Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec 24:12:809806.
doi: 10.3389/fimmu.2021.809806. eCollection 2021.

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

Jianan Zhao  1   2 , Ping Jiang  1   2 , Shicheng Guo  3 , Steven J Schrodi  3 , Dongyi He  2   4
Affiliations
Review

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

Jianan Zhao et al. Front Immunol. .

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can lead to clinical manifestations of systemic diseases. Its leading features include chronic synovial inflammation and degeneration of the bones and joints. In the past decades, multiple susceptibilities for rheumatoid arthritis have been identified along with the development of a remarkable variety of drugs for its treatment; which include analgesics, glucocorticoids, nonsteroidal anti-inflammatory medications (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), and biologic response modifiers (bDMARDs). Despite the existence of many clinical treatment options, the prognosis of some patients remains poor due to complex mechanism of the disease. Programmed cell death (PCD) has been extensively studied and ascertained to be one of the essential pathological mechanisms of RA. Its dysregulation in various associated cell types contributes to the development of RA. In this review, we summarize the role of apoptosis, cell death-associated neutrophil extracellular trap formation, necroptosis, pyroptosis, and autophagy in the pathophysiology of RA to provide a theoretical reference and insightful direction to the discovery and development of novel therapeutic targets for RA.

Keywords: NETosis; apoptosis; autophagy; necroptosis; programmed cell death; pyroptosis; rheumatoid arthritis.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Role of apoptosis in the pathophysiology of rheumatoid arthritis. Multiple cellular subtypes express different molecules in RA, including FLS, monocyte-macrophages, T cells, B cells, osteoblasts, and chondrocytes. The differential gene expression influences the apoptosis of various cells through the molecules related to the exogenous death pathway and the endogenous mitochondrial pathway, thereby affecting the development of RA. MCL-1, myelogenous cell leukemia-1; SYVN1, the E3 ubiquitin ligase synoviolin; CARD6, caspase recruitment domain protein 6; PDCD5, programmed cell death 5; DR5, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor; mFas, membrane-bound Fas; Bcl-2, B cell lymphoma/leukemia -2; Bax, accumulation of Bcl-2–associated X protein; Bak, Bcl-2 homologous antagonist/killer; Bim, Bcl-2 interacting mediator of cell death; Cyt c, cytochrome c; ERK, extracellular signal-regulated kinase; IκBα, intracellular calcium, phosphorylated I-kappa-Bα; TNFR1, tumor necrosis factor receptor 1; PI3K, phosphatidylinositol 3-kinase; TLR, Toll-like receptor; FLS, fibroblast-like synoviocytes.
Figure 2
Figure 2
Role of autophagy in the pathophysiology of rheumatoid arthritis. Autophagy and apoptosis appear to be antagonistic to each other. FLS enhances autophagy by expressing different molecular patterns and antagonizes apoptosis to promote synovial cell proliferation. In addition, insufficient autophagy flux in T cells causes premature senescence and apoptosis. Autophagy of antigen-presenting cells is involved in inflammation. Autophagy of osteoblasts and osteoclasts affects the process of bone destruction. Other cells affect RA through different mechanisms. TNF, tumor necrosis factor; IL, interleukin; PTPN2, phosphatase nonreceptor type 2; ROS, reactive oxygen species; LC3, light chain 3; ULK-1, UNC51-like kinase 1; FLS, fibroblast-like synoviocytes; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3; FIP200, focal adhesion kinase family interacting protein of 200 Kd; HMGB1, high mobility group box 1; ATG5, autophagy related 5.
Figure 3
Figure 3
Role of NETosis in the pathophysiology of rheumatoid arthritis. Neutrophils respond to diverse stimuli for developing NETosis, which starts with the NADPH oxidase complex and promotes ROS production. ROS activate the hydrolytic activity of PAD4 and neutrophil elastase in an MPO-dependent manner, cleaving the histones over-citrullinated by PAD4. This triggers a series of events, including the rupture of the nuclear membrane, the formation of NETs, and the release of various biological agents, which interact with a variety of cells affecting RA progression. IL, interleukin; PAD, peptidylarginine deiminase; chcap-18, cathelicidin human cationic antimicrobial protein-18; NETs, neutrophil extracellular traps; NADPH, nicotinamide adenine dinucleotide phosphate; TLR, Toll-like receptor; MHCII, MHC class II; ACPA, anti-citrullinated protein antibodies; FLS, fibroblast-like synoviocytes; ROS, reactive oxygen species.
Figure 4
Figure 4
Role of necroptosis in the pathophysiology of rheumatoid arthritis. The critical molecules of necroptosis, RIPK1, RIPK3, and MLKL, are elevated in RA. Various cell types undergo necroptosis in response to diverse stimuli and release various pro-inflammatory mediators to promote inflammation, bone destruction, and other RA associated pathological processes. Necroptosis in cardiomyocytes may cause RA-related heart damage. Accordingly, inhibition of RIPK1 and other necroptotic molecules may be beneficial for disease treatment. GM-CSF, granulocyte-macrophage colony-stimulating factor; RIPK, receptor-interacting protein kinase; MLKL, pseudokinase mixed lineage kinase domain-like; TNF, tumor necrosis factor; VDAC1, voltage-dependent anion-selective channel 1.
Figure 5
Figure 5
Role of pyroptosis in the pathophysiology of rheumatoid arthritis. Pyroptosis mainly involves the assembly of the NLRP3 inflammasome and the release of the pro-inflammatory mediators including IL-1β and IL-18. Most pyroptosis-related molecules are elevated in RA. Predominantly, the FLS, CD4+T cells, and monocytes-macrophages express different molecular patterns and promote pyroptosis, inflammation, bone destruction, and angiogenesis, that ultimately worsens exacerbates RA. FLS, fibroblast-like synoviocytes; PTX3, pentaxin 3; GSDMD, gasdermin D; mtDNA, mitochondrial DNA; TGF, transforming growth factor; HIF-1α, hypoxia-inducible factor-1α.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Aletaha D, Neogi T, Silman A, Funovits J, Felson D, Bingham C, et al. . 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum-us (2010) 62(9):2569–81. doi: 10.1002/art.27584 - DOI - PubMed
    1. Alamanos Y, Voulgari P, Drosos A. Incidence and Prevalence of Rheumatoid Arthritis, Based on the 1987 American College of Rheumatology Criteria: A Systematic Review. Semin Arthritis Rheum (2006) 36(3):182–8. doi: 10.1016/j.semarthrit.2006.08.006 - DOI - PubMed
    1. Firestein G, McInnes I. Immunopathogenesis of Rheumatoid Arthritis. Immunity (2017) 46(2):183–96. doi: 10.1016/j.immuni.2017.02.006 - DOI - PMC - PubMed
    1. Guo S, Jin Y, Zhou J, Zhu Q, Jiang T, Bian Y, et al. . MicroRNA Variants and HLA-miRNA Interactionsare Novel Rheumatoid Arthritis Susceptibility Factors. Front Genet (2021) 12:747274(747274). doi: 10.3389/fgene.2021.747274 - DOI - PMC - PubMed
    1. Zhao J, Guo S, Schrodi SJ, D H. Molecular and Cellular Heterogeneity in Rheumatoid Arthritis:Mechanisms and Clinical Implications. Front Immunol (2021) 12:790122(790122). doi: 10.3389/fimmu.2021.790122 - DOI - PMC - PubMed

Publication types