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Review
. 2014 Sep;128(3):363-80.
doi: 10.1007/s00401-014-1330-y. Epub 2014 Aug 9.

The role of microglia in human disease: therapeutic tool or target?

Nathalie Cartier  1 , Coral-Ann Lewis, Regan Zhang, Fabio M V Rossi
Affiliations
Review

The role of microglia in human disease: therapeutic tool or target?

Nathalie Cartier et al. Acta Neuropathol. 2014 Sep.

Abstract

Microglia have long been the focus of much attention due to their strong proliferative response (microgliosis) to essentially any kind of damage to the CNS. More recently, we reached the realization that these cells play specific roles in determining progression and outcomes of essentially all CNS disease. Thus, microglia has ceased to be viewed as an accessory to underlying pathologies and has now taken center stage as a therapeutic target. Here, we review how our understanding of microglia's involvement in promoting or limiting the pathogenesis of diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, multiple sclerosis, X-linked adrenoleukodystrophy (X-ALD) and lysosomal storage diseases (LSD) has changed over time. While strategies to suppress the deleterious and promote the virtuous functions of microglia will undoubtedly be forthcoming, replacement of these cells has already proven its usefulness in a clinical setting. Over the past few years, we have reached the realization that microglia have a developmental origin that is distinct from that of bone marrow-derived myelomonocytic cells. Nevertheless, microglia can be replaced, in specific situations, by the progeny of hematopoietic stem cells (HSCs), pointing to a strategy to engineer the CNS environment through the transplantation of modified HSCs. Thus, microglia replacement has been successfully exploited to deliver therapeutics to the CNS in human diseases such as X-ALD and LSD. With this outlook in mind, we will discuss the evidence existing so far for microglial involvement in the pathogenesis and the therapy of specific CNS disease.

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Figures

Fig. 1
Fig. 1
Illustration of the multiple roles of microglia during the initiation, progression and resolution of experimental autoimmune encephalitis. The spinal cord sections are derived from mice in which circulating cells and their progeny are marked by GFP expression (green), while tissue-resident microglia are not (see text). a Microscopic leaks in the CNS vasculature allow the extravasation of plasma components such as fibrinogen, which contributes to the induction of microglia expansion. b This leads to microgliosis well before circulating cells are capable of crossing the blood–brain barrier. Staining for the mature microglia/macrophage marker IBA-1 is shown in red, staining for CD31 (endothelium) in blue, circulating cells are green. c Expanded microglia play a role in attracting circulating inflammatory monocytes, possibly by the expression of chemokines such as CCL2/MCP1. d Inflammatory monocytes infiltrate the CNS parenchyma and, through a variety of mechanisms likely to involve myelin stripping and secretion of neurotoxic cytokines, exacerbate the damage and trigger progression toward severe disease. e, f Next, inflammatory monocytes mature into IBA-1 expressing macrophages, adopting a microglia-like morphology. This signals the beginning of remission. g Eventually, macrophages derived from circulating monocytes are completely cleared from the CNS, while microglia is reduced in numbers but persists to maintain the resident population of innate immune cells
Fig. 2
Fig. 2
Transplantation of genetically modified hematopoietic stem cells to treat CNS diseases. After harvesting hematopoietic cells from the bone marrow of the patient, the CD34+ cell fraction containing hematopoietic stem cells (HSC) is purified and transduced with a lentiviral vector carrying the therapeutic gene. This gene can be the normal version of a deficient gene in patients with genetic diseases (ABDC1 in X-ALD, MeCP2 in Rett syndrome, lysosomal enzymes) or genes coding proteins of therapeutic interest like trophic factors, chemokines, and guidance molecules. Transduction with the lentiviral vector leads to stable integration of the therapeutic gene in the population of stem/progenitor cells. Genetically modified cells are re-infused into the patient and reconstitute the bone marrow stem cell compartment. A fraction of stem cells or myeloid progenitors is able to migrate to the CNS, cross the brain barrier and locally differentiate into genetically modified microglia-like cells. Chemokines (cell migration/chemotaxis inducing cytokines), such as monocyte chemoattractant protein 1 CCL2/MCP-1 and fractalkine CX3CL1/Fkn, produced by neurons, astrocytes and microglia, appear to attract peripheral blood mononuclear cells (PBMC) across the BBB into the brain parenchyma. Particularly, monocyte chemoattractant protein 1 (MCP-1) is and its receptor CCR2 have been implicated in a number of inflammatory diseases and are likely to be essential in this recruitment of bone marrow-derived cells. Migration of blood peripheral blood monocytic cells (PBMC) across the BBB into the brain parenchyma also depends on increased expression of various adhesion molecules, such as VCAM-1 ICAM-1, IG9 and E-selectin, all of which may promote PBMC attachment and transmigration. In the case of lysosomal diseases, lentivirus-mediated lysosomal enzyme overexpression allows efficient cross-correction of neurons and glial cells with diffusion of the therapeutic effect (left). HSC can also be engineered to express trophic factors with potential beneficial effects on surrounding neurons or glial cells (center). In diseases like X-ALD or Rett syndrome, the correction of deficient microglial function by transplantation of cells genetically modified with lentiviral vectors allows mitigation of neuronal damages induced by endogenous dysfunctioning microglia (right)
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