Macrophages and the immune system: the role of microglia in immunity and neurodegenerative disease
The body’s immune system is our first line of defence against foreign substances, protecting us against infection and disease. It consists of a complex network of organs and cells that work to recognize and destroy these harmful substances, containing them at the site of infection. Macrophages play a crucial role in this; engulfing and destroying anything dangerous via phagocytosis.
Macrophages originate from circulating peripheral blood monocytes . During the immune response, monocytes rapidly move to tissue infection sites, where they differentiate into specialized tissue macrophages. For example, monocytes responding to an infection in the alveoli of the lungs differentiate into alveolar macrophages, while in the liver they become Kupffer cells.
Another of these tissue specific macrophages is microglia, one of the primary forms of immune defence in the central nervous system (CNS). Below we delve into the intriguing origins of microglia, the key role they play in the immune response, and why they are increasingly becoming cells of interest in neurodegenerative disease and drug development.
Where do microglia come from and what do they do?
Over the past few years, incredible progress has been made in understanding the origin and functions of microglia. We now know that they are present at birth, originating from yolk-sac macrophage progenitors that migrate to the CNS during early embryogenesis. In adults, circulating monocytes are recruited to the CNS under inflammatory conditions , where they differentiate into microglia. Recent research has uncovered that both the differentiation and proliferation of macrophages are dependent on a set of transcription factors and growth factor receptors (including PU.1 and colony-stimulating factor 1 (CSF1) receptors) being present in the tissue where the monocytes settle.
Microglia are key to numerous important functions in the CNS, such as regulating brain development and maintaining neural networks. On top of this, they play a significant role in the immune response by repairing neuronal injury through mediating neuroinflammation and eradicating any antigens that may endanger the CNS.
Why are microglia important cells to study in disease research?
As a key part of the inflammatory response to CNS injury and disease, microglia can become activated and/or dysregulated in the context of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. For example, the pro-inflammatory activation of microglia can contribute to the progression of Parkinson’s disease by inducing the death of dopaminergic neurons . This has stimulated great interest in microglia as indicators of neurodegenerative disease, as well as in their potential as therapeutic targets.
Until recently, the conventional method for studying microglia in disease research was in vivo animal models (for example, genetic or chemical disease mimicking in mice). However, these methods have recently come under scrutiny due to their limited physiological relevance, and therefore translation, to humans. These models also restrict the study of multicellular interactions between microglia and their neighbouring cells, such as neurons and astrocytes, which are important in the pathology of neurodegenerative disease .
Axol iPSC-Derived Macrophages show expression of the ionized calcium-binding adapter molecule 1 (IBA1), which is typically expressed by macrophages/microglia upon activation.
An alternative approach to this has come from recent advances in stem cell biology, enabling the generation of macrophages from human induced pluripotent stem cells (hiPSCs) to use in in vitro experiments.
How can hiPSC-Derived Macrophages benefit your research?
Here at Axol, we produce a wide variety of hiPSC-Derived cells for use in drug discovery and disease research , which includes the generation of hiPSC-Derived Monocytes and Macrophages . These cells can then be co-cultured alongside your CNS tissue of choice to produce specialized microglial cells. They can also be co-cultured with neurons and other glial cells in three-dimensional culture systems to mimic in vivo multicellular interactions, to offer a neurodegenerative disease model with even greater physiological relevance.
Our hiPSC-Derived Macrophages offer various advantages over traditional sources of monocytes and macrophages from immortalised cell lines (e.g. THP-1) and peripheral blood. For example, unlike commercially available myeloid cell lines that display an abnormal karyotype and proliferate in vitro , our hiPSC-Derived Macrophages are terminally differentiated and so do not proliferate.
In addition, as blood samples produce a mixed culture of cells and therefore a lower proportion of macrophages, they require pooling of donor samples and can reduce the reproducibility of your experiments. As our hiPSC-Derived Macrophages are produced from one stable donor, and are generated from hiPSC-Derived Monocytes, they offer much purer populations of macrophages and so do not require pooling.
