PXD035018-2

PXD035018 is an original dataset announced via ProteomeXchange.

Title	Inhibition of pro-inflammatory signalling in human primary macrophages by enhancing Arginase-2 via target site blockers
Description	A favourable immunotherapeutic strategy in the treatment of chronic inflammatory disease, is to dampen the pro-inflammatory macrophage response and upregulate the anti-inflammatory macrophage response. Previous studies have shown that Arginase-2 (Arg2), a mitochondrial enzyme, is a key regulator of the macrophage anti-inflammatory response with an essential role in IL-10 signalling. Here we show that IL-10 in the presence of LPS increased Arg2 expression in human macrophages and peripheral blood mononuclear cells. Target site blockers (TSBs) (locked nucleic acid antisense oligonucleotides) specifically designed to target the 3’ UTR of Arg2 messenger RNA were used to inhibit binding of specific microRNAs thus enhancing Arg2 expression. Eleven Arg2-TSBs were screened and the TSB targeting miR-155 (TSB-155) and the TSB targeting miR-3202 (TSB-3202) were found to increase Arg2 expression in human macrophages resulting in decreased gene expression and cytokine production of TNF-α and CCL2. In addition, following TSB-3202 stimulation, there were statistically significant increases in the ‘M2-like’ macrophage marker, CD206; and CD16, associated with an IL-10 response, and a decrease in the ‘M1-like’ macrophage marker, HLA-DR, indicating a shift in the macrophage phenotype. Proteomic analysis demonstrated that multiple pro-inflammatory responsive proteins including Signal Transducer and Activator of Transcription 1 (STAT-1), Toll-like receptors, Signalling Lymphocytic Activation Molecule F7 (SLAMF7) and Interferon Induced Protein with Tetratricopeptide Repeats 3 (IFIT3), were downregulated by TSB-155 and TSB-3202 while Sequestomsome-1 (SQSTM1) was increased after treatment. In silico analysis of significantly dysregulated proteins predicted that TSB-3202 supressed several upstream pro-inflammatory regulators including STAT-1 and Interferon α2 (IFNA2) while enhancing anti-inflammatory associated interleukin 1 receptor antagonist (IL1RN) and STAT-3. Proteomic data was validated by confirming increased levels of SQSTM1, decreased levels of phosphoylated-STAT-1 and STAT-1, and downregulation of Ifit3 and Slamf7 by TSB treatment. In conclusion, upregulation of Arg2 protein by TSBs inhibits several pro-inflammatory signalling proteins resulting in reduced pro-inflammatory cytokine secretion, reduced ‘M1-like’ marker expression and enhanced ‘M2-like’ macrophage marker expression. Arg2 is a promising novel therapeutic target to modulate inflammatory signalling in macrophages.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:06:57.773.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD035018
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Eugene Dillon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-30 06:53:30	ID requested
1	2023-10-24 10:58:38	announced
⏵ 2	2023-11-14 09:07:02	announced	2023-11-14: Updated project metadata.
3	2024-10-22 06:08:24	announced	2024-10-22: Updated project metadata.

10.6019/PXD035018;

Fitzsimons S, Mu, ñ, oz-San Mart, í, n M, Nally F, Dillon E, Fashina IA, Strowitzki MJ, Rami, ó, -Torrent, à L, Dowling JK, De Santi C, McCoy CE, Inhibition of pro-inflammatory signaling in human primary macrophages by enhancing arginase-2 via target site blockers. Mol Ther Nucleic Acids, 33():941-959(2023) [pubmed]

submitter keyword: macrophage, proteomics, multiple sclerosis,Inflammation

Claire McCoy
contact affiliation	School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, 123 St Stephen’s Green, Dublin 2, Ireland
contact email	stephen.fitzsimons@ucdconnect.ie
lab head
Eugene Dillon
contact affiliation	UCD
contact email	eugene.dillon@ucd.ie
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035018
     1. Label: PRIDE project
     2. Name: Inhibition of pro-inflammatory signalling in human primary macrophages by enhancing Arginase-2 via target site blockers