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Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells
Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB sub...
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Published in: | Frontiers in immunology 2021-10, Vol.12, p.669906-669906 |
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description | Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the
gene as the most common monogenic cause of common variable immunodeficiencies in Europeans.
encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit.
is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for
in the control of the immune system is apparent from
mouse studies, we know relatively little of the role of
in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of
human macrophages. Transcriptomic analysis reveals that activated
macrophages are more pro-inflammatory than wild type controls and express elevated levels of
,
, and
, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as
,
and
.
THP1 macrophages recapitulate key observations in individuals with
haploinsufficiency including decreased
expression. These data supporting their utility as an
model for understanding the role of
in human monocytes and macrophages and indicate that of loss of function
mutations in these cells is an important component in the associated pathology. |
doi_str_mv | 10.3389/fimmu.2021.669906 |
format | article |
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gene as the most common monogenic cause of common variable immunodeficiencies in Europeans.
encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit.
is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for
in the control of the immune system is apparent from
mouse studies, we know relatively little of the role of
in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of
human macrophages. Transcriptomic analysis reveals that activated
macrophages are more pro-inflammatory than wild type controls and express elevated levels of
,
, and
, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as
,
and
.
THP1 macrophages recapitulate key observations in individuals with
haploinsufficiency including decreased
expression. These data supporting their utility as an
model for understanding the role of
in human monocytes and macrophages and indicate that of loss of function
mutations in these cells is an important component in the associated pathology.</description><identifier>ISSN: 1664-3224</identifier><identifier>EISSN: 1664-3224</identifier><identifier>DOI: 10.3389/fimmu.2021.669906</identifier><identifier>PMID: 34721373</identifier><language>eng</language><publisher>Switzerland: Frontiers Media S.A</publisher><subject>Adaptive Immunity ; CRISPR-Cas Systems ; Cytokines - genetics ; Cytokines - metabolism ; Gene Expression Profiling ; Gene Knockout Techniques ; Humans ; Immunity, Cellular ; Immunology ; Inflammation - genetics ; Inflammation - immunology ; Inflammation - metabolism ; macrophage ; Macrophage Activation ; Macrophages - immunology ; Macrophages - metabolism ; NF-kappa B p50 Subunit - deficiency ; NF-kappa B p50 Subunit - genetics ; NF-κB ; NFKB1 ; Phenotype ; RNA-Seq ; THP-1 Cells ; THP1 cells ; toll-like receptors ; Toll-Like Receptors - genetics ; Toll-Like Receptors - metabolism ; Transcriptome ; transcriptomics</subject><ispartof>Frontiers in immunology, 2021-10, Vol.12, p.669906-669906</ispartof><rights>Copyright © 2021 Somma, Kok, Kerrigan, Wells and Carmody.</rights><rights>Copyright © 2021 Somma, Kok, Kerrigan, Wells and Carmody 2021 Somma, Kok, Kerrigan, Wells and Carmody</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3806-db4bf1e7b3665a35da194af9a551608c48f91512b391609e4df9488d283743323</citedby><cites>FETCH-LOGICAL-c3806-db4bf1e7b3665a35da194af9a551608c48f91512b391609e4df9488d283743323</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548695/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548695/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34721373$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Somma, Domenico</creatorcontrib><creatorcontrib>Kok, Fatma O</creatorcontrib><creatorcontrib>Kerrigan, David</creatorcontrib><creatorcontrib>Wells, Christine A</creatorcontrib><creatorcontrib>Carmody, Ruaidhrí J</creatorcontrib><title>Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells</title><title>Frontiers in immunology</title><addtitle>Front Immunol</addtitle><description>Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the
gene as the most common monogenic cause of common variable immunodeficiencies in Europeans.
encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit.
is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for
in the control of the immune system is apparent from
mouse studies, we know relatively little of the role of
in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of
human macrophages. Transcriptomic analysis reveals that activated
macrophages are more pro-inflammatory than wild type controls and express elevated levels of
,
, and
, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as
,
and
.
THP1 macrophages recapitulate key observations in individuals with
haploinsufficiency including decreased
expression. These data supporting their utility as an
model for understanding the role of
in human monocytes and macrophages and indicate that of loss of function
mutations in these cells is an important component in the associated pathology.</description><subject>Adaptive Immunity</subject><subject>CRISPR-Cas Systems</subject><subject>Cytokines - genetics</subject><subject>Cytokines - metabolism</subject><subject>Gene Expression Profiling</subject><subject>Gene Knockout Techniques</subject><subject>Humans</subject><subject>Immunity, Cellular</subject><subject>Immunology</subject><subject>Inflammation - genetics</subject><subject>Inflammation - immunology</subject><subject>Inflammation - metabolism</subject><subject>macrophage</subject><subject>Macrophage Activation</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>NF-kappa B p50 Subunit - deficiency</subject><subject>NF-kappa B p50 Subunit - genetics</subject><subject>NF-κB</subject><subject>NFKB1</subject><subject>Phenotype</subject><subject>RNA-Seq</subject><subject>THP-1 Cells</subject><subject>THP1 cells</subject><subject>toll-like receptors</subject><subject>Toll-Like Receptors - genetics</subject><subject>Toll-Like Receptors - metabolism</subject><subject>Transcriptome</subject><subject>transcriptomics</subject><issn>1664-3224</issn><issn>1664-3224</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpVks1u1DAQxyMEolXpA3BBPpZDFn8nviC1C8tWLQXBcrZsx951SezUTpD2AXgpHoJnIrtbqnYunrFnfmOP_0XxGsEZIbV453zXjTMMMZpxLgTkz4pjxDktCcb0-SP_qDjN-RZORgUhhL0sjgitMCIVOS5-f7DOBx_WYNhY8C22FkQHbkbTWpXAQpkhJnB2s3hb_v1zAXoEGfg-6jH4AfgAlmOnAvisTIr9Rq0t0FuwSipkk3w_xM4bcB5Uu80-77GLqwsErkI0P-M4gNXyKwJz27b5VfHCqTbb0_v1pPix-LiaL8vrL58u5-fXpSE15GWjqXbIVppwzhRhjUKCKicUY4jD2tDaCcQQ1kRMsbC0cYLWdYNrUlFCMDkpLg_cJqpb2SffqbSVUXm534hpLVUa_PR4aQxRljnRaK0o5VojZBjEu55IVLaZWO8PrH7UnW2MDUNS7RPo05PgN3Idf8ma0ZoLNgHO7gEp3o02D7Lz2UzjUMHGMUvMBMIEQS6mVHRInQadc7LuoQ2CcqcGuVeD3KlBHtQw1bx5fL-Hiv9_T_4BSGCwwQ</recordid><startdate>20211013</startdate><enddate>20211013</enddate><creator>Somma, Domenico</creator><creator>Kok, Fatma O</creator><creator>Kerrigan, David</creator><creator>Wells, Christine A</creator><creator>Carmody, Ruaidhrí J</creator><general>Frontiers Media S.A</general><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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20211013</creationdate><title>Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells</title><author>Somma, Domenico ; Kok, Fatma O ; Kerrigan, David ; Wells, Christine A ; Carmody, Ruaidhrí J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3806-db4bf1e7b3665a35da194af9a551608c48f91512b391609e4df9488d283743323</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adaptive Immunity</topic><topic>CRISPR-Cas Systems</topic><topic>Cytokines - genetics</topic><topic>Cytokines - metabolism</topic><topic>Gene Expression Profiling</topic><topic>Gene Knockout Techniques</topic><topic>Humans</topic><topic>Immunity, Cellular</topic><topic>Immunology</topic><topic>Inflammation - genetics</topic><topic>Inflammation - immunology</topic><topic>Inflammation - metabolism</topic><topic>macrophage</topic><topic>Macrophage Activation</topic><topic>Macrophages - immunology</topic><topic>Macrophages - metabolism</topic><topic>NF-kappa B p50 Subunit - deficiency</topic><topic>NF-kappa B p50 Subunit - genetics</topic><topic>NF-κB</topic><topic>NFKB1</topic><topic>Phenotype</topic><topic>RNA-Seq</topic><topic>THP-1 Cells</topic><topic>THP1 cells</topic><topic>toll-like receptors</topic><topic>Toll-Like Receptors - genetics</topic><topic>Toll-Like Receptors - metabolism</topic><topic>Transcriptome</topic><topic>transcriptomics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Somma, Domenico</creatorcontrib><creatorcontrib>Kok, Fatma O</creatorcontrib><creatorcontrib>Kerrigan, David</creatorcontrib><creatorcontrib>Wells, Christine A</creatorcontrib><creatorcontrib>Carmody, Ruaidhrí J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Frontiers in immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Somma, Domenico</au><au>Kok, Fatma O</au><au>Kerrigan, David</au><au>Wells, Christine A</au><au>Carmody, Ruaidhrí J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells</atitle><jtitle>Frontiers in immunology</jtitle><addtitle>Front Immunol</addtitle><date>2021-10-13</date><risdate>2021</risdate><volume>12</volume><spage>669906</spage><epage>669906</epage><pages>669906-669906</pages><issn>1664-3224</issn><eissn>1664-3224</eissn><abstract>Since its discovery over 30 years ago the NF-ĸB family of transcription factors has gained the status of master regulator of the immune response. Much of what we understand of the role of NF-ĸB in immune development, homeostasis and inflammation comes from studies of mice null for specific NF-ĸB subunit encoding genes. The role of inflammation in diseases that affect a majority of individuals with health problems globally further establishes NF-ĸB as an important pathogenic factor. More recently, genomic sequencing has revealed loss of function mutations in the
gene as the most common monogenic cause of common variable immunodeficiencies in Europeans.
encodes the p105 subunit of NF-ĸB which is processed to generate the NF-ĸB p50 subunit.
is the most highly expressed transcription factor in macrophages, key cellular drivers of inflammation and immunity. Although a key role for
in the control of the immune system is apparent from
mouse studies, we know relatively little of the role of
in regulating human macrophage responses. In this study we use the THP1 monocyte cell line and CRISPR/Cas9 gene editing to generate a model of
human macrophages. Transcriptomic analysis reveals that activated
macrophages are more pro-inflammatory than wild type controls and express elevated levels of
,
, and
, but also have reduced expression of co-stimulatory factors important for the activation of T cells and adaptive immune responses such as
,
and
.
THP1 macrophages recapitulate key observations in individuals with
haploinsufficiency including decreased
expression. These data supporting their utility as an
model for understanding the role of
in human monocytes and macrophages and indicate that of loss of function
mutations in these cells is an important component in the associated pathology.</abstract><cop>Switzerland</cop><pub>Frontiers Media S.A</pub><pmid>34721373</pmid><doi>10.3389/fimmu.2021.669906</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adaptive Immunity CRISPR-Cas Systems Cytokines - genetics Cytokines - metabolism Gene Expression Profiling Gene Knockout Techniques Humans Immunity, Cellular Immunology Inflammation - genetics Inflammation - immunology Inflammation - metabolism macrophage Macrophage Activation Macrophages - immunology Macrophages - metabolism NF-kappa B p50 Subunit - deficiency NF-kappa B p50 Subunit - genetics NF-κB NFKB1 Phenotype RNA-Seq THP-1 Cells THP1 cells toll-like receptors Toll-Like Receptors - genetics Toll-Like Receptors - metabolism Transcriptome transcriptomics |
title | Defining the Role of Nuclear Factor (NF)-κB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells |
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