Attack of the clones: microglia in health and disease
Manjally, Amritha Vinayak
Tay, Tuan Leng
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Citation (published version)A.V. Manjally, T.L. Tay. 2022. "Attack of the Clones: Microglia in Health and Disease.." Front Cell Neurosci, Volume 16: 831747. https://doi.org/10.3389/fncel.2022.831747
[INTRODUCTION] Microglia are brain-resident macrophages that carry out immune surveillance, support neurogenesis and neuronal survival, shape the neuronal network, and maintain tissue homeostasis (Nimmerjahn et al., 2005; Hanisch and Kettenmann, 2007; Sierra et al., 2010; Tremblay et al., 2010; Schafer et al., 2012; Ueno et al., 2013; Squarzoni et al., 2014; Schafer and Stevens, 2015; Diaz-Aparicio et al., 2020). The adult resident pool of microglia is primarily derived from yolk sac (YS) erythromyeloid progenitors (EMPs) that have clonally proliferated within the brain parenchyma during development (Alliot et al., 1999; Ginhoux et al., 2010; Hashimoto et al., 2013; Gomez Perdiguero et al., 2015). To maintain their cell density in adulthood, the resident microglial cells undergo local clonal self-renewal (Ajami et al., 2007; Askew et al., 2017; Réu et al., 2017; Tay et al., 2017). A study on parabiotic chimeric mice revealed that the resident microglial population is exclusively replenished by locally derived microglial clones with no evidence of contribution from peripheral myeloid progenitors (Ajami et al., 2007). Clonal expansion of non-ablated residual microglia was also found to be responsible for re-establishing steady state microglial cell densities following a pharmacological ablation (Huang et al., 2018). Homeostatic microglia continuously monitor the brain environment, scavenge dying cells and cellular debris, and rapidly respond to any tissue damage (Kreutzberg, 1996; Streit et al., 1999). In response to acute pathology, resident microglia rapidly accumulate around the lesion via clonal microgliosis (Streit et al., 1999; Ladeby et al., 2005; Ajami et al., 2007; Ransohoff, 2007). Microgliosis at the site of CNS damage has been shown to be governed by signaling molecules like colony-stimulating factor-1 (CSF1), fractalkine receptor (CX3CR1) and purinergic receptor P2Y12 (P2RY12) (Guan et al., 2016; Gu et al., 2016; Peng et al., 2016). To repair damage, microglia elicit proinflammatory cytokines and later transition to anti-inflammatory phenotypes (Colton, 2009; Lloyd et al., 2019). Several studies have suggested that clinical recovery of acute lesions is accompanied by the resolution of proliferated microglia by migration and cell death (Dihné et al., 2001; Wilson et al., 2004; Tay et al., 2017; Lloyd et al., 2019). However, in severe or chronic neurodegenerative pathologies like Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and motor neuron diseases, microglial clonal expansion has been persistently observed around lesions and plaques (Glass et al., 2010; Streit et al., 2020). In AD and MS animal models, microglial proliferation around the Aβ plaques and demyelinating neurons was actively promoted by CSF1R and triggering receptor expressed on myeloid cells 2 (TREM2) (Cantoni et al., 2015; Olmos-Alonso et al., 2016; Wang et al., 2016; Jay et al., 2017; Gushchina et al., 2018; Zhao et al., 2018). CSF1R, transforming growth factor beta (TGFβ), and purinergic signaling pathways that influence microglial cell densities are impaired in neurodegenerative diseases (Gómez-Nicola et al., 2013; Von Bernhardi et al., 2015; Olmos-Alonso et al., 2016; Pietrowski et al., 2021). Taken together, the capacity for microglial clonal expansion, proliferation, or renewal, clearly play an important function across CNS development, health, and disease. Although clonal expansion and renewal of microglia appears necessary for physiological brain development, maintenance of CNS health, and response to acute damage, whether microglial clones are beneficial or detrimental in chronic neurodegeneration remains unclear. In this opinion article, we discuss the implications of the formation of microglial clones in health and disease, independent of peripheral myeloid recruitment to the CNS in similar contexts (Figure 1). Several studies have claimed that microglia surrounding plaques and lesions exert detrimental effects and exacerbate disease conditions (Streit et al., 2009; Lassmann et al., 2012; Keren-Shaul et al., 2017; Krasemann et al., 2017; Shahidehpour et al., 2021). Considering that the restoration of tissue homeostasis coincides with the resolution of microglial clones to regain steady state microglial tiling (Dihné et al., 2001; Wilson et al., 2004; Tay et al., 2017; Lloyd et al., 2019), we hypothesize that unresolved microglial clones contribute to the prolongation of neurodegenerative states in chronic neuropathologies. As a hallmark of CNS pathology, microgliosis is likely important to limit tissue damage and infection and for local repair, as is typical in inflammatory responses of tissue-resident macrophages (Jenkins et al., 2011). A timely resolution of excess microglia resulting from clonal expansion is expected to aid or accompany the restoration of homeostasis and clinical recovery. However, sustained presence of reactive microglial clones at high densities around lesions or plaques with no signs of resolution likely lead to neurotoxic outcomes. To explore our hypothesis, we examine various contexts in which microglial clonal expansion has taken place and consider if strategic targeting of microglial clones could ameliorate chronic disease states.
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