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Peptidylarginine deiminase 4 promotes the renal infiltration of neutrophils and exacerbates the TLR7 agonist-induced lupus mice

ABSTRACT: Peptidylarginine deiminase 4 (PAD4), encoded by PADI4, plays critical roles in the immune system. The pathological roles of PAD4 were investigated in lupus model mice. PAD4-regulated pathways were identified by RNA-sequencing of WT and Padi4 KO neutrophils.

ORGANISM(S): Mus musculus

PROVIDER: GSE145422 | GEO | 2020/02/19

REPOSITORIES: GEO

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Peptidylarginine deiminase 4 promotes the renal infiltration of neutrophils and exacerbates the TLR7 agonist-induced lupus mice

Project description:Peptidylarginine deiminase 4 promotes the renal infiltration of neutrophils and exacerbates the TLR7 agonist-induced lupus mice

| PRJNA607201 | ENA

Peptidylarginine Deiminase 4 Promotes the Renal Infiltration of Neutrophils and Exacerbates the TLR7 Agonist-Induced Lupus Mice.

Project description:Peptidylarginine deiminase 4 (PAD4), encoded by PADI4, plays critical roles in the immune system; however, its contribution to the pathogenesis of lupus nephritis remains controversial. The pathological roles of PAD4 were investigated in lupus model mice. An imiquimod (IMQ)-induced lupus model was analyzed in wild-type (WT) and Padi4-knockout (KO) mice. Proteinuria, serum anti-double stranded DNA (anti-dsDNA) antibody, and renal infiltrated cells were evaluated. Neutrophil migration and adhesion were assessed using adoptive transfer and adhesion assay. PAD4-regulated pathways were identified by RNA-sequencing of Padi4 KO neutrophils. Padi4 KO mice exhibited significant improvements in proteinuria progression compared with WT mice, whereas, serum anti-dsDNA antibody and immune complex deposition in the glomeruli showed no difference between both mice strains. Padi4 KO mice showed decreased neutrophil infiltration in the kidneys. Adoptively transferred Padi4 KO neutrophils showed decreased migration to the kidneys of IMQ-treated WT mice, and adhesion to ICAM-1 was impaired in Padi4 KO neutrophils. Padi4 KO neutrophils exhibited reduced upregulation of p38 mitogen-activated protein kinase (MAPK) pathways. Toll-like receptor 7 (TLR7)-primed Padi4 KO neutrophils demonstrated reduced phosphorylation of p38 MAPK and lower expression of JNK-associated leucine zipper protein (JLP), a p38 MAPK scaffold protein. Neutrophils from heterozygous Jlp KO mice showed impaired adhesion to ICAM-1 and decreased migration to the kidneys of IMQ-treated WT mice. These results indicated a pivotal role of PAD4-p38 MAPK pathway in renal neutrophil infiltration in TLR7 agonist-induced lupus nephritis, and the importance of neutrophil-mediated kidney inflammation. Inhibition of the PAD4-p38 MAPK pathway may help in formulating a novel therapeutic strategy against lupus nephritis.

| S-EPMC7324481 | biostudies-literature

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [Array]

Project description:Peptidylarginine deiminases (PADIs) catalyze post-translational modification of many target proteins and have been suggested to play a role in carcinogenesis. Since citrullination of histones by PADI4 was recently implicated in regulating embryonic stem and hematopoietic progenitor cells, here we investigated a possible role for PADI4 in regulating breast cancer stem cells. We showed by genetic and pharmacologic approaches that PADI4 activity limits the number of cancer stem cells (CSCs) in vitro and in vivo in multiple breast cancer models. A gene signature reflecting tumor cell-autonomous PADI4 inhibition is associated with poor outcome in human breast cancer datasets, consistent with a tumor suppressive role for PADI4. Mechanistically, PADI4 inhibition resulted in a global redistribution of histone H3 with accumulation around transcriptional start sites. Interestingly, epigenetic effects of PADI4 on the bulk tumor cell population did not explain the CSC phenotype. However, in sorted tumor cell populations, PADI4 down-regulated expression of the master transcription factors of stemness, NANOG and POU5F1, specifically in the cancer stem cell compartment, by reducing the transcriptionally activating H3R17me2a histone mark at those loci. This effect was not seen in the non-stem cells. Our findings reveal a novel role for PADI4 as a tumor suppressor in regulating breast cancer stem cells, and provide insights into context-specific effects of PADI4 in epigenetic modulation.

2021-01-11 | GSE138407 | GEO

Presence of peptidylarginine deiminase in Porphyromonas gingivalis-related species

Project description:Presence of peptidylarginine deiminase in Porphyromonas gingivalis-related species

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Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_2]

2021-01-11 | GSE143442 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [ChIP-Seq]

2021-01-11 | GSE138505 | GEO

Peptidylarginine deiminase IV (PADI4) has a novel tumor cell-autonomous suppressor role in regulating breast cancer stem cells [RNA-Seq_1]

2021-01-11 | GSE138415 | GEO

Examination of the role of peptidylarginine deiminase 2 (PAD2) in gene expression in MCF-7 breast cancer cells

2012-04-07 | GSE37087 | GEO

Examination of the role of peptidylarginine deiminase 2 (PAD2) in gene expression in MCF-7 breast cancer cells

Project description:To investigate the potential role of peptidylarginine deiminase 2 (PAD2) in gene expression, we created stable shRNA scrambled control and PAD2 knockdown MCF-7 breast cancer cell lines. After validating the specific knockdown of PAD2 at the mRNA and protein level, we utilized an Agilent microarray platform to compare the gene expression profile of the two cell lines to generate a candidate list of genes regulated by PAD2. Control and PAD2 knockdown cells were created by stably transfecting shRNA constructs into MCF-7 cells. Stable cells were selected using puromycin and knockdown validate at the mRNA and protein level. Microarray data represents 4 independent biological replicates contain control and PAD2 knockdown samples.

2012-04-06 | E-GEOD-37087 | biostudies-arrayexpress

Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7 dependent lupus

Project description:Peptidylarginine deiminases (PADs) play critical roles in the development and progression of autoimmune diseases. PAD4 is involved in systemic lupus erythematosus (SLE) pathogenesis while the role of PAD2 in immune dysregulation in SLE is not clear. The differential roles of PAD2 and PAD4 in the progression of murine SLE and in modulation of innate and adaptive immunity were examined. The transcriptome of lymphoid organs from imiquimod-treated PAD2/4 and control mice was characterized and elucidated using RNASeq technology.

2019-01-17 | GSE121751 | GEO

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