CSF1 overexpression has pleiotropic effects on microglia in vivo
Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were gene...
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| Veröffentlicht in: | Glia 2014-12, Vol.62 (12), p.1955-1967 |
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| container_end_page | 1967 |
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| container_issue | 12 |
| container_start_page | 1955 |
| container_title | Glia |
| container_volume | 62 |
| creator | De, Ishani Nikodemova, Maria Steffen, Megan D. Sokn, Emily Maklakova, Vilena I. Watters, Jyoti J. Collier, Lara S. |
| description | Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 overexpressing mice have increased microglial proliferation and increased microglial numbers compared with controls. Treatment with PLX3397, a small molecule inhibitor of the CSF1 receptor CSF1R and related kinases, decreases microglial numbers by promoting microglial apoptosis in both CSF1 overexpressing and control mice. Microglia in CSF1 overexpressing mice exhibit gene expression profiles indicating that they are not basally M1 or M2 polarized, but they do have defects in inducing expression of certain genes in response to the inflammatory stimulus lipopolysaccharide. These results indicate that the CSF1 overexpression observed in CNS pathologies likely has pleiotropic influences on microglia. Furthermore, small molecule inhibition of CSF1R has the potential to reverse CSF1‐driven microglial accumulation that is frequently observed in CNS pathologies, but can also promote apoptosis of normal microglia. GLIA 2014;62:1955–1967
Main Points
CSF1 over‐expression in the GFAP compartment was found to modulate microglial proliferation and response to LPS. An inhibitor of CSF1R promoted microglial apoptosis, indicating that signaling through CSF1R is required for adult microglial survival. |
| doi_str_mv | 10.1002/glia.22717 |
| format | Article |
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Main Points
CSF1 over‐expression in the GFAP compartment was found to modulate microglial proliferation and response to LPS. An inhibitor of CSF1R promoted microglial apoptosis, indicating that signaling through CSF1R is required for adult microglial survival.</description><identifier>ISSN: 0894-1491</identifier><identifier>EISSN: 1098-1136</identifier><identifier>DOI: 10.1002/glia.22717</identifier><identifier>PMID: 25042473</identifier><identifier>CODEN: GLIAEJ</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Animals ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Brain Stem - cytology ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; CD11b Antigen - genetics ; CD11b Antigen - metabolism ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Cerebellum - cytology ; Csf1 (Mcsf) ; Cytokines - genetics ; Cytokines - metabolism ; Gene expression ; Genetic Pleiotropy - drug effects ; Genetic Pleiotropy - physiology ; Glial Fibrillary Acidic Protein - metabolism ; Green Fluorescent Proteins - genetics ; Green Fluorescent Proteins - metabolism ; In Situ Nick-End Labeling ; Indoles - pharmacology ; Kinases ; Lipopolysaccharides - pharmacology ; M1 M2 polarization ; Macrophage Colony-Stimulating Factor - genetics ; Macrophage Colony-Stimulating Factor - metabolism ; Medical research ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins - genetics ; Microfilament Proteins - metabolism ; microglia ; Microglia - drug effects ; Microglia - metabolism ; PLX3397 ; RNA, Messenger - metabolism ; Sulfonamides - pharmacology</subject><ispartof>Glia, 2014-12, Vol.62 (12), p.1955-1967</ispartof><rights>2014 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4287-9ec349b14e9a775893b5502ef48c4059b65b655cfc2aa664b496bb93c9236b123</citedby><cites>FETCH-LOGICAL-c4287-9ec349b14e9a775893b5502ef48c4059b65b655cfc2aa664b496bb93c9236b123</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fglia.22717$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fglia.22717$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25042473$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De, Ishani</creatorcontrib><creatorcontrib>Nikodemova, Maria</creatorcontrib><creatorcontrib>Steffen, Megan D.</creatorcontrib><creatorcontrib>Sokn, Emily</creatorcontrib><creatorcontrib>Maklakova, Vilena I.</creatorcontrib><creatorcontrib>Watters, Jyoti J.</creatorcontrib><creatorcontrib>Collier, Lara S.</creatorcontrib><title>CSF1 overexpression has pleiotropic effects on microglia in vivo</title><title>Glia</title><addtitle>Glia</addtitle><description>Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 overexpressing mice have increased microglial proliferation and increased microglial numbers compared with controls. Treatment with PLX3397, a small molecule inhibitor of the CSF1 receptor CSF1R and related kinases, decreases microglial numbers by promoting microglial apoptosis in both CSF1 overexpressing and control mice. Microglia in CSF1 overexpressing mice exhibit gene expression profiles indicating that they are not basally M1 or M2 polarized, but they do have defects in inducing expression of certain genes in response to the inflammatory stimulus lipopolysaccharide. These results indicate that the CSF1 overexpression observed in CNS pathologies likely has pleiotropic influences on microglia. Furthermore, small molecule inhibition of CSF1R has the potential to reverse CSF1‐driven microglial accumulation that is frequently observed in CNS pathologies, but can also promote apoptosis of normal microglia. GLIA 2014;62:1955–1967
Main Points
CSF1 over‐expression in the GFAP compartment was found to modulate microglial proliferation and response to LPS. An inhibitor of CSF1R promoted microglial apoptosis, indicating that signaling through CSF1R is required for adult microglial survival.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Brain Stem - cytology</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>CD11b Antigen - genetics</subject><subject>CD11b Antigen - metabolism</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Proliferation - genetics</subject><subject>Cerebellum - cytology</subject><subject>Csf1 (Mcsf)</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Gene expression</subject><subject>Genetic Pleiotropy - drug effects</subject><subject>Genetic Pleiotropy - physiology</subject><subject>Glial Fibrillary Acidic Protein - metabolism</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>In Situ Nick-End Labeling</subject><subject>Indoles - pharmacology</subject><subject>Kinases</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>M1 M2 polarization</subject><subject>Macrophage Colony-Stimulating Factor - genetics</subject><subject>Macrophage Colony-Stimulating Factor - metabolism</subject><subject>Medical research</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Microfilament Proteins - genetics</subject><subject>Microfilament Proteins - metabolism</subject><subject>microglia</subject><subject>Microglia - drug effects</subject><subject>Microglia - metabolism</subject><subject>PLX3397</subject><subject>RNA, Messenger - metabolism</subject><subject>Sulfonamides - pharmacology</subject><issn>0894-1491</issn><issn>1098-1136</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1PGzEQhq2qVQnQS38AWqkXVGmpx5_rW1EoKWoECKh6tLxmFkw38WInAf59nQY49FDJ0siaZx57XkI-Aj0AStmXmz64A8Y06DdkBNQ0NQBXb8mINkbUIAxske2c7yiFctHvyRaTVDCh-Yh8HV8eQxVXmPBxSJhziPPq1uVq6DHERYpD8BV2HfpFrkprFnyK6werMK9WYRV3ybvO9Rk_PNcd8vP429X4ez09m5yMD6e1F6zRtUHPhWlBoHFay8bwVkrKsBONF1SaVslypO88c04p0Qqj2tZwbxhXLTC-Q_Y33iHF-yXmhZ2F7LHv3RzjMltQjCmQXIiCfvoHvYvLNC-_KxRwAYyqtfDzhioL5Zyws0MKM5eeLFC7ztWu17R_cy3w3rNy2c7w-hV9CbIAsAEeQo9P_1HZyfTk8EVab2ZCXuDj64xLv63SXEv763Ri4ZzqH5OjC3vJ_wDbVI9Z</recordid><startdate>201412</startdate><enddate>201412</enddate><creator>De, Ishani</creator><creator>Nikodemova, Maria</creator><creator>Steffen, Megan D.</creator><creator>Sokn, Emily</creator><creator>Maklakova, Vilena I.</creator><creator>Watters, Jyoti J.</creator><creator>Collier, Lara S.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7T7</scope><scope>7TK</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope></search><sort><creationdate>201412</creationdate><title>CSF1 overexpression has pleiotropic effects on microglia in vivo</title><author>De, Ishani ; Nikodemova, Maria ; Steffen, Megan D. ; Sokn, Emily ; Maklakova, Vilena I. ; Watters, Jyoti J. ; Collier, Lara S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4287-9ec349b14e9a775893b5502ef48c4059b65b655cfc2aa664b496bb93c9236b123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Brain Stem - cytology</topic><topic>Calcium-Binding Proteins - genetics</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>CD11b Antigen - genetics</topic><topic>CD11b Antigen - metabolism</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Proliferation - genetics</topic><topic>Cerebellum - cytology</topic><topic>Csf1 (Mcsf)</topic><topic>Cytokines - genetics</topic><topic>Cytokines - metabolism</topic><topic>Gene expression</topic><topic>Genetic Pleiotropy - drug effects</topic><topic>Genetic Pleiotropy - physiology</topic><topic>Glial Fibrillary Acidic Protein - metabolism</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>In Situ Nick-End Labeling</topic><topic>Indoles - pharmacology</topic><topic>Kinases</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>M1 M2 polarization</topic><topic>Macrophage Colony-Stimulating Factor - genetics</topic><topic>Macrophage Colony-Stimulating Factor - metabolism</topic><topic>Medical research</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Microfilament Proteins - genetics</topic><topic>Microfilament Proteins - metabolism</topic><topic>microglia</topic><topic>Microglia - drug effects</topic><topic>Microglia - metabolism</topic><topic>PLX3397</topic><topic>RNA, Messenger - metabolism</topic><topic>Sulfonamides - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De, Ishani</creatorcontrib><creatorcontrib>Nikodemova, Maria</creatorcontrib><creatorcontrib>Steffen, Megan D.</creatorcontrib><creatorcontrib>Sokn, Emily</creatorcontrib><creatorcontrib>Maklakova, Vilena I.</creatorcontrib><creatorcontrib>Watters, Jyoti J.</creatorcontrib><creatorcontrib>Collier, Lara S.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Glia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De, Ishani</au><au>Nikodemova, Maria</au><au>Steffen, Megan D.</au><au>Sokn, Emily</au><au>Maklakova, Vilena I.</au><au>Watters, Jyoti J.</au><au>Collier, Lara S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>CSF1 overexpression has pleiotropic effects on microglia in vivo</atitle><jtitle>Glia</jtitle><addtitle>Glia</addtitle><date>2014-12</date><risdate>2014</risdate><volume>62</volume><issue>12</issue><spage>1955</spage><epage>1967</epage><pages>1955-1967</pages><issn>0894-1491</issn><eissn>1098-1136</eissn><coden>GLIAEJ</coden><abstract>Macrophage colony stimulating factor (CSF1) is a cytokine that is upregulated in several diseases of the central nervous system (CNS). To examine the effects of CSF1 overexpression on microglia, transgenic mice that overexpress CSF1 in the glial fibrillary acidic protein (GFAP) compartment were generated. CSF1 overexpressing mice have increased microglial proliferation and increased microglial numbers compared with controls. Treatment with PLX3397, a small molecule inhibitor of the CSF1 receptor CSF1R and related kinases, decreases microglial numbers by promoting microglial apoptosis in both CSF1 overexpressing and control mice. Microglia in CSF1 overexpressing mice exhibit gene expression profiles indicating that they are not basally M1 or M2 polarized, but they do have defects in inducing expression of certain genes in response to the inflammatory stimulus lipopolysaccharide. These results indicate that the CSF1 overexpression observed in CNS pathologies likely has pleiotropic influences on microglia. Furthermore, small molecule inhibition of CSF1R has the potential to reverse CSF1‐driven microglial accumulation that is frequently observed in CNS pathologies, but can also promote apoptosis of normal microglia. GLIA 2014;62:1955–1967
Main Points
CSF1 over‐expression in the GFAP compartment was found to modulate microglial proliferation and response to LPS. An inhibitor of CSF1R promoted microglial apoptosis, indicating that signaling through CSF1R is required for adult microglial survival.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>25042473</pmid><doi>10.1002/glia.22717</doi><tpages>13</tpages></addata></record> |
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| subjects | Animals Apoptosis Apoptosis - drug effects Apoptosis - genetics Brain Stem - cytology Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism CD11b Antigen - genetics CD11b Antigen - metabolism Cell Proliferation - drug effects Cell Proliferation - genetics Cerebellum - cytology Csf1 (Mcsf) Cytokines - genetics Cytokines - metabolism Gene expression Genetic Pleiotropy - drug effects Genetic Pleiotropy - physiology Glial Fibrillary Acidic Protein - metabolism Green Fluorescent Proteins - genetics Green Fluorescent Proteins - metabolism In Situ Nick-End Labeling Indoles - pharmacology Kinases Lipopolysaccharides - pharmacology M1 M2 polarization Macrophage Colony-Stimulating Factor - genetics Macrophage Colony-Stimulating Factor - metabolism Medical research Mice Mice, Inbred C57BL Mice, Transgenic Microfilament Proteins - genetics Microfilament Proteins - metabolism microglia Microglia - drug effects Microglia - metabolism PLX3397 RNA, Messenger - metabolism Sulfonamides - pharmacology |
| title | CSF1 overexpression has pleiotropic effects on microglia in vivo |
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