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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE121751 | GEO | 2019/01/17

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 (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.

2020-02-19 | GSE145422 | GEO

Peptidylarginine deiminase 2 citrullinates MZB1 and promotes the secretion of IgM and IgA

Project description:MZB1 is an endoplasmic reticulum residential protein preferentially expressed in plasma cells, marginal zone and B1 B cells. Recent studies on murine B cells shows that it interacts with the tail piece of IgM and IgA heavy chain and promotes the secretion of these two classes of immunoglobulin. However, its role in primary human B cells has yet to be determined and how its function is regulated is still unknown. The conversion of peptidylarginine to peptidycitrulline, also known as citrullination, by peptidylarginine deiminases (PADs) can critically influence the function of proteins in immune cells, such as neutrophils and T cells; however, the role of PADs in B cells remains to be elucidated. In an unbiased analysis of the human citrullinomeic analysis, we found that MZB1 was preferentially enriched in the pool of citrullinated lung proteins obtained from patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) compared to those from idiopathic pulmonary fibrosis or chronic obstructive pulmonary diseases. The citrullination of MZB1 was confirmed with mass spectrometry, in vitro citrullination, and binding by phenylglyoxal in the absence or presence of a PAD2-specific inhibitor AFM-30a. Ablation or pharmacological inhibition of PAD2 in primary human B cells attenuated the secretion of IgM and IgA but not IgG or the differentiation of IgM or IgA-expressing plasmablasts, recapitulating the effect of ablating MZB1. In addition, the physical interaction between endogenous MZB1 and IgM/IgA was attenuated by AFM-30a. Taken together, our data confirm the function of MZB1 in primary human plasmablasts and suggest that PAD2 promotes IgM/IgA secretion by citrullinating MZB1, thereby contributing to the pathogenesis of rheumatoid arthritis and RA-ILD.

2023-11-23 | PXD047044 | Pride

Disrupted development and altered hormone signaling in male Padi2/Padi4 double knockout mice

Project description:Peptidylarginine deiminase enzymes (PADs) convert arginine residues to citrulline in a process called citrullination or deimination. Recently, two PADs, PAD2 and PAD4, have been linked to hormone signaling in vitro and the goal of this study was to test for links between PAD2/PAD4 and hormone signaling in vivo. Preliminary analysis of Padi2 and Padi4 single knockout (SKO) mice did not find any overt reproductive defects and we predicted that this was likely due to genetic compensation. To test this hypothesis, we created a Padi2/Padi4 double knockout (DKO) mouse model and tested these mice for a range of reproductive defects. Results from controlled breeding trials found that DKO breeding pairs appeared to take longer to have their first litter than WT controls and that DKO male weanlings weighed significantly less than their WT counterparts. Additionally, DKO males took significantly longer than WT males to reach puberty and also had lower serum testosterone levels. Furthermore, DKO males had smaller testes than WT males and also had increased rates of germ cell apoptosis. The DKO mouse model provides a new tool for investigating PAD function and outcomes from our studies provide the first in vivo evidence linking PADs with hormone signaling.

2022-10-19 | GSE194034 | 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

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

2012-04-07 | GSE37087 | GEO

Data in support of Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis

Project description:The presence or absence of autoantibodies against citrullinated proteins (ACPAs) distinguishes two main groups of rheumatoid arthritis (RA) patients with different etiology, prognosis, disease severity, and, presumably, disease pathogenesis. The heterogeneous responses of RA patients to various biologics, even among ACPA-positive patients, emphasize the need for further stratification of the patients. We use high-density protein array technology to evaluate ACPA reactivity. Identification of the proteome recognized by ACPAs may be a step to stratify RA patients according to immune reactivity. Methods: Pooled plasma samples from 10 anti-CCP negative and 15 anti-CCP positive RA patients were assessed for ACPA-content using a modified protein microarray containing 1,631 different natively folded proteins citrullinated in situ by protein arginine deiminases (PAD) 2 and PAD4. Results: IgG antibodies from anti-CCP positive RA plasma showed high-intensity binding to 87 proteins citrullinated by PAD2 and 99 proteins citrullinated by PAD4 without binding significantly to the corresponding native proteins. Curiously, the binding of IgG antibodies in anti-CCP-negative plasma was also enhanced by PAD2- and PAD4-mediated citrullination for 29 and 26 proteins, respectively. For only 4 proteins, significantly more ACPA-binding occurred after citrullination with PAD2 compared to citrullination with PAD4, while the opposite was true for 1 protein.

2022-01-05 | PXD024955 | Pride

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

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

| PRJNA498311 | ENA

Proteomics of THP-1 macrophages polarization to M1 and M2 phenotype and treated with BB-Cl-amidine

Project description:Macrophages are effector cells of the innate immune system and undergo phenotypical changes in response to organ injury and repair. They are most often classified as proinflammatory M1 and anti-inflammatory M2 macrophages. Protein arginine deiminase (PAD) enzymes, that catalyze the conversion of protein-bound arginine into citrulline, an irreversible posttranslational modification, are expressed in macrophages. However, the substrate scope of the PADs and their role in the immune cells remain not well defined. This study aims to investigate the role of PADs in the THP-1 macrophage polarization to M1 and M2 phenotype and identify the citrullinated proteins, and the modified Arg that are associated with this biological switch using mass spectrometry. Our study showed that PAD2, and to a lesser extent PAD1 and PAD4 were dominantly expressed in M1 macrophages. We showed that inhibiting PADs by BB-Cl-amidine decreased the macrophage’s polarization to M1 and increased to M2 phenotype. The process was mediated by the downregulation of proteins involved in NF-kβ pathway. Silencing of PAD2 confirmed activation to M2 macrophages through upregulation of the antiviral innate immune response and interferon signaling. 192 novel citrullination sites that belong to inflammation, cell death and DNA/RNA processing pathways were identified in M1 and M2 macrophages.

2023-03-11 | PXD034591 | Pride

Transcription profiling of effected genes by PAD2 and compound 1B8

Project description:To understand the growth inhibition of peptidylarginine deiminase 2 (PAD2) and small molecule 1B8, colon cancer SW480 cells were treated with compound 1B8 for 24 hours, SW480 cells were transfected with humanPAD2 vector for 24 hours. Cells were harvested and total RNA was extracted using TRIZol method followed by Agilent DNA microarray analysis. To profile the effected genes by compound 1B8, SW480 cells were treated with DMSO (control) and 10uM 1B8 in triplicates in 6-well plate, cells were harvested 24 hours later. To compare the effected genes by compound 1B8 and PAD2 overexpression, SW480 cells were transfected with PAD2 and pIRES2-EGFP empty vector in triplicates in 6 well plates, cells were harvested in 24 hours. All the cells were harvested and total RNA was extracted using TRIZol method followed by Agilent DNA microarray analysis.

2016-09-30 | E-MTAB-4452 | biostudies-arrayexpress

Liver metastatic growth in colorectal cancer depends on PAD4 leading to modification of the extracellular matrix by citrullination

Project description:Colorectal cancer is one of the most frequently occurring malignancies and a major cause of cancer death. Distant metastases in this disease most commonly develop in the liver and are often untreatable. Here, we show that citrullination of the extracellular matrix (ECM) by cancer cell derived peptidylarginine deiminase 4 (PAD4) is essential for the growth of liver metastases. Citrullination of proteins, a post-translational conversion of arginine residues to citrulline, is well recognized in rheumatoid arthritis, but largely undocumented in cancer. PAD4, a key enzyme responsible for catalyzing citrullination, is produced by metastatic colorectal cancer cells and found at higher levels in human liver metastases than in normal liver. Functional significance for citrullination in metastatic growth was evident in murine models where inhibition of citrullination, either globally by pharmacologic inhibition of PADs or specifically in colorectal cancer cells by PAD4 knockdown substantially reduced liver metastatic burden. Additionally, citrullination of a key ECM component collagen type I led to greater adhesion and decreased migration of colorectal cancer cells along with increased expression of characteristic epithelial markers, suggesting a role for citrullination in promoting mesenchymal-to-epithelial transition (MET) and liver metastasis. Overall, our study revealed the potential for PAD4-dependant citrullination to drive the progression of liver metastasis. These data indicate that inhibition of citrullination could be exploited to prevent the development of liver metastases in colorectal cancer.

2018-10-18 | PXD010252 | Pride

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