Granzyme A Contributes to Inflammatory Arthritis in Mice Through Stimulation of Osteoclastogenesis

Santiago, Llipsy; Menaa, Cheikh; Arias, Maykel; Martin, Praxedis; Jaime-Sánchez, Paula; Metkar, Sunil S.; Comas, Laura; Erill, Nadina; González‐Rumayor, Víctor; Esser, E.; Gálvez, Eva M.; Raja, Sri; Simon, Markus M.; Sprague, Stuart M.; Gabay, Cem; Martínez-Lostao, Luis; Pardo, Julián; Froelich, Christopher J.

doi:10.1002/art.39857

Cited by 33 publications

(46 citation statements)

References 53 publications

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“…Most studies to date in both mice and humans have shown that Tc17 cells lack cytolytic function (29,31,46,47), although some evidence for cytotoxic function has been reported (24,48). An interesting alternative interpretation of our data is that the secretion of granzymes is not cytolytic but leads to extracellular matrix degradation or promotion of inflammation (49,50). Taken together, these data show that Tc17 cells are armed with an array of proinflammatory mediators, which could act directly on surrounding cells to promote inflammation in the synovial joint.…”

Section: Discussionmentioning

confidence: 71%

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Steel

Srenathan

Ridley

et al. 2020

Arthritis & Rheumatology

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Objective Genetic associations imply a role for CD8+ T cells and the interleukin‐23 (IL‐23)/IL‐17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL‐17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL‐17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis. Methods Peripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6–18), T cell receptor β (TCRβ) sequencing (n = 3), RNA‐Seq (n = 3), quantitative reverse transcriptase–polymerase chain reaction (n = 4), and Luminex or enzyme‐linked immunosorbent assay (n = 4–16). Results IL‐17A+CD8+ T cells were predominantly TCRαβ+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRβ sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA‐Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue‐resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint. Conclusion Our results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.

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Section: Discussionmentioning

confidence: 71%

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Steel

Srenathan

Ridley

et al. 2020

Arthritis & Rheumatology

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“…The mouse granzyme A inhibitor, Serpinb6b, significantly reduced foot swelling in chikungunya virus–infected mice, indicating that granzyme A may be a potential therapeutic candidate . Granzyme A was also recently shown to be important in a mouse model of rheumatoid arthritis (RA) , an example of the significant overlap between chikungunya arthritis and RA .…”

Section: Chronic Stage Of Chikungunya Virus (>3 Months After the Onsementioning

confidence: 99%

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

Zaid

Gérardin

Taylor

et al. 2018

Arthritis & Rheumatology

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In the past decade, arboviruses-arthropod-borne viruses-have been the focus of public health institutions worldwide following a spate of devastating outbreaks. Chikungunya virus, an arbovirus that belongs to the alphavirus genus, is a reemerging arthritogenic virus that has caused explosive outbreaks since 2006, notably on Réunion Island, and more recently in the Caribbean, South America, India, and Southeast Asia. The severity of arthritic disease caused by chikungunya virus has prompted public health authorities in affected countries to develop specific guidelines to tackle this pathogen. Chikungunya virus disease manifests first as an acute stage of severe joint inflammation and febrile illness, which later progresses to a chronic stage, during which patients may experience debilitating and persisting articular pain for extended periods. This review aims to provide a broad perspective on current knowledge of chikungunya virus pathogenesis by identifying key clinical and experimental studies that have contributed to our understanding of chikungunya virus to date. In addition, the review explores the practical aspects of treatment and management of both acute and chronic chikungunya virus based on clinical experience during chikungunya virus outbreaks. Finally, recent findings on potential therapeutic solutions-from antiviral agents to immunomodulators-are reviewed to provide both viral immunologists and clinical rheumatologists with a balanced perspective on the nature of a reemerging arboviral disease of significant public health concern, and insight into future therapeutic approaches to better address the treatment and management of chikungunya virus.

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“…In CIA, granzyme A‐deficient mice exhibited reduced joint damage, bone erosion and inflammatory cytokine production compared to wild‐type controls. Interestingly, the authors also demonstrated that granzyme A induces osteoclastogenesis, which may have relevance to its observed function in disease (Santiago et al ., ).…”

Section: Serine Proteinases and Cartilage Ecm Turnovermentioning

confidence: 99%

Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics

Wilkinson

Arques

Huesa

et al. 2018

British J Pharmacology

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Cartilage destruction is a key characteristic of arthritic disease, a process now widely established to be mediated by metzincins such as MMPs. Despite showing promise in preclinical trials during the 1990s, MMP inhibitors for the blockade of extracellular matrix turnover in the treatment of cancer and arthritis failed clinically, primarily due to poor selectivity for target MMPs. In recent years, roles for serine proteinases in the proteolytic cascades leading to cartilage destruction have become increasingly apparent, renewing interest in the potential for new therapeutic strategies that utilize pharmacological inhibitors against this class of proteinases. Herein, we describe key serine proteinases with likely importance in arthritic disease and highlight recent advances in this field. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

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Granzyme A Contributes to Inflammatory Arthritis in Mice Through Stimulation of Osteoclastogenesis

Abstract: GzmA contributes to the joint destruction of RA partly by promoting osteoclast differentiation.

Cited by 33 publications

References 53 publications

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Polyfunctional, Proinflammatory, Tissue‐Resident Memory Phenotype and Function of Synovial Interleukin‐17A+CD8+ T Cells in Psoriatic Arthritis

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

Serine proteinases in the turnover of the cartilage extracellular matrix in the joint: implications for therapeutics

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