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Colony stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), and CD115 (Cluster of Differentiation 115), is a cell-surface protein encoded by the human ''CSF1R'' gene (known also as c-FMS). CSF1R is a Immune receptor, receptor that can be activated by two Ligand, ligands: Macrophage colony-stimulating factor, colony stimulating factor 1 (CSF-1) and Interleukin 34, interleukin-34 (IL-34). CSF1R is highly expressed in Myeloid tissue, myeloid cells, and CSF1R signaling is necessary for the Cell survival, survival, Cell proliferation, proliferation, and Cell differentiation, differentiation of many myeloid cell types ''in vivo'' and ''in vitro.'' CSF1R signaling is involved in many diseases and is targeted in therapies for cancer, neurodegeneration, and Bone disease, inflammatory bone diseases.
CSF1R, the protein encoded by the ''CSF1R'' gene is a Receptor tyrosine kinase, tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. CSF1R has 972 amino acids, is predicted to have a Molecular-weight, molecular weight of 107.984 kiloDalton (unit), Daltons, and is composed of an extracellular and an cytoplasmic Protein domain, domain. The extracellular domain has 3 N-terminal immunoglobulin (Ig) domains (D1-D3) which bind ligand, 2 Ig domains (D4-D5) which stabilize the ligand, a linker region, and a single-pass transmembrane helix. The cytoplasmic domain has a juxtamembrane domain and tyrosine kinase domain that is interrupted by a kinase insert domain. At rest, the juxtamembrane domain of CSF1R enters an autoinhibitory position to prevent signaling of the CSF1R cytosolic domain. Upon binding of ligand to extracellular Ig domains, CSF1R Dimer (chemistry), dimerizes noncovalently and Autophosphorylation, autophosphorylates several tyrosine residues. This first wave of CSF1R tyrosine phosphorylation creates Phosphotyrosine-binding domain, phosphotyrosine-binding domains to which Effector protein, effector proteins can bind and initiate various cellular responses. Many proteins become tyrosine phosphorylated in response to CSF1R signaling (Table 1) including P85a, p85, CBL (gene), Cbl, and GAB3, Gab3 which are important for survival, differentiation, chemotaxis, and actin cytoskeleton of myeloid cells. The first wave of tyrosine phosphorylation also leads to the covalent dimerization of CSF1R via disulfide bonds. Covalent CSF1R dimerization is important for a series of modifications to CSF1R itself including a second wave of tyrosine phosphorylation, serine phosphorylation, ubiquitination, and eventually endocytosis which terminates signaling by trafficking the ligand-CSF1R complex to the lysosome for degradation. Macrophage colony-stimulating factor, Colony stimulating factor 1 (CSF-1) and Interleukin 34, interleukin-34 (IL-34) are both CSF1R Ligand, ligands. Both ligands regulate myeloid cell survival, proliferation, and differentiation, but CSF-1 and IL-34 differ in their structure, distribution in the body, and the specific cellular Signaling cascade, signaling cascades triggered upon binding to CSF1R.
Osteoclast are multi-nucleated cells that that absorb and remove bone which is critical for growth of new bones and maintenance of bone strength. Osteoclasts are critical for the Bone remodeling, bone remodeling cycle which is achieved by the building of bone by Osteoblast, osteoblasts, reabsorption by osteoclasts, and remodeling by osteoblasts. Osteoclasts precursor cells and mature osteoclast require stimulation of CSF1R for survival. Blockage of CSF1R signaling prevents osteoclast precursor cells from proliferating, maturing, and fusing into multi-nucleated cells. Stimulation of CSF1R promotes osteoclastogenesis (differentiation of monocytes into osteoclasts). CSF1R signaling in osteoclasts precursors promotes survival by upregulation of the Bcl-xL, Bcl-X(L) protein, an inhibitor of pro-apototic caspase-9. CSF1R signaling in mature osteoclasts promotes survival by stimulating MTOR, mTOR/S6 kinase and the Na/HCO3 co-transporter, NBCn1. CSF1R signaling also directly regulates osteoclast function. Osteoclasts migrate along the bone surface, then adhere to the bone to degrade and reabsorb the bone matrix. CSF1R signaling positively regulates this behavior, increasing osteoclast chemotaxis and bone reabsorption.
Monocytes and macrophages are Mononuclear phagocyte system, mononuclear phagocytes. Monocytes circulate in the blood and are capable of differentiating into macrophages or Dendritic cell, dendritic cells, and macrophages are terminally differentiated tissue-resident cells. CSF1R signaling is Necessity and sufficiency, necessary for differentiation of microglia and Langerhans cell, Langerhans cells which are derived from yolk sac progenitor cells with high expression of CSF1R. CSF1R signaling is only partially required for other tissue macrophages, and it is not necessary for monocytopoiesis (production of monocytes and macrophages) from Hematopoietic stem cell, hematopoietic stem cells. Macrophages of thymus and Lymph node, lymph nodes are almost completely independent of CSF1R signaling. In macrophages whose survival is fully or partially dependent on CSF1R signaling, CSF1R promotes survival by activating Phosphoinositide 3-kinase, PI3K. CSF1R signaling also regulates macrophage function. One function of CSF1R signaling is to promote tissue protection and healing following damage. Damage to the kidney causes upregulation of CSF-1 and CSF1R in tubular epithelial cells. This promotes proliferation and survival of injured tubular epithelial cells and promotes anti-inflammatory phenotypes in resident macrophage to promote kidney healing. Lastly, activation of CSF1R is a strong Chemokinesis, chemokinetic signal, inducing macrophage polarization and chemotaxis towards the source of CSF1R ligand. This macrophage response requires rapid morphological changes which is achieved by remodeling of the actin cytoskeleton via the Src family kinase, Src/PYK2, Pyk2 and PI3K signaling pathways.
Microglia are the tissue-resident Phagocyte, phagocytes of the central nervous system. CSF1R signaling promotes migration of primitive microglia precursor cells from the embryonic yolk sac to the developing brain prior to formation of the Blood–brain barrier, blood-brain-barrier. In perinatal development, microglia are instrumental in synaptic pruning, a process in which microglia Phagocytosis, phagocytose weak and inactive synapses via binding of microglial Complement Receptor 3, complement receptor 3 (CR3) (complex of CD11b and Integrin beta 2, CD18) to synapse-bound iC3b. ''Csf1r'' Mutation, loss-of-function inhibits synaptic pruning and leads to excessive non-functional synapses in the brain. In adulthood, CSF1R is required for the proliferation and survival of microglia. Inhibition of CSF1R signaling in adulthood causes near-complete (>99%) depletion (death) of brain microglia, however reversal of CSF1R inhibition stimulates remaining microglia to proliferate and repopulate microglia-free niches in the brain. Production of CSF1R ligands CSF-1 and IL-34 is increased in the brain following injury or viral infection, which directs microglia to proliferate and execute immune responses.
Bone remodeling is regulated by mutual cross-regulation between osteoclasts and osteoblasts. As a result, the dysfunction of CSF1R signaling directly affects the reabsorption (osteoclasts) and indirectly affects bone deposition (osteoblasts). In inflammatory arthritis conditions such as rheumatoid arthritis, psoriatic arthritis, and Crohn's disease, Inflammatory cytokine, proinflammatory cytokine Tumor necrosis factor, TNF-α is secreted by synovial macrophages which stimulates Stromal cell, stromal cells and osteoblasts to produce CSF-1. Increased CSF-1 promotes proliferation of osteoclasts and osteoclast precursors and increases osteoclast bone reabsorption. This pathogenic increase in osteoclast activity causes abnormal bone loss or osteolysis. In animal models of rheumatoid arthritis, administration of CSF-1 increases the severity of disease whereas ''Csf1r'' loss-of-function reduces inflammation and joint erosion. In a rare bone disease called Gorham's disease, Gorham‐Stout disease, elevated production of CSF-1 by lymphatic endothelial cells similarly produces excessive osteoclastogenesis and osteolysis. Additionally, Menopause, postmenopausal loss of estrogen has also been found to impact CSF1R signaling and cause osteoporosis. Estrogen deficiency causes osteoporosis by upregulating production of Tumor necrosis factor, TNF-α by activated T cell, T cells. As in inflammatory arthritis, TNF-α stimulates stromal cells to produce CSF-1 which increases CSF1R signaling in osteoclasts.
CSF1R signaling is involved in several diseases and disorders of the central nervous system. Research using animal models of epilepsy (kainic acid-induced seizures) suggests that CSF1 signaling during Seizure, seizures protects neurons by activating neuronal CREB signaling. CSF1R Agonist, agonism during seizures increases neuronal survival whereas neuron-specific ''Csf1r'' loss-of-function worsens kainic acid excitotoxicity, suggesting CSF1R signaling in neurons directly protects against seizure-related neuronal damage. Although CSF1R signaling is beneficial in certain contexts, it is detrimental in diseases where microglia drive tissue damage. In Charcot-Marie-Tooth disease type 1, CSF-1 secretion from Endoneurium, endoneurial cells stimulates proliferation and activation of macrophages and microglia that cause demyelination. Likewise in multiple sclerosis, CSF1R signaling supports the survival of inflammatory microglia which promote demyelination. CSF1R inhibition Preventive healthcare, prophylactically reduces demyelination in the experimental autoimmune encephalomyelitis animal model. The role of CSF1R signaling in Alzheimer's disease is more complicated because microglia both protect and damage the brain in response to Alzheimer's disease pathology. CSF-1 stimulates Primary cell culture, primary cultured human microglia to phagocytose toxic Amyloid beta, Aβ1–42 peptides. Microglia also initiate TREM2-dependent immune responses to amyloid plaques which protects neurons. However, Alzheimer's disease microglia also excessively secrete inflammatory cytokines and prune synapses promoting synapse loss, neuronal death, and Mild cognitive impairment, cognitive impairment. Both CSF1R stimulation and inhibition improves cognitive function in Alzheimer's disease models. Thus, microglia seem to have both protective and neurotoxic functions during Alzheimer's disease neurodegeneration. Similar findings have been reported in lesion studies of the mouse brain, which showed that inhibition of CSF1R after lesioning improves recovery but inhibition during lesioning worsens recovery. CSF1R-targeting therapies for neurological disorders may impact both detrimental and beneficial microglia functions.
Because Tumor-associated macrophage, TAM CSF1R signaling is tumor-permissive and can tumor treatment-resistance, CSF1R signaling is a promising therapeutic target in the treatment of cancer. Several studies have investigated the efficacy of CSF1R inhibitor as a monotherapy and as a combination therapy in Refractory cancer, refractory and metastatic cancers. Several small molecule inhibitors and monoclonal antibodies targeting CSF1R are in clinical development for cancer therapy (Table 2). Pexidartinib, Pexidartinib (PLX3397) is a small molecule inhibitor tyrosine of CSFR (as well as cKIT, FLT3, and VEGF receptor, VEGFR) with the most clinical development so far. Several completed and concurrent clinical trials have tested the efficacy and safety of Pexidartinib as a monotherapy for c-kit-mutated melanoma, prostate cancer, glioblastoma, Hodgkin lymphoma, classical Hodgkin lymphoma, neurofibroma, sarcoma, and Leukemia, leukemias. In 2019, Pexidartinib was FDA approval, FDA-approved for treatment of Tenosynovial giant cell tumor, diffuse-type tenosynovial giant cell tumors, a non-malignant tumor that develops from Synovial membrane, synovial tissue lining the joints.
Gene
In the human genome, the ''CSF1R'' gene is located on chromosome 5 (5q32), and in mice the ''Csf1r'' gene is located on chromosome 18 (18D). ''CSF1R'' is 60.002 kilobases (kbs) in length. Hematopoietic stem cell, Hematopoietic stem cells express ''CSF1R'' at low levels, but ''CSF1R'' is highly expressed in Cellular differentiation, more differentiated myeloid cell types such as Monocyte, monocytes, Macrophage, macrophages, Osteoclast, osteoclasts, Dendritic cell, myeloid dendritic cells, microglia, and Paneth cell, Paneth cells. ''CSF1R'' expression is controlled by two alternative Promoter (genetics), promoters that are active in specific tissue types. Exon 1 of ''CSF1R'' is specifically Transcription (biology), transcribed in Trophoblast, trophoblastic cells whereas exon 2 is specifically transcribed in macrophages. Activation of ''CSF1R'' transcription is regulated by several transcription factors including ETS transcription factor family, Ets and PU.1. Macrophage expression of the ''CSF1R'' gene is regulated by the promoter Upstream and downstream (transduction), upstream of exon 2 and another highly Conserved sequence, conserved region termed the fms intronic regulatory element (FIRE). The FIRE is a 250-bp region in intron 2 that regulates transcript elongation during transcription of ''CSF1R'' in macrophages. Specific deletion of FIRE prevents differentiation of only specific macrophage types such as brain microglia and macrophages in the skin, kidney, heart, and peritoneum whereas deletion of the entire mouse ''Csf1r'' gene widely prevents macrophage differentiation, causing profound developmental defects. Additionally, the first intron of the ''CSF1R'' gene contains a Transcription (genetics), transcriptionally inactive RPL7, ribosomal protein L7 processed pseudogene, oriented in the opposite direction to the ''CSF1R'' gene.Protein
CSF1R, the protein encoded by the ''CSF1R'' gene is a Receptor tyrosine kinase, tyrosine kinase transmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. CSF1R has 972 amino acids, is predicted to have a Molecular-weight, molecular weight of 107.984 kiloDalton (unit), Daltons, and is composed of an extracellular and an cytoplasmic Protein domain, domain. The extracellular domain has 3 N-terminal immunoglobulin (Ig) domains (D1-D3) which bind ligand, 2 Ig domains (D4-D5) which stabilize the ligand, a linker region, and a single-pass transmembrane helix. The cytoplasmic domain has a juxtamembrane domain and tyrosine kinase domain that is interrupted by a kinase insert domain. At rest, the juxtamembrane domain of CSF1R enters an autoinhibitory position to prevent signaling of the CSF1R cytosolic domain. Upon binding of ligand to extracellular Ig domains, CSF1R Dimer (chemistry), dimerizes noncovalently and Autophosphorylation, autophosphorylates several tyrosine residues. This first wave of CSF1R tyrosine phosphorylation creates Phosphotyrosine-binding domain, phosphotyrosine-binding domains to which Effector protein, effector proteins can bind and initiate various cellular responses. Many proteins become tyrosine phosphorylated in response to CSF1R signaling (Table 1) including P85a, p85, CBL (gene), Cbl, and GAB3, Gab3 which are important for survival, differentiation, chemotaxis, and actin cytoskeleton of myeloid cells. The first wave of tyrosine phosphorylation also leads to the covalent dimerization of CSF1R via disulfide bonds. Covalent CSF1R dimerization is important for a series of modifications to CSF1R itself including a second wave of tyrosine phosphorylation, serine phosphorylation, ubiquitination, and eventually endocytosis which terminates signaling by trafficking the ligand-CSF1R complex to the lysosome for degradation. Macrophage colony-stimulating factor, Colony stimulating factor 1 (CSF-1) and Interleukin 34, interleukin-34 (IL-34) are both CSF1R Ligand, ligands. Both ligands regulate myeloid cell survival, proliferation, and differentiation, but CSF-1 and IL-34 differ in their structure, distribution in the body, and the specific cellular Signaling cascade, signaling cascades triggered upon binding to CSF1R.
Function
Osteoclasts
Osteoclast are multi-nucleated cells that that absorb and remove bone which is critical for growth of new bones and maintenance of bone strength. Osteoclasts are critical for the Bone remodeling, bone remodeling cycle which is achieved by the building of bone by Osteoblast, osteoblasts, reabsorption by osteoclasts, and remodeling by osteoblasts. Osteoclasts precursor cells and mature osteoclast require stimulation of CSF1R for survival. Blockage of CSF1R signaling prevents osteoclast precursor cells from proliferating, maturing, and fusing into multi-nucleated cells. Stimulation of CSF1R promotes osteoclastogenesis (differentiation of monocytes into osteoclasts). CSF1R signaling in osteoclasts precursors promotes survival by upregulation of the Bcl-xL, Bcl-X(L) protein, an inhibitor of pro-apototic caspase-9. CSF1R signaling in mature osteoclasts promotes survival by stimulating MTOR, mTOR/S6 kinase and the Na/HCO3 co-transporter, NBCn1. CSF1R signaling also directly regulates osteoclast function. Osteoclasts migrate along the bone surface, then adhere to the bone to degrade and reabsorb the bone matrix. CSF1R signaling positively regulates this behavior, increasing osteoclast chemotaxis and bone reabsorption.
Monocytes and macrophages
Monocytes and macrophages are Mononuclear phagocyte system, mononuclear phagocytes. Monocytes circulate in the blood and are capable of differentiating into macrophages or Dendritic cell, dendritic cells, and macrophages are terminally differentiated tissue-resident cells. CSF1R signaling is Necessity and sufficiency, necessary for differentiation of microglia and Langerhans cell, Langerhans cells which are derived from yolk sac progenitor cells with high expression of CSF1R. CSF1R signaling is only partially required for other tissue macrophages, and it is not necessary for monocytopoiesis (production of monocytes and macrophages) from Hematopoietic stem cell, hematopoietic stem cells. Macrophages of thymus and Lymph node, lymph nodes are almost completely independent of CSF1R signaling. In macrophages whose survival is fully or partially dependent on CSF1R signaling, CSF1R promotes survival by activating Phosphoinositide 3-kinase, PI3K. CSF1R signaling also regulates macrophage function. One function of CSF1R signaling is to promote tissue protection and healing following damage. Damage to the kidney causes upregulation of CSF-1 and CSF1R in tubular epithelial cells. This promotes proliferation and survival of injured tubular epithelial cells and promotes anti-inflammatory phenotypes in resident macrophage to promote kidney healing. Lastly, activation of CSF1R is a strong Chemokinesis, chemokinetic signal, inducing macrophage polarization and chemotaxis towards the source of CSF1R ligand. This macrophage response requires rapid morphological changes which is achieved by remodeling of the actin cytoskeleton via the Src family kinase, Src/PYK2, Pyk2 and PI3K signaling pathways.
Microglia
Microglia are the tissue-resident Phagocyte, phagocytes of the central nervous system. CSF1R signaling promotes migration of primitive microglia precursor cells from the embryonic yolk sac to the developing brain prior to formation of the Blood–brain barrier, blood-brain-barrier. In perinatal development, microglia are instrumental in synaptic pruning, a process in which microglia Phagocytosis, phagocytose weak and inactive synapses via binding of microglial Complement Receptor 3, complement receptor 3 (CR3) (complex of CD11b and Integrin beta 2, CD18) to synapse-bound iC3b. ''Csf1r'' Mutation, loss-of-function inhibits synaptic pruning and leads to excessive non-functional synapses in the brain. In adulthood, CSF1R is required for the proliferation and survival of microglia. Inhibition of CSF1R signaling in adulthood causes near-complete (>99%) depletion (death) of brain microglia, however reversal of CSF1R inhibition stimulates remaining microglia to proliferate and repopulate microglia-free niches in the brain. Production of CSF1R ligands CSF-1 and IL-34 is increased in the brain following injury or viral infection, which directs microglia to proliferate and execute immune responses.
Neural progenitor cells
CSF1R signaling has been found to play important roles in non-myeloid cells such as neural progenitor cells, multipotent cells that are able to self-renew or terminally differentiate into Neuron, neurons, Astrocyte, astrocytes and Oligodendrocyte, oligodendrocytes. Mice with ''Csf1r'' loss-of-function have a significantly more neural progenitor cells in Neurogenesis, generative zones and fewer matured neurons in forebrain Cerebral cortex, laminae due to failure of progenitor cell maturation and radial migration. These phenotypes were also seen in animals with ''Csf1r'' Conditional gene knockout, conditional knock-out specifically in neural progenitor cells, suggesting that CSF1R signaling by neural progenitor cells is important for maturation of certain neurons. Studies using Cell culture, cultured neural progenitor cells also show that CSF1R signaling stimulates neural progenitor cells maturation.Germline cells
CSF1R is expressed in Oocyte, oocytes, the trophoblast, and fertilized embryos prior to Implantation (embryology), implantation in the uterus. Studies using early mouse embryos ''in vitro'' have shown that activation of CSF1R stimulates formation of the Blastocyst, blastocyst cavity and enhances the number of trophoblast cells. ''Csf1r'' loss-of-function mice exhibit several reproductive system abnormalities in the estrous cycle and ovulation rates as well as reduced Antral follicle, antral follicles and ovarian macrophages. It is not clear whether ovulation dysfunction in ''Csf1r'' loss-of-function mice is due to loss of the protective effects of ovarian macrophages or loss of CSF1R signaling in oocytes themselves.Clinical significance
Bone disease
Bone remodeling is regulated by mutual cross-regulation between osteoclasts and osteoblasts. As a result, the dysfunction of CSF1R signaling directly affects the reabsorption (osteoclasts) and indirectly affects bone deposition (osteoblasts). In inflammatory arthritis conditions such as rheumatoid arthritis, psoriatic arthritis, and Crohn's disease, Inflammatory cytokine, proinflammatory cytokine Tumor necrosis factor, TNF-α is secreted by synovial macrophages which stimulates Stromal cell, stromal cells and osteoblasts to produce CSF-1. Increased CSF-1 promotes proliferation of osteoclasts and osteoclast precursors and increases osteoclast bone reabsorption. This pathogenic increase in osteoclast activity causes abnormal bone loss or osteolysis. In animal models of rheumatoid arthritis, administration of CSF-1 increases the severity of disease whereas ''Csf1r'' loss-of-function reduces inflammation and joint erosion. In a rare bone disease called Gorham's disease, Gorham‐Stout disease, elevated production of CSF-1 by lymphatic endothelial cells similarly produces excessive osteoclastogenesis and osteolysis. Additionally, Menopause, postmenopausal loss of estrogen has also been found to impact CSF1R signaling and cause osteoporosis. Estrogen deficiency causes osteoporosis by upregulating production of Tumor necrosis factor, TNF-α by activated T cell, T cells. As in inflammatory arthritis, TNF-α stimulates stromal cells to produce CSF-1 which increases CSF1R signaling in osteoclasts.
Cancer
Tumor-associated macrophage, Tumor-associated macrophages (TAMs) react to early stage cancers with anti-inflammatory immune responses that support tumor survival at the expense of healthy tissue. Tumor-infiltrating lymphocytes, Tumor infiltration by CSF1R-expressing TAMs yields a negative prognosis and is correlated with poor survival rates for individuals with lymphoma and solid tumors. The tumor microenvironment often produces high levels of CSF-1, creating a Positive feedback, positive feedback loop in which the tumor stimulates survival of TAMs and TAMs promote tumor survival and growth. Thus, CSF1R signaling in TAMs is associated tumor survival, angiogenesis, Resistant cancer, therapy resistance, and metastasis. Production of CSF-1 by brain tumors called Glioblastoma, glioblastomas causes microglia (brain-resident macrophages) to exhibit immunosuppressive, tumor-permissive phenotypes. CSF1R inhibition in mouse glioblastoma models is beneficial and improves survival by inhibiting tumor-promoting functions of microglia. MMTV-PyMT, Mouse models of breast cancer also show that ''Csf1r'' loss-of-function delays TAM infiltration and metastasis. Because Tumoricidal, anti-cancer macrophages and microglia rely on GM-CSF and IFN-γ signaling instead CSF-1, inhibition of CSF1R signaling has been posited as a therapeutic target in cancer to preferentially deplete tumor-permissive TAMs. Additionally, mutations in ''CSF1R'' gene itself are associated with certain cancers such as chronic myelomonocytic leukemia and type M4 acute myeloblastic leukemia.Neurological disorders
Adult-onset leukoencephalopathy
Because of the importance of the ''CSF1R'' gene in myeloid cell survival, maturation, and function, loss-of-function in both inherited copies of the ''CSF1R'' gene causes postnatal mortality. Heterozygous mutations in the ''CSF1R'' gene prevent downstream CSF1R signaling and cause an autosomal dominant neurodegenerative disease called Leukoencephalopathy with neuroaxonal spheroids, adult-onset leukoencephalopathy, which is characterized by dementia, executive dysfunction, and Seizure, seizures. Partial loss of ''CSF1R'' in adult-onset leukoencephalopathy causes microglia to exhibit morphological and functional deficits (impaired cytokine production and phagocytosis) which is associated with Axon, axonal damage, Demyelinating disease, demyelination, and neuronal loss. Signaling by a DAP12-TREM2 complex in microglia is downstream of CSF1R signaling and is needed for microglia phagocytosis of cellular debris and maintenance of brain homeostasis. ''TREM2'' deficiency in cultured myeloid cells prevents stimulation of proliferation by treatment with CSF-1. Similarities between Nasu-Hakola disease (caused by mutations in either ''DAP12'' or ''TREM2'') and adult-onset leukoencephalopathy suggest partial loss of microglia CSF1R signaling promotes neurodegeneration. Defects in neurogenesis and neuronal survival are also seen in adult-onset leukoencephalopathy due to impaired CSF1R signaling in neural progenitor cells.Other brain diseases and disorders
CSF1R signaling is involved in several diseases and disorders of the central nervous system. Research using animal models of epilepsy (kainic acid-induced seizures) suggests that CSF1 signaling during Seizure, seizures protects neurons by activating neuronal CREB signaling. CSF1R Agonist, agonism during seizures increases neuronal survival whereas neuron-specific ''Csf1r'' loss-of-function worsens kainic acid excitotoxicity, suggesting CSF1R signaling in neurons directly protects against seizure-related neuronal damage. Although CSF1R signaling is beneficial in certain contexts, it is detrimental in diseases where microglia drive tissue damage. In Charcot-Marie-Tooth disease type 1, CSF-1 secretion from Endoneurium, endoneurial cells stimulates proliferation and activation of macrophages and microglia that cause demyelination. Likewise in multiple sclerosis, CSF1R signaling supports the survival of inflammatory microglia which promote demyelination. CSF1R inhibition Preventive healthcare, prophylactically reduces demyelination in the experimental autoimmune encephalomyelitis animal model. The role of CSF1R signaling in Alzheimer's disease is more complicated because microglia both protect and damage the brain in response to Alzheimer's disease pathology. CSF-1 stimulates Primary cell culture, primary cultured human microglia to phagocytose toxic Amyloid beta, Aβ1–42 peptides. Microglia also initiate TREM2-dependent immune responses to amyloid plaques which protects neurons. However, Alzheimer's disease microglia also excessively secrete inflammatory cytokines and prune synapses promoting synapse loss, neuronal death, and Mild cognitive impairment, cognitive impairment. Both CSF1R stimulation and inhibition improves cognitive function in Alzheimer's disease models. Thus, microglia seem to have both protective and neurotoxic functions during Alzheimer's disease neurodegeneration. Similar findings have been reported in lesion studies of the mouse brain, which showed that inhibition of CSF1R after lesioning improves recovery but inhibition during lesioning worsens recovery. CSF1R-targeting therapies for neurological disorders may impact both detrimental and beneficial microglia functions.
Therapeutics
Because Tumor-associated macrophage, TAM CSF1R signaling is tumor-permissive and can tumor treatment-resistance, CSF1R signaling is a promising therapeutic target in the treatment of cancer. Several studies have investigated the efficacy of CSF1R inhibitor as a monotherapy and as a combination therapy in Refractory cancer, refractory and metastatic cancers. Several small molecule inhibitors and monoclonal antibodies targeting CSF1R are in clinical development for cancer therapy (Table 2). Pexidartinib, Pexidartinib (PLX3397) is a small molecule inhibitor tyrosine of CSFR (as well as cKIT, FLT3, and VEGF receptor, VEGFR) with the most clinical development so far. Several completed and concurrent clinical trials have tested the efficacy and safety of Pexidartinib as a monotherapy for c-kit-mutated melanoma, prostate cancer, glioblastoma, Hodgkin lymphoma, classical Hodgkin lymphoma, neurofibroma, sarcoma, and Leukemia, leukemias. In 2019, Pexidartinib was FDA approval, FDA-approved for treatment of Tenosynovial giant cell tumor, diffuse-type tenosynovial giant cell tumors, a non-malignant tumor that develops from Synovial membrane, synovial tissue lining the joints.
Safety of CSF1R inhibition
The safety of CSF1R inhibitors has been extensively characterized in Clinical trial, clinical trials for the different small molecules and monoclonal antibodies in Table 2. In some studies, CSF1R inhibitors were not found to have Dose–response relationship, dose-limiting toxicity while other studies did observe toxicity at high doses and have defined a maximum tolerated dose. Across multiple studies, the most frequent Adverse effect, adverse effects included fatigue, elevated Liver function tests, liver enzymes (creatine kinase, lactate dehydrogenase, Aspartate transaminase, aspartate aminotransferase, Elevated transaminases, alanine transaminase), edema, nausea, lacrimation, and reduced appetite, but no signs of Hepatotoxicity, liver toxicity were found. There are some differences in the side effects of monoclonal antibody compared to small molecule CSF1R inhibitors. Edema was more common with monoclonal antibody treatment compared to small molecules, suggesting that Monoclonal antibody therapy, immune response to monoclonal antibodies may drive some side effects. Additionally, some small molecule inhibitors are not specific for CSF1R, and off-target effects could explain observed side effects. For example, Pexidartinib treatment was found to change hair color, presumably by its impact on KIT (gene), KIT kinase. Overall, CSF1R inhibitors have favorable safety profiles with limited toxicity.Controversy
CSF1R inhibitors such as PLX5622 are widely used to study the role of microglia in mouse Animal models, preclinical models of Alzheimer's disease, stroke, traumatic brain injury, and Aging brain, aging. PLX5622 is typically used for microglia research because PLX5622 has higher brain bioavailability and CSF1R-specificity compared to other CSF1R inhibitors such as Pexidartinib, PLX3397. In 2020, researchers David Hume (University of Queensland) and Kim Green (University of California, Irvine, UCI) published a letter in the academic journal Proceedings of the National Academy of Sciences of the United States of America, PNAS defending the use small molecule CSF1R inhibitors to study microglia in brain disease. This letter was in response to a Research, primary research paper published in PNAS by lead correspondent Eleftherios Paschalis (Harvard Medical School, HMS) and others which provided evidence that microglia research using PLX5622 is Confounding, confounded by CSF1R inhibition in peripheral macrophages. Paschalis and collegues published a subsequent letter in PNAS defending the findings of their published research.Interactions
Colony stimulating factor 1 receptor has been shown to Protein-protein interaction, interact with: * Cbl gene, * FYN, * Grb2, * Suppressor of cytokine signaling 1, This receptor is also linked with the cells of MPS.See also
* Cluster of differentiation * Mouse models of breast cancer metastasisReferences
Further reading
* * * * * * * * * * * * * * * * *External links
* {{Portal bar, Biology, border=no Clusters of differentiation Immunoglobulin superfamily cytokine receptors Tyrosine kinase receptors