A role for miRNAs in adenosine-dependent alternative macrophage activation
A role for miRNAs in adenosine-dependent alternative macrophage activation
批准号:
8717565
负责人:
Samuel Joseph Leibovich
金额:
$22.42万
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-07-01 至 2015-07-31
关键词:
3&apos Untranslated RegionsAdenosineAgonistBinding SitesBioinformaticsBiological AssayBloodCell surfaceCellsExhibitsGene ExpressionGene Expression RegulationGenesGrowth FactorHealthHumanIL4 geneInflammationInflammatoryInterleukin-10Interleukin-12Interleukin-13LigationLuciferasesMacrophage ActivationMediatingMessenger RNAMicroRNAsModificationMusNatural ImmunityOrganismPathway interactionsPhagocytesPhenotypePhospholipasePlasmidsPlayProcessPurinergic P1 ReceptorsRNARNA StabilityRNA-Binding ProteinsReadingReporterRoleSiteSite-Directed MutagenesisStimulusSubgroupTissuesVascular Endothelial Growth FactorsWound Healingabstractingacquired immunityangiogenesiscytokinecytosolic receptorinsightmRNA ExpressionmRNA Stabilitymacrophagemonocytenovelprotein expressionreceptorresearch studyresponse
中文摘要
文摘:
英文摘要
Abstract:
Macrophages play key roles in regulating inflammation, wound healing and innate and acquired immunity. In
response to activational stimuli, macrophages produce cytokines and growth factors that mediate these
processes. Activation of macrophages has been classified as "classical" (inflammatory, M1) and "alternative"
(angiogenic or wound healing, M2). M1 activation is mediated by IFNg and/or TLR agonists such as LPS, while
M2 activation is broadly defined as mediated by IL4 or IL13 through the common IL4Ra. We have discovered a
novel IL4Ra-independent pathway that is mediated by TLR agonists together with adenosine A2A/A2B receptor
(A2AR/A2BR) agonists. This synergistic pathway suppresses TNFa and IL-12 expression and induces VEGF
and IL-10 expression, switching macrophages into an M2-like phenotype that we have termed "M2d". This
novel pathway requires the LPS-dependent induction of A2AR and A2BR expression, induction of HIF-1a
expression, and suppression of phospholipase-Cb2 (PLCb2) expression at the post-transcriptional level by
destabilization of its mRNA. We have found recently that a subset of miRNAs are specifically regulated in
macrophages by LPS alone (miR-155, miR146a, miR-146b, miR-221 and miR-222), or by combined LPS/
A2AR/A2BR challenge (miR-483, miR-877, miR-337-5p, miR-546 and miR-494 are up-regulated, while miR-770-
5p, miR-487b, miR-220, miR-212 and miR-712 are strongly down-regulated). In this proposal we will first
analyze the effects of the subgroup of miRNAs that are specifically regulated by LPS on the stability of PLCb2
mRNA by determining the effects of mimics and antagonists of these miRNAs on luciferase expression from
our pPLC¿2-3'UTR-Luc reporter plasmid in RAW264.7 cells. We will then determine the role(s) of the specific
miRNAs that are regulated by A2AR/A2BR agonists in LPS-treated macrophages that result in "M2d" activation
of macrophage gene expression. We hypothesize that miRNAs in this specific subset play a role in switching
macrophages from an M1 to an "M2d" phenotype. We will study the effects of mimics and antagonists of these
miRNAs on macrophage expression of TNFa and IL-12 (flagship cytokines produced by M1 activation), and
VEGF and IL-10 (flagship factors produced by M2d activation). Finally, we will analyze the mechanism of
destabilization of PLCb2 mRNA by LPS in macrophages. We hypothesize that LPS regulates the interaction of
the PLCb2 3'UTR with regulatory factors such as miRNAs or RNA binding proteins that are involved in
stabilizing the mRNA. Conserved overlapping sites for miR-466L and for the RNA binding proteins HuR and
TTP are present in the 3'UTR. We will analyze the role of these factors in regulating PLCb2 mRNA stability by
over-expressing or inhibiting these factors, and by modifying the binding sites in the 3'UTR by site-directed
mutagenesis. These studies should provide novel insights into differential gene regulation in macrophages
under conditions that induce "M2d" activation.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1007/s10753-017-0511-y
发表时间:
2017-04
期刊:
Inflammation
影响因子:
5.1
作者:
[Shukla S, Elson G, Blackshear PJ, Lutz CS, Leibovich SJ]
通讯作者:
Leibovich SJ
DOI:
10.1155/2018/7852742
发表时间:
2018
期刊:
Mediators of inflammation
影响因子:
4.6
作者:
[Shukla S, Levine C, Sripathi RP, Elson G, Lutz CS, Leibovich SJ]
通讯作者:
Leibovich SJ
A role for miRNAs in adenosine-dependent alternative macrophage activation
-
批准号:8706377
-
项目类别:
-
资助金额:$2.17万
-
财政年份:2013
-
负责人:Samuel Joseph Leibovich
-
依托单位:
A role for miRNAs in adenosine-dependent alternative macrophage activation
-
批准号:8385795
-
项目类别:
-
资助金额:$17.59万
-
财政年份:2012
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Adenosine, Toll-Like Receptors and Angiogenesis
-
批准号:7942244
-
项目类别:
-
资助金额:$35.62万
-
财政年份:2009
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Toll-Like Receptors, Adenosine and Angiogenesis
-
批准号:7067191
-
项目类别:
-
资助金额:$36.3万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Adenosine, Toll-Like Receptors and Angiogenesis
-
批准号:8118626
-
项目类别:
-
资助金额:$37.08万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Toll-Like Receptors, Adenosine and Angiogenesis
-
批准号:7006488
-
项目类别:
-
资助金额:$2.36万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Adenosine, Toll-Like Receptors and Angiogenesis
-
批准号:7691357
-
项目类别:
-
资助金额:$37.83万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Toll-Like Receptors, Adenosine and Angiogenesis
-
批准号:6891423
-
项目类别:
-
资助金额:$37.17万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Adenosine, Toll-Like Receptors and Angiogenesis
-
批准号:7581793
-
项目类别:
-
资助金额:$37.83万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Adenosine, Toll-Like Receptors and Angiogenesis
-
批准号:8753386
-
项目类别:
-
资助金额:$0.0万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Toll-Like Receptors, Adenosine and Angiogenesis
-
批准号:6671690
-
项目类别:
-
资助金额:$32.66万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
Toll-Like Receptors, Adenosine and Angiogenesis
-
批准号:6752142
-
项目类别:
-
资助金额:$32.66万
-
财政年份:2003
-
负责人:Samuel Joseph Leibovich
-
依托单位:
REGULATION OF MACROPHAGE DEPENDENT ANGIOGENIC ACTIVITY
-
批准号:6386961
-
项目类别:
-
资助金额:$28.35万
-
财政年份:1999
-
负责人:Samuel Joseph Leibovich
-
依托单位:
REGULATION OF MACROPHAGE DEPENDENT ANGIOGENIC ACTIVITY
-
批准号:2848508
-
项目类别:
-
资助金额:$26.74万
-
财政年份:1999
-
负责人:Samuel Joseph Leibovich
-
依托单位:
REGULATION OF MACROPHAGE DEPENDENT ANGIOGENIC ACTIVITY
-
批准号:6519909
-
项目类别:
-
资助金额:$29.19万
-
财政年份:1999
-
负责人:Samuel Joseph Leibovich
-
依托单位:
REGULATION OF MACROPHAGE DEPENDENT ANGIOGENIC ACTIVITY
-
批准号:6180821
-
项目类别:
-
资助金额:$27.53万
-
财政年份:1999
-
负责人:Samuel Joseph Leibovich
-
依托单位:
LISST
-
批准号:2007034
-
项目类别:
-
资助金额:$0.55万
-
财政年份:1997
-
负责人:Samuel Joseph Leibovich
-
依托单位:
MACROPHAGE-DERIVED ANGIOGENIC ACTIVITY
-
批准号:2175403
-
项目类别:
-
资助金额:$17.6万
-
财政年份:1992
-
负责人:Samuel Joseph Leibovich
-
依托单位:
MACROPHAGE DERIVED ANGIOGENIC ACTIVITY
-
批准号:3276645
-
项目类别:
-
资助金额:$13.05万
-
财政年份:1992
-
负责人:Samuel Joseph Leibovich
-
依托单位:
SMALL INSTRUMENTATION GRANT
-
批准号:3523079
-
项目类别:
-
资助金额:$1.83万
-
财政年份:1990
-
负责人:Samuel Joseph Leibovich
-
依托单位:
海外基金