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-surfaceprotein encoded by the humanCSF1Rgene (known also as c-FMS).[5][6] CSF1R is areceptor that can be activated by twoligands:colony stimulating factor 1 (CSF-1) andinterleukin-34 (IL-34). CSF1R is highly expressed inmyeloid cells, and CSF1R signaling is necessary for thesurvival,proliferation, anddifferentiation of many myeloid cell typesin vivo andin vitro. CSF1R signaling is involved in many diseases and is targeted in therapies forcancer,neurodegeneration, andinflammatory bone diseases.
In the human genome, theCSF1R gene is located on chromosome 5 (5q32), and in mice theCsf1r gene is located on chromosome 18 (18D).CSF1R is 60.002 kilobases (kbs) in length.Hematopoietic stem cells expressCSF1R at low levels, butCSF1R is highly expressed inmore differentiated myeloid cell types such asmonocytes,macrophages,osteoclasts,myeloid dendritic cells,microglia, andPaneth cells.[7]CSF1R expression is controlled by two alternativepromoters that are active in specific tissue types.Exon 1 ofCSF1R is specificallytranscribed introphoblastic cells whereas exon 2 is specifically transcribed in macrophages. Activation ofCSF1R transcription is regulated by several transcription factors includingEts andPU.1. Macrophage expression of theCSF1R gene is regulated by the promoterupstream of exon 2 and another highlyconserved region termed the fms intronic regulatory element (FIRE). The FIRE is a 250-bp region inintron 2 that regulates transcript elongation during transcription ofCSF1R 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 mouseCsf1r gene widely prevents macrophage differentiation, causing profound developmental defects.[8] Additionally, the firstintron of theCSF1R gene contains atranscriptionally inactiveribosomal protein L7 processedpseudogene, oriented in the opposite direction to theCSF1R gene.[5]
CSF1R, the protein encoded by theCSF1R gene is atyrosine kinasetransmembrane receptor and member of the CSF1/PDGF receptor family of tyrosine-protein kinases. CSF1R has 972 amino acids, is predicted to have amolecular weight of 107.984 kilodaltons, and is composed of an extracellular and a cytoplasmicdomain. The extracellular domain has 3 N-terminalimmunoglobulin (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.[8] Upon binding of ligand to extracellular Ig domains, CSF1Rdimerizes noncovalently andautophosphorylates several tyrosine residues. This first wave of CSF1R tyrosine phosphorylation createsphosphotyrosine-binding domains to whicheffector proteins can bind and initiate various cellular responses. Many proteins become tyrosine phosphorylated in response to CSF1R signaling (Table 1) includingp85,Cbl, andGab3 which are important for survival, differentiation,chemotaxis, andactin cytoskeleton of myeloid cells. The first wave of tyrosine phosphorylation also leads to the covalent dimerization of CSF1R viadisulfide 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 eventuallyendocytosis which terminates signaling by trafficking the ligand-CSF1R complex to thelysosome for degradation.[9]Colony stimulating factor 1 (CSF-1) andinterleukin-34 (IL-34) are both CSF1Rligands. 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 cellularsignaling cascades triggered upon binding to CSF1R.[8]
| Protein | Full protein name; function |
|---|---|
| SFK | Src family tyrosine kinases |
| Grb2 | Adaptor |
| Mona | Monocyte adaptor; adaptor |
| Socs1 | Suppressor of cytokine signaling-1; adaptor |
| PLCγ | Phospholipase C-γ |
| p85 PI3K | Regulatory subunit ofPI3K |
| Cbl | Casitas B lineage; ubiquitin ligase, adaptor |
| FMIP | FMS-interacting protein; function unknown |
| PP2A | Protein phosphatase 2A; serine/threonine phosphatase |
| Pyk2 | Proline-rich and Ca2C-activated tyrosine kinase |
| Paxilin | Focal complex adaptor |
| PTPφ | PTP for phosphopaxillin |
| MAYP/PSTPIP2 | Macrophage actin-associated and tyrosine-phosphorylated protein; actin bundling |
| Iba1 | Ionized Ca2C-binding adaptor protein 1; actin bundling |
| Gab2 | Grb2-associated binder-2; Adaptor |
| Gab3 | Grb2-associated binder-3; adaptor |
| SHIP1 | SH2-domain-containing polyinositol phosphatase-1 |
| SHP1 | SH2-domain-containing phosphatase-1; PTP |
| SHP2 | SH2-domain-containing phosphatase-2; PTP |
| PKC-δ | Protein kinase C-d |
| Pkare | PKA-related gene (Pkare); protein kinase |
| MysPDZ | 110-kDa myosin XVIIIA |
| STAT1,STAT3,STAT5 | Signal transducers and activators of transcription-1, -2, -3; transcription factors |
| Dok1,Dok2,Dok3 | Downstream of kinase-1, -2, -3; adaptors |
| Vav | Rho family guanine-nucleotide-exchange factor |
| BLIMP-1 | B-lymphocyte-induced maturation protein-1; transcriptional repressor |
Osteoclast are multi-nucleated cells that absorb and remove bone which is critical for growth of new bones and maintenance of bone strength. Osteoclasts are critical for thebone remodeling cycle which is achieved by the building of bone byosteoblasts, reabsorption by osteoclasts, and remodeling by osteoblasts.[10] 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 theBcl-X(L) protein, an inhibitor of pro-apoptoticcaspase-9. CSF1R signaling in mature osteoclasts promotes survival by stimulatingmTOR/S6 kinase and the Na/HCO3 co-transporter, NBCn1.[11] 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 osteoclastchemotaxis and bone reabsorption.[10]
Monocytes and macrophages aremononuclear phagocytes. Monocytes circulate in the blood and are capable of differentiating into macrophages ordendritic cells, and macrophages areterminally differentiated tissue-resident cells. CSF1R signaling isnecessary for differentiation ofmicroglia andLangerhans cells which are derived from yolk sac progenitor cells with high expression of CSF1R.[7] CSF1R signaling is only partially required for other tissue macrophages, and it is not necessary formonocytopoiesis (production of monocytes and macrophages) fromhematopoietic stem cells.[7] Macrophages ofthymus andlymph nodes are almost completely independent of CSF1R signaling. In macrophages whose survival is fully or partially dependent on CSF1R signaling, CSF1R promotes survival by activatingPI3K.[9] 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.[10] Lastly, activation of CSF1R is a strongchemokinetic signal, inducingmacrophage 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 theSrc/Pyk2 andPI3K signaling pathways.[9]
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Microglia are the tissue-residentphagocytes of thecentral nervous system. CSF1R signaling promotes migration of primitive microglia precursor cells from the embryonicyolk sac to the developing brain prior to formation of theblood-brain-barrier. In perinatal development, microglia are instrumental insynaptic pruning, a process in which microgliaphagocytose weak and inactive synapses via binding of microglialcomplement receptor 3 (CR3) (complex ofCD11b andCD18) to synapse-bound iC3b.Csf1rloss-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.[12] 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.[13] 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.[12]
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 intoneurons,astrocytes andoligodendrocytes. Mice withCsf1r loss-of-function have a significantly more neural progenitor cells ingenerative zones and fewer matured neurons in forebrainlaminae due to failure of progenitor cell maturation and radial migration. These phenotypes were also seen in animals withCsf1rconditional knock-out specifically in neural progenitor cells, suggesting that CSF1R signaling by neural progenitor cells is important for maturation of certain neurons.[11] Studies usingcultured neural progenitor cells also show that CSF1R signaling stimulates neural progenitor cells maturation.[12]
CSF1R is expressed inoocytes, thetrophoblast, and fertilized embryos prior toimplantation in theuterus.[8] Studies using early mouse embryosin vitro have shown that activation of CSF1R stimulates formation of theblastocyst cavity and enhances the number of trophoblast cells.Csf1r loss-of-function mice exhibit several reproductive system abnormalities in theestrous cycle andovulation rates as well as reducedantral follicles and ovarian macrophages. It is not clear whether ovulation dysfunction inCsf1r loss-of-function mice is due to loss of the protective effects of ovarian macrophages or loss of CSF1R signaling in oocytes themselves.[11]
 | This section needs to beupdated. Please help update this article to reflect recent events or newly available information.(August 2019) |
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 asrheumatoid arthritis,psoriatic arthritis, andCrohn's disease,proinflammatory cytokineTNF-α is secreted by synovial macrophages which stimulatesstromal 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 orosteolysis.[14] In animal models of rheumatoid arthritis, administration of CSF-1 increases the severity of disease whereasCsf1r loss-of-function reduces inflammation and joint erosion.[10] In a rare bone disease calledGorham‐Stout disease, elevated production of CSF-1 by lymphaticendothelial cells similarly produces excessive osteoclastogenesis andosteolysis.[8] Additionally,postmenopausal loss ofestrogen has also been found to impact CSF1R signaling and causeosteoporosis.Estrogen deficiency causes osteoporosis by upregulating production ofTNF-α by activatedT cells. As in inflammatory arthritis, TNF-α stimulates stromal cells to produce CSF-1 which increases CSF1R signaling in osteoclasts.[15]
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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 infiltration by CSF1R-expressing TAMs yields a negativeprognosis and is correlated with poor survival rates for individuals withlymphoma and solid tumors. Thetumor microenvironment often produces high levels of CSF-1, creating apositive 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,therapy resistance, andmetastasis. Production of CSF-1 by brain tumors calledglioblastomas causes microglia (brain-resident macrophages) to exhibit immunosuppressive, tumor-permissive phenotypes.[16] CSF1R inhibition in mouse glioblastoma models is beneficial and improves survival by inhibiting tumor-promoting functions of microglia. In a murine model of metastaticrenal cell carcinoma, the IL-34/CSF1R axis can drive the migration and accumulation of monocyte-derivedtumor-associated macrophages in thetumor microenvironment and consequently induces immunosuppression and nonfunctional vasculature, two key features of therapy resistance. Blocking CSF1R withpexidartinib reduces IL-34 driven MD-TAMs accumulation, improves vascular integrity, and when combined withsunitinib or antiPD-1 therapy, limits metastatic growth better than monotherapies in treated mice.[17]Mouse models of breast cancer also show thatCsf1r loss-of-function delays TAM infiltration and metastasis. Becauseanti-cancer macrophages and microglia rely onGM-CSF andIFN-γ signaling instead CSF-1, inhibition of CSF1R signaling has been posited as a therapeutic target in cancer to preferentially deplete tumor-permissive TAMs.[8][12] Additionally, mutations inCSF1R gene itself are associated with certain cancers such aschronic myelomonocytic leukemia and type M4acute myeloblastic leukemia.[18]
Because of the importance of theCSF1R gene in myeloid cell survival, maturation, and function, loss-of-function in both inherited copies of theCSF1R gene causes postnatal mortality.Heterozygous mutations in theCSF1R gene prevent downstream CSF1R signaling and cause anautosomal dominant neurodegenerative disease calledadult-onset leukoencephalopathy, which is characterized bydementia,executive dysfunction, andseizures. Partial loss ofCSF1R in adult-onset leukoencephalopathy causes microglia to exhibit morphological and functional deficits (impaired cytokine production andphagocytosis) which is associated withaxonal damage,demyelination, and neuronal loss. Signaling by aDAP12-TREM2 complex in microglia is downstream of CSF1R signaling and is needed for microglia phagocytosis of cellular debris and maintenance of brain homeostasis.[19][12]TREM2 deficiency in cultured myeloid cells prevents stimulation of proliferation by treatment with CSF-1. Similarities betweenNasu-Hakola disease (caused by mutations in eitherDAP12 orTREM2) 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.[12]
CSF1R signaling is involved in several diseases and disorders of thecentral nervous system. Research using animal models ofepilepsy (kainic acid-induced seizures) suggests that CSF1 signaling duringseizures protects neurons by activating neuronalCREB signaling. CSF1Ragonism during seizures increases neuronal survival whereas neuron-specificCsf1r loss-of-function worsens kainic acidexcitotoxicity, suggesting CSF1R signaling in neurons directly protects against seizure-related neuronal damage.[12] Although CSF1R signaling is beneficial in certain contexts, it is detrimental in diseases where microglia drive tissue damage. InCharcot-Marie-Tooth disease type 1, CSF-1 secretion fromendoneurial cells stimulates proliferation and activation of macrophages and microglia that cause demyelination. Likewise inmultiple sclerosis, CSF1R signaling supports the survival of inflammatory microglia which promote demyelination. CSF1R inhibitionprophylactically reduces demyelination in theexperimental autoimmune encephalomyelitis animal model. The role of CSF1R signaling inAlzheimer's disease is more complicated because microglia both protect and damage the brain in response to Alzheimer's disease pathology. CSF-1 stimulatesprimary cultured human microglia to phagocytose toxicAβ1–42 peptides. Microglia also initiate TREM2-dependent immune responses toamyloid plaques which protects neurons.[20][21] However, Alzheimer's disease microglia also excessively secrete inflammatory cytokines and prune synapses promoting synapse loss, neuronal death, andcognitive impairment.[22] Both CSF1R stimulation and inhibition improves cognitive function in Alzheimer's disease models.[12] Thus, microglia seem to have both protective and neurotoxic functions during Alzheimer's disease neurodegeneration.[23][24] Similar findings have been reported inlesion studies of the mouse brain, which showed that inhibition of CSF1R after lesioning improves recovery but inhibition during lesioning worsens recovery.[12] CSF1R-targeting therapies for neurological disorders may impact both detrimental and beneficial microglia functions.
BecauseTAM CSF1R signaling is tumor-permissive and can cause 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 amonotherapy and as a combination therapy inrefractory and metastatic cancers. Several small molecule inhibitors and monoclonal antibodies targeting CSF1R are in clinical development for cancer therapy (Table 2).Pexidartinib (PLX3397) is a small molecule inhibitor tyrosine of CSFR (as well ascKIT,FLT3, andVEGFR) 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-mutatedmelanoma,prostate cancer,glioblastoma,classical Hodgkin lymphoma,neurofibroma,sarcoma, andleukemias.[16] In 2019, Pexidartinib wasFDA-approved for treatment ofdiffuse-type tenosynovial giant cell tumors, a non-malignant tumor that develops fromsynovial tissue lining the joints.[25]
| Drug name | Form | Targets | Clinical trial diseases |
|---|---|---|---|
| Pexidartinib (PLX3397) | Small molecule | CSF1R,c-KIT,VEGFR, andFlt3 | Autoimmune diseases,Alzheimer's disease,Leukemia,acral melanoma,mucosal melanoma |
| Imatinib | Small molecule | CSF1R,ABL, c-KIT, andPDGFR-β | Osteoporosis,osteolysis,chronic myeloid leukemia (CML),breast cancer |
| PLX5622 | Small molecule | CSF1R | Rheumatoid arthritis, cancer,neuropathic pain, Alzheimer's disease |
| Sotuletinib (BLZ945) | Small molecule | CSF1R, c-KIT, PDGFRβ, and Flt3 | Solid tumors,amyotrophic lateral sclerosis |
| GW2580 | Small molecule | CSF1R | Arthritis, osteoporosis, cancer |
| Ki20227 | Small molecule | CSF1R, VEGFR2, c-KIT, and PDGFRβ | Osteolysis, breast cancer |
| Edicotinib (JNJ-40346527) | Small molecule | CSF1R, c-KIT, and Flt3 | Alzheimer's disease,cHL, rheumatoid arthritis, neurodegenerative diseases |
| Emactuzumab (RG7155) | Monoclonal antibody | CSF1R | Solid tumors |
| IMC-CS4 (LY3022855) | Monoclonal antibody | CSF1R | Solid tumors, breast cancer,prostate cancer |
| AMG820 | Monoclonal antibody | CSF1R | Solid tumors |
The safety of CSF1R inhibitors has been extensively characterized inclinical trials for the different small molecules and monoclonal antibodies in Table 2. In some studies, CSF1R inhibitors were not found to havedose-limiting toxicity while other studies did observe toxicity at high doses and have defined amaximum tolerated dose. Across multiple studies, the most frequentadverse effects includedfatigue, elevatedliver enzymes (creatine kinase,lactate dehydrogenase,aspartate aminotransferase,alanine transaminase),edema,nausea,lacrimation, and reduced appetite, but no signs ofliver 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 thatimmune 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 onKIT kinase. Overall, CSF1R inhibitors have favorable safety profiles with limited toxicity.[16]
CSF1R inhibitors such as PLX5622 are widely used to study the role of microglia in mousepreclinical models of Alzheimer's disease,stroke,traumatic brain injury, andaging. PLX5622 is typically used for microglia research because PLX5622 has higher brainbioavailability and CSF1R-specificity compared to other CSF1R inhibitors such asPLX3397.[13] In 2020, researchers David Hume (University of Queensland) and Kim Green (UCI) published a letter in the academic journalPNAS defending the use small molecule CSF1R inhibitors to study microglia in brain disease.[26] This letter was in response to aprimary research paper published in PNAS by lead correspondent Eleftherios Paschalis (HMS) and others which provided evidence that microglia research using PLX5622 isconfounded by CSF1R inhibition in peripheral macrophages. Paschalis and colleagues published a subsequent letter in PNAS defending the findings of their published research.[27]
Colony stimulating factor 1 receptor has been shown tointeract with:
This article incorporates text from theUnited States National Library of Medicine, which is in thepublic domain.
