Contact with stimulated T cells up-regulates expression of peptidylarginine deiminase 2 and 4 by human monocytes

Ferrari‐Lacraz, Sylvie; Sebbag, Mireille; Chicheportiche, Rachel; Foulquier, Céline; Serre, Guy; Dayer, Jean‐Michel

doi:10.1684/ecn.2012.0303

Cited by 12 publications

(3 citation statements)

References 32 publications

(47 reference statements)

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“…No mRNA or protein of any PAD isotype was detected in resting or stimulated synovial fibroblasts. Thus, they suggested that contact between stimulated T cells and monocytes/macrophages or cytokine-activated monocytes−/macrophages constitutes a highly likely source of PADI2 and PADI4, which are observed in inflamed synovial tissues [37]. Calabrese et al.…”

Section: Discussionmentioning

confidence: 99%

PADI2 Is Significantly Associated with Rheumatoid Arthritis

et al. 2013

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Citrullination, a posttranslational modification of peptidyl arginine to citrulline, plays an essential role in rheumatoid arthritis (RA). Citrullination is catalyzed by a group of peptidylarginine deiminases (PADs) including PADI 1, 2, 3, 4 and 6. Many studies have indicated that the gene encoding PADI4 is a factor in susceptibility to RA. Some studies have detected PADI2 expression in RA synovial tissues, suggesting that PADI2 also plays an important role in the disease. This study evaluated the possible association between the PADI2-encoding gene and RA. Seventeen tag SNPs across the PAD locus were genotyped using a custom-designed Illumina 96-SNP VeraCode microarray. Peripheral blood samples were collected from patients with RA (n = 267), ankylosing spondylitis (AS, n = 51) and healthy controls (n = 160). The results of genotyping were verified using Sequenom MassARRAY in an independent cohort of 307 patients with RA, 324 patients with AS and 509 healthy controls. A western blot analysis was performed using synovial tissue from patients with RA (n = 7), osteoarthritis (OA, n = 7) and AS (n = 5) to determine the levels of expression of PADI2. A microarray analysis revealed a significant association between three selected PADI2 SNPs (rs2235926, rs2057094, rs2076616) and the presence of RA. The increased susceptibility to RA associated with rs2235926 (OR = 1.706733, 95% CI = [1.576366–1.866587], p = 0.000839) and rs2057094 (OR = 1.360432, 95% CI = [1.065483–1.869482], p = 0.003291) was further confirmed by the Sequenom MassARRAY. No tag SNPs in the PADI2 locus showed a significant association with AS. Increased expression of PADI2 was detected in RA synovial tissues compared with samples from patients with OA and AS. PADI2 is significantly associated with RA and may be involved in the pathogenesis of the disease.

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Section: Discussionmentioning

confidence: 99%

PADI2 Is Significantly Associated with Rheumatoid Arthritis

et al. 2013

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“…It is as yet unknown how osteoclast lineage cells may be affected by the costimulation system in a similar manner to professional APCs. That costimulation molecules influence the activation state of not only T cells but also APCs (17) suggests that the crosstalk between T cells and osteoclasts may go beyond the expression of pro-and anti-osteoclastogenic cytokines (5,7,18,19). Most importantly, the engagement of CD80/86 expressed on the surface of osteoclast lineage cells may constitute a mechanism by which the differentiation state of osteoclast linage cells could be regulated in a physiological manner by the immune system.…”

Section: Introductionmentioning

confidence: 99%

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway

et al. 2014

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Bone resorption is seminal for the physiological remodeling of bone during life. However, this process needs to be strictly controlled; excessive bone resorption results in pathologic bone loss, osteoporosis, and fracture. We describe a control mechanism of bone resorption by the adaptive immune system. CD80/86, a pair of molecules expressed by antigen-presenting cells and involved in T cell costimulation, act as negative regulator for the generation of bone-resorbing osteoclasts. CD80/86-deficient mice were osteopenic because of increased osteoclast differentiation. CD80/86-deficient osteoclasts escaped physiological inhibition by CTLA-4 or regulatory T cells. Mechanistically, engagement of CD80/86 by CTLA-4 induced activation of the enzyme indoleamine 2,3-dioxygenase (IDO) in osteoclast precursors, which degraded tryptophan and promoted apoptosis. Concordantly, IDO-deficient mice also showed an osteopenic bone phenotype with higher numbers of osteoclast precursors and osteoclasts. Also, IDO-deficient mononuclear cells escaped the anti-osteoclastogenic effect of CTLA-4. This molecular mechanism was also present in humans because targeting CD80/86 by abatacept, a CTLA-4-immunoglobulin fusion protein, reduced, whereas blockade of CTLA-4 by ipilimumab antibody enhanced, the frequency of peripheral osteoclast precursors and osteoclastogenesis. In summary, these data show an important role of the adaptive immune system, in particular T cell CD80/86 costimulation molecules, in the physiological regulation of bone resorption and preservation of bone mass, as well as affect the understanding of the function of current and future drugs fostering or blocking the effects of CTLA-4 in humans.

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“…Similarly, increased protein expression of PADI2 during the differentiation of monocytes to macrophages using PBMCs from RA patients and controls were reported [13]. The expression of PADI2 and PADI4 was found to increase in human monocytes after being stimulated by activated T cells [14]. We believe that the increased PADI expression during the differentiation of macrophage could lead to citrullination of certain proteins, and resulting in inflammatory responses.…”

Section: Introductionmentioning

confidence: 57%

Increased peptidylarginine deiminases expression during the macrophage differentiation and participated inflammatory responses

Lai

Yu²,

Tung

et al. 2019

Arthritis Res Ther

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Objective To investigate the expression of peptidylarginine deiminases (PADIs) during macrophage differentiation and its role in inflammatory responses. Methods The protein expression of PADI2, PADI4, and citrullinated histone 3 in U937 cells, differentiated macrophages, and macrophages stimulated with lipopolysaccharides (LPS) were analyzed by Western blotting. Three PADI inhibitors were used for assessing their effects on the secretion of proinflammatory cytokines in macrophages. The differential expressed citrullinated proteins during macrophage differentiation were probed by self-prepared anti-citrullinated protein antibodies, and the reactive bands were sent for proteomic analyses. Transfection studies were conducted to search for the functions of specific proteins. A specific protein was cloned and citrullinated for its protein binding study. Results The expression of PADI2 and PADI4 markedly increased during macrophage differentiation, whereas the formation of citrullinated histone 3 increased after stimulated with lipopolysaccharides. Three PADI inhibitors suppressed the LPS mediated proinflammatory cytokines secretion, but did not affect the expression of PADI2 and PADI4. Plasminogen activator inhibitor-2 (PAI-2) was citrullinated during macrophage differentiation. The expression of PAI-2 increased during macrophage differentiation and further increased after stimulated with LPS. Suppressed PAI-2 expression decreased the expression and secretion of proinflammatory cytokines. Decreased PADI2 expression also suppressed the expression of PAI-2 and protein levels of citrullinated PAI-2. The citrullination of PAI-2 inhibited its binding ability to proteasome subunit beta type-1 (PSMB1). Conclusion PADI2 and PADI4 protein levels increased during the macrophage differentiation resulting in protein citrullination, including PAI-2. The increased expression of PAI-2 promoted inflammatory response, and the citrullination of PAI-2 impaired its binding to PSMB1. Therefore, protein citrullination could play a critical role in macrophage differentiation and function.

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Contact with stimulated T cells up-regulates expression of peptidylarginine deiminase 2 and 4 by human monocytes

Cited by 12 publications

References 32 publications

PADI2 Is Significantly Associated with Rheumatoid Arthritis

PADI2 Is Significantly Associated with Rheumatoid Arthritis

T Cell Costimulation Molecules CD80/86 Inhibit Osteoclast Differentiation by Inducing the IDO/Tryptophan Pathway

Increased peptidylarginine deiminases expression during the macrophage differentiation and participated inflammatory responses

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