Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

Weldon, Abby J.; Moldovan, Ioana; Cabling, Marven G; Hernandez, Elvin A.; Hsu, Sheri; González, Jennifer A.; Parra, Alicia Lagarto; Benitez, Abigail; Daoud, Nasim; Colburn, Keith K.; Payne, Kimberly J.

doi:10.3899/jrheum.140630

Cited by 25 publications

(31 citation statements)

References 51 publications

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“…Based on their expression of the surface markers CD14 and CD16 three major subsets defined as CD14++CD16− for classical monocytes, CD14++CD16+ for intermediate monocytes and CD14+CD16+ for non-classical monocytes can be distinguished in men 3 . Several clinical studies point towards an association of CD16+ subsets with pathologies characterized by a chronic inflammatory state such as coronary artery disease, obesity, arthritis, inflammatory diseases of the intestinal tract or systemic lupus erythematous 8 29 30 31 32 .…”

Section: Discussionmentioning

confidence: 99%

Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans

Thaler

Hohensinner

Krychtiuk

et al. 2016

Sci Rep

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Human monocytes are a heterogeneous cell population, which can be divided into a classical (CD14++CD16−), a non-classical (CD14+CD16+), and an intermediate (CD14++CD16+) subset. We hypothesized that low-grade inflammation may differentially affect monocyte subsets. We used a human lipopolysaccharide (LPS) infusion model to mimic low-grade inflammation to identify, which monocyte subsets are preferentially activated under these conditions. Monocyte subsets were identified by staining for CD14 and CD16, activation status of monocytes was analyzed by staining for CD11b and a novel in situ mRNA hybridization approach to detect IL-6 and IL-8 specific mRNA at the single-cell level by flow cytometry. After LPS challenge, cell numbers of monocyte subsets dropped after 2 h with cell numbers recovering after 6 h. Distribution of monocyte subsets was skewed dramatically towards the intermediate subset after 24 h. Furthermore, intermediate monocytes displayed the largest increase of CD11b expression after 2 h. Finally, IL-6 and IL-8 mRNA levels increased in intermediate and non-classical monocytes after 6 h whereas these mRNA levels in classical monocytes changed only marginally. In conclusion, our data indicates that the main responding subset of monocytes to standardized low-grade inflammation induced by LPS in humans is the CD14++CD16+ intermediate subset followed by the CD14+CD16+ non-classical monocyte subset. Circulating classical monocytes showed comparably less reaction to LPS challenge in vivo.

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Section: Discussionmentioning

confidence: 99%

Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans

Thaler

Hohensinner

Krychtiuk

et al. 2016

Sci Rep

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“…In several clinical studies an association of CD16 þ subsets with such pathologies has been described. [10][11][12] Our results presented here suggest that mostly the CD16 À Mon1 subset responds to inflammatory activation with an upregulation of PAR1 and PAR3. It would therefore be of interest to determine in future studies if also in chronic inflammatory In vivo and in vitro regulation of plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) through PAR1.…”

Section: Discussionmentioning

confidence: 81%

“…8,9 In various clinical studies an association of CD16 þ subsets with pathologies characterized by a chronic inflammatory state such as coronary artery disease, obesity, arthritis, inflammatory diseases of the intestinal tract, or systemic lupus erythematosus has been described. [10][11][12][13][14] Recently, we showed that Mon2 were associated with 30-day mortality in critically ill patients. 15 Furthermore, we established in a human endotoxemia model that especially CD16 þ cells respond to lipopolysaccharide (LPS)-induced activation with an increased production of the inflammatory cytokines interleukin-6 (IL-6) and IL-8.…”

Section: Introductionmentioning

confidence: 99%

Protease-Activated Receptors 1 and 3 are Differentially Expressed on Human Monocyte Subsets and are Upregulated by Lipopolysaccharide Ex Vivo and In Vivo

et al. 2019

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Monocytes are activated in inflammatory conditions via a variety of cytokine receptors as well as in a procoagulatory setting through thrombin, acting upon protease-activated receptors (PARs). This study investigated the expression pattern of PAR1 and PAR3 on human monocyte subsets. Furthermore, a possible regulation of the expression of PAR1 and PAR3 in these cells by inflammatory activation were studied. CD16+ monocytes showed significantly higher levels of PAR1 and PAR3 as compared with CD16− monocytes. Ex vivo treatment of whole blood with lipopolysaccharide (LPS) increased PAR1 and PAR3 messenger ribonucleic acid (mRNA) in human monocytes. In addition, increase of PAR1 was seen in all three subsets upon LPS treatment, whereas PAR3 increased significantly only in CD16− monocytes and nonclassical CD16+ monocytes. Protein levels of PAR1 and PAR3 significantly increased on monocytes in vivo in human endotoxemia 1 hour after LPS infusion. PAR1 increased significantly in CD16− monocytes and nonclassical CD16+ monocytes. In this in vivo model, PAR3 was also significantly elevated in CD16− monocytes and increased slightly albeit not significantly in CD16+ monocytes. Endotoxemia increased plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression in monocytes in humans. Pretreatment of healthy volunteers with the PAR1 antagonist vorapaxar blocked the increase in PAI-1 but not the increase in TF. We here provide new evidence for a critical role for monocytes as cellular mediators that contribute to the activation of coagulation in diseases characterized by an inflammatory state.

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“…Accumulation of APRIL-secreting cells has also been observed in synovial tissues of RA patients. Moreover, in comparison to healthy individuals of which APRIL expression are only detected in nonclassical monocytes, myeloid cells and all monocytes in RA patients exhibited upregulation of surface APRIL expression with an association to disease severity [ 137 ]. Stimulation of synoviocytes from the patients also resulted to higher production of pro-inflammatory cytokines and upregulation of receptor activator of nuclear factor kappa-B ligand (RANKL) expression.…”

Section: Breg-inducing Cytokinesmentioning

confidence: 99%

Paradoxical role of Breg-inducing cytokines in autoimmune diseases

Jaya

García

Borràs

et al. 2019

Journal of Translational Autoimmunity

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Regulatory B cells (Breg) are crucial immunoregulators that maintain peripheral tolerance and suppress inflammatory autoimmune responses. In recent years, our understanding on the nature and mechanism of action of Bregs has revealed the important role of cytokines in promoting the regulatory properties of this unique B cell subset, both in animal and human models. In this review, we compiled the cytokines that have been reported by multiple studies to induce the expansion of Breg. The Breg-inducing cytokines which are currently known include IL-21, IL-6, IL1β, IFNα, IL-33, IL-35, BAFF and APRIL. As cytokines are also known to play a pivotal role in the pathogenesis of autoimmune diseases, in parallel we reviewed the pattern of expression of the Breg-inducing cytokines in Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Inflammatory Bowel Diseases (IBD) and Multiple Sclerosis (MS). We show here that Breg-inducing cytokines are commonly implicated in these inflammatory diseases where they typically have a higher expression than in healthy individuals, suggesting their paradoxical nature. Interestingly, despite the general overexpression of Breg-inducing cytokines, it is known that Breg cells are often numerically or functionally impaired in various autoimmune conditions. Considering these alterations, we explored the possible parameters that may influence the function of Breg-inducing cytokines in exhibiting either their regulatory or pro-inflammatory properties in the context of autoimmune conditions.

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Surface APRIL Is Elevated on Myeloid Cells and Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

Cited by 25 publications

References 51 publications

Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans

Differential in vivo activation of monocyte subsets during low-grade inflammation through experimental endotoxemia in humans

Protease-Activated Receptors 1 and 3 are Differentially Expressed on Human Monocyte Subsets and are Upregulated by Lipopolysaccharide Ex Vivo and In Vivo

Paradoxical role of Breg-inducing cytokines in autoimmune diseases

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