarelli et al. findings in a fresh context: Irradiation may disrupt neurogenesis, but it does so through inflammation. Inflammation is likely to have effects beyond neurogenesis with concomitant cognitive consequences. It will be interesting to see whether the loss of effectiveness of antidepressants in alleviating the anxious behavior of irradiated mice reported by Santarelli et al. (5) is due to a block in neurogenesis, irradiation-induced inflammation, or both.

Proinflammatory mediators released by microglia seem to be important contributors to the block in hippocampal neurogenesis. In vivo, the number of activated microglia correlates negatively with the production of new neurons (1). Neurogenesis is also inhibited when neural stem cells are exposed to activated microglia (but not quiescent microglia) in cell culture. The cytokine interleukin-6 (IL-6) is a key regulator of this inhibition (see the figure) (1). Addition of an antibody that blocks IL-6 to neural stem cell cultures abolishes the negative effects of activated microglia on neurogenesis in vitro.

Microglia—friend and foe.

(Top) Unlike other structures in the adult brain, the hippocampus contains neural stem cells that give rise to new neurons throughout adult life. Under normal conditions, hippocampal neural stem cells (which have a radial glia-like morphology and vascular end-feet) are thought to give rise to both neuronal progenitor cells and astrocytes, which are a type of glia. Neuronal progenitor cells with a high proliferative capacity then give rise to granule cell neurons. (Bottom) During brain inflammation in response to infection or damage induced by, for example, irradiation, inflammatory cytokines—including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6—are secreted by activated microglia and invading macrophages. IL-6 interferes with the production of new neurons in adult brain tissue, perhaps by perturbing the hippocampal stem cell microenvironment. IL-6 may induce bipotent neural stem cells to generate more astrocytes than neuronal progenitor cells. Alternatively, IL-6 may cause a reduction in proliferation of neuronal progenitor cells or trigger them to undergo programmed cell death.

CREDIT: KATHARINE SUTLIFF/SCIENCE

IL-6 and its downstream JAK-STAT signaling pathway have been implicated in the selective differentiation of cerebral cortical precursor cells into astrocytes (6). Inhibition of neurogenesis by IL-6 might be due to increased production of astrocytes (or perhaps other glial cells) at the expense of neuronal progenitor cells, particularly as astrocytes and neuronal precursor cells seem to share a common stem cell (see the figure). Alternatively, inhibition of neurogenesis by IL-6 may be a consequence of a decrease in neuronal progenitor cell proliferation or an increase in the number of these cells undergoing apoptosis.

Microglia are usually helpful cells that may even supply neurons with trophic factors such as brain-derived neurotrophic factor (BDNF). However, the apparent benefits of microglia have come under increasing scrutiny. It seems that the brain's innate immune response to injury is a double-edged sword, simultaneously beneficial and detrimental. So where do we stand with respect to microglia? Are they the enemy within? The fact that microglia secrete potent growth and differentiation factors, such as BDNF and IL-6, with effects that reach far beyond the immune system supports the idea that they may be central players in repairing brain tissue and maintaining its integrity. Moreover, microglia may contribute to the rearrangement of neural connections and hence to the plasticity of normal brain tissue.

The Monje et al. (1) and Ekdahl et al. (4) studies introduce microglia, the innate immune system, and inflammatory cytokines to the world of neural stem cell biology and adult neurogenesis. At first sight the observations of the two studies may seem confirmatory, as it was shown several years ago that cytokines regulate neuronal differentiation of hippocampal progenitor cells in vitro (7). But the power of the new work lies in its potential clinical application to the treatment of brain cancer patients. Both studies firmly establish that blocking inflammation by treatment with nonsteroidal anti-inflammatory drugs restores hippocampal neurogenesis and neuroplasticity, with the potential for ameliorating the cognitive decline that may accompany irradiation treatment of brain cancer patients.

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