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The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes

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Abstract

P53 is a transcription factor that regulates many signaling pathways like apoptosis, cell cycle, DNA repair, and cellular stress responses. P53 is involved in inflammatory responses through the regulation of inflammatory signaling pathways, induction of cytokines, and matrix metalloproteinase expression. Also, p53 regulates immune responses through modulating Toll-like receptors expression and innate and adaptive immune cell differentiation and maturation. P53 is a modulator of the apoptosis and proliferation processes through regulating multiple anti and pro-apoptotic genes. Rheumatoid arthritis (RA) is categorized as an invasive inflammatory autoimmune disease with irreversible deformity of joints and bone resorption. Different immune and non-immune cells contribute to RA pathogenesis. Fibroblast-like synoviocytes (FLSs) have been recently introduced as a key player in the pathogenesis of RA. These cells in RA synovium produce inflammatory cytokines and matrix metalloproteinases which results in synovitis and joint destruction. Besides, hyper proliferation and apoptosis resistance of FLSs lead to synovial hyperplasia and bone and cartilage destruction. Given the critical role of p53 in inflammation, apoptosis, and cell proliferation, lack of p53 function (due to mutation or low expression) exerts a prominent role for this gene in the pathogenesis of RA. This review focuses on the role of p53 in different mechanisms and cells (specially FLSs) that involved in RA pathogenesis.

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Abbreviations

Ag:

Antigen

AGO2:

Argonaute RISC catalytic component 2

AID:

Activation-induced cytidine deaminase

AP-1:

Activator protein 1

APCs:

Antigen-presenting cells

autoAbs:

Autoantibodies

Bcl2:

B cell lymphoma 2

BRG1:

Brahma-related gene 1

CKI:

Cyclin-dependent kinase inhibitor 1

cyr61:

Cysteine-rich angiogenic inducer 61

DC:

Dendritic cells

DD1α:

Death domain1α

DDRs:

DNA damage responses

DN:

Double negative

DNMTs:

DNA methyltransferases

DUSP:

Dual-specificity phosphatases

ECM:

Extracellular matrix

ERK:

Extracellular regulated kinase

FLSs:

Fibroblast-like synoviocytes

Foxp3:

Forkhead box P3

GADD45A:

Growth arrest and DNA damage-inducible alpha

HATs:

Histone acetyltransferases

HDACs:

Histone deacetylases

HIF-1α:

Hypoxia-inducible factor 1-alpha

IFN-γ:

Interferon-γ

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

iTreg:

Induced Treg

JNK:

C-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinases

MDM-2:

Mouse double minute 2 homolog

MIF:

Macrophage migration inhibitory factor

MKP-1:

MAPK phosphatase-1

MLSs:

Macrophage-like synoviocytes

MMPs:

Matrix metalloproteinases

MSH6:

MutS Homolog 6

NF-κB:

Nuclear factor-κB

NO:

Nitric oxide

OA:

Osteoarthritis

P53AIP1:

P53-regulated apoptosis-inducing protein 1

PADI4:

Peptidyl arginine deiminase 4

PBMCs:

Peripheral blood mononuclear cells

PCNA:

Proliferating cell nuclear Ag

PERP:

P53 apoptosis effector related to PMP-22

PGs:

Prostaglandins

PRR:

Pattern recognition receptor

PUMA:

P53 upregulated mediator of apoptosis

REs:

Responsive elements

RA:

Rheumatoid arthritis

RANKL:

Receptor activator of nuclear factor-κB ligand

Rb:

Retinoblastoma

RGS:

Regulator of G protein signaling

RNSs:

Reactive nitrogen species

ROSs:

Reactive oxygen species

SCID:

Severe combined immunodeficiency

SP:

Single positive

TLRs:

Toll-like receptors

TNF-α:

Tumor necrosis factor-α

TP53:

P53 tumor suppressor gene

Treg :

T regulatory

TSP-1:

Thrombospondin-1

VEGF:

Vascular endothelial growth factor

WIP-1:

Wild-type p53-induced phosphatase-1

wt-P53:

Wild-type P53

XIAP:

X-linked inhibitor of apoptosis protein

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Authors and Affiliations

  1. Immunology Department, Kermanshah University of Medical Sciences, Kermanshah, Iran

    Mahdi Taghadosi & Mehrnoosh Adib

  2. Rheumatology Research Center, Shariati Hospital, Tehran University of Medical Sciences, Kargar Ave, PO-BOX: 1411713137, Tehran, Iran

    Ahmadreza Jamshidi, Mahdi Mahmoudi & Elham Farhadi

  3. Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Mahdi Mahmoudi & Elham Farhadi

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  1. Mahdi Taghadosi
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  2. Mehrnoosh Adib
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MT and MA: acquisition of data, drafting the article, designed the figures, final approval of the version to be submitted. EF and MM: the conception and design of the study, revising it critically for important intellectual content, designed the figures, final approval of the version to be submitted. AJ: interpretation of data, revising it critically for important intellectual content, final approval of the version to be submitted.

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Correspondence to Mahdi Mahmoudi or Elham Farhadi.

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Mahdi Taghadosi and Mehrnoosh Adib Contributed equally to this paper.

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Taghadosi, M., Adib, M., Jamshidi, A. et al. The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes. Immunol Res 69, 225–238 (2021). https://doi.org/10.1007/s12026-021-09202-7

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