The Role of TGFβ Signaling in Microglia Maturation and Activation

Activation of transforming growth factor-beta 1 (TGFβ) signaling in early postnatal mouse microglia is essential for the induction of a microglia-specific gene expression signature including Tmem119, Olfml3, P2ry12, Sall1, Hexb, Gpr34, Fcrls, and SiglecH. Proper activation of TGFβ1 from its latent complex and subsequent microglia-surface binding of active TGFβ1 is as essential as the presence of TGFβ signaling receptors. Loss of TGFβ1-induced microglia maturation in mice results in impaired oligodendrocyte maturation, hypomyelination, loss of inhibitory cortical interneurons, and the development of spastic motor deficits. TGFβ signaling is pivotal in the prevention of excessive activation of adult mouse microglia under physiological conditions. Silencing of TGFβ signaling in mature microglia does not seem to affect the homeostatic microglia gene expression signature. The first approaches to silencing microglial TGFβ signaling in mouse models of CNS diseases has resulted in exacerbated disease progression due to uncontrolled microglia reactivity. The pleiotropic cytokine transforming growth factor-beta 1 (TGFβ1) plays pivotal roles in different cell types, including immune cells such as T cells, monocytes/macrophages, and microglia. Microglia are essential during physiological and pathological events. Maturation of postnatal microglia, as well as the regulation of the complex functional repertoire of microglia, needs to be carefully orchestrated. However, an understanding of how mammalian microglia maturation and disease-associated microglia activation is regulated remains fragmentary. Here, we summarize recent observations made by employing transgenic approaches to silence microglial TGFβ signaling in mice. These revealed that TGFβ1 and TGFβ signaling are indispensable for microglia maturation, adult microglia homeostasis, and the control of microglia activation in central nervous system pathologies. The pleiotropic cytokine transforming growth factor-beta 1 (TGFβ1) plays pivotal roles in different cell types, including immune cells such as T cells, monocytes/macrophages, and microglia. Microglia are essential during physiological and pathological events. Maturation of postnatal microglia, as well as the regulation of the complex functional repertoire of microglia, needs to be carefully orchestrated. However, an understanding of how mammalian microglia maturation and disease-associated microglia activation is regulated remains fragmentary. Here, we summarize recent observations made by employing transgenic approaches to silence microglial TGFβ signaling in mice. These revealed that TGFβ1 and TGFβ signaling are indispensable for microglia maturation, adult microglia homeostasis, and the control of microglia activation in central nervous system pathologies. degenerative disease of the retina; atrophy of the retinal pigment epithelium and new blood vessels trigger photoreceptor death. the most common neurodegenerative disease, accompanied by amyloid plaques and neurofibrillary tangles. Aging and inherited risk factors contribute to disease onset and progression. involved in fat metabolism; a significant risk factor for AD. Crucial molecule for the transition of microglia from a homeostatic to a neurodegeneration-associated phenotype. double transgenic mouse line expressing mutated amyloid precursor protein and presenilin 1 resulting in early-onset AD. CNS microvasculature separating circulating blood from the CNS parenchyma. belongs to the neurotrophin family of proteins and is one of the most potent neurotrophic factors. defined as the brain and spinal cord; contains glial cells such as astrocytes, oligodendrocytes, and microglia. tyrosine kinase receptor; expressed by macrophages and microglia; interacts with CSF1 and IL-34. tool to specifically delete genes or exons from genomic DNA. Cell type-specific promoters regulate the expression of a Cre recombinase, which binds to LoxP site flanking sequences to be targeted. chemokine receptor expressed by cells from the myeloid lineage, including monocytes, macrophages, and microglia. mouse model of microglia depletion. Cre-induced expression of diphtheria toxin A (DTA) results in CNS-resident microglia death. host molecules released from dying or dead cells that can trigger noninfectious inflammatory responses. microglia subset with reduced expression of homeostatic markers and increased expression of genes involved in lysosomal, phagocytic, and lipid metabolism pathways in neurodegenerative diseases. reduced myelin content due to abnormal oligodendrocyte development or perturbations in myelin production. transmembrane receptors facilitating cell–extracellular matrix (ECM) and cell-TGFβ interactions. Important during cell growth, division, survival, apoptosis, and differentiation. the most crucial homing factor for microglia during CNS development. blood accumulation in the brain parenchyma and ventricles caused by disruption of brain-supplying arteries. plays crucial roles during the lineage commitment and maturation of myeloid cells. GABAergic interneuron population with important functions during normal CNS development and in several mental disorders. reaction of microglia to pathological insults; accompanied by an increase in microglia numbers at the lesion site, loss of process ramifications, and the formation of an ameboid cell shape. collective term for pathological processes resulting in progressive structural and functional loss of neurons. Trem2–ApoE signaling transformation of DAMs into a microglia population fostering neuron degeneration and the progression of neurodegenerative diseases. express chondroitin sulfate proteoglycan 4 and give rise to oligodendrocyte progenitor cells. progressive CNS disorder affecting dopamine-producing neurons of the midbrain. Loss of dopamine causes the clinic symptoms tremor, bradykinesia, and rigidity. small molecular motifs conserved in several classes of infectious microorganisms; activate innate immune responses after interaction with distinct surface receptors. ETS-family transcription factor with essential functions in the early fate determination of myeloid and B lymphoid cell development. GC-rich consensus sequence (GGCGC or GGCCG) serving as a DNA-binding site for SMADs. family of highly conserved proteins; primary signal transducers of TGFβ receptors; include receptor-regulated SMADs (R-SMADs), common partner SMADs (Co-SMADs), and inhibitory SMADs (I-SMADs). process of synapse elimination during development and pathological conditions. regulator of innate immunity; involved in the production of inflammatory cytokines in microglia. family of highly conserved, structurally related signaling proteins, including TGFβ isoforms, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, and inhibins.