scholarly journals TNF-α Activating Osteoclasts in Patients with Psoriatic Arthritis Enhances the Recruitment of Osteoclast Precursors: A Plausible Role of WNT5A-MCP-1 in Osteoclast Engagement in Psoriatic Arthritis

2022 ◽  
Vol 23 (2) ◽  
pp. 921
Author(s):  
Shang-Hung Lin ◽  
Ji-Chen Ho ◽  
Sung-Chou Li ◽  
Yu-Wen Cheng ◽  
Chung-Yuan Hsu ◽  
...  

Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. The promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from five PsA patients and five healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. The number of CD68+WNT5A+ osteoclasts increased in PsA joints. CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by the MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-α but not IL-17. We conclude that TNF-α recruits OCP by increased MCP-1 production but does not directly activate osteoclastogenesis in PsA.

2021 ◽  
Author(s):  
Shang-Hung Lin ◽  
Ji-Chen Ho ◽  
Chung-Yuan Hsu ◽  
Sung-Chou Li ◽  
Wen-Yi Chou ◽  
...  

Abstract Background: Psoriatic arthritis (PsA) results from joint destruction by osteoclasts. Promising efficacy of TNF-α blockage indicates its important role in osteoclastogenesis of PsA. WNT ligands actively regulate osteoclastogenesis. We investigated how WNT ligands activate osteoclasts amid the TNF-α milieu in PsA. Methods: We first profiled the expression of WNT ligands in CD14+ monocyte-derived osteoclasts (MDOC) from 3 PsA patients and 3 healthy controls (HC) and then validated the candidate WNT ligands in 32 PsA patients and 16 HC. Through RNA interference against WNT ligands in MDOC, we determined the mechanisms by which TNF-α exerts its effects on osteclastogenesis or chemotaxis. Results: The results showed numbers of CD68+WNT5A+ osteoclasts are increased in PsA joints. WNT5A was selectively upregulated by TNF-α in MDOC from PsA patients. However, direct osteoclastogenesis effect (RANK expression) by TNF-αwas not inhibited by WNT5A siRNA. Instead, CXCL1, CXCL16, and MCP-1 was selectively increased in supernatants of MDOC from PsA patients. RNA interference against WNT5A abolished the increased MCP-1 from MDOC and THP-1-cell-derived osteoclasts. The increased migration of osteoclast precursors (OCP) induced by supernatant from PsA MDOC was abolished by MCP-1 neutralizing antibody. WNT5A and MCP-1 expressions were decreased in MDOC from PsA patients treated by biologics against TNF-a but not IL-17. Conclusion: We conclude TNF-α recruits OCP by WNT5A-mediated MCP-1 production but not directly activates osteoclastogenesis in PsA.


2014 ◽  
Vol 74 (6) ◽  
pp. 1284-1292 ◽  
Author(s):  
Iannis E Adamopoulos ◽  
Erika Suzuki ◽  
Cheng-Chi Chao ◽  
Dan Gorman ◽  
Sarvesh Adda ◽  
...  

BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory disease characterised by clinical features that include bone loss and epidermal hyperplasia. Aberrant cytokine expression has been linked to joint and skin pathology; however, it is unclear which cytokines are critical for disease initiation. Interleukin 17A (IL-17A) participates in many pathological immune responses; however, its role in PsA has not been fully elucidated.ObjectiveTo determine the role of IL-17A in epidermal hyperplasia and bone destruction associated with psoriatic arthritis.DesignAn in vivo gene transfer approach was used to investigate the role of IL-17A in animal models of inflammatory (collagen-induced arthritis) and non-inflammatory (receptor activator of NF-κB ligand (RANKL)-gene transfer) bone loss.ResultsIL-17A gene transfer induced the expansion of IL-17RA+CD11b+Gr1low osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption. This occurred at a time preceding noticeable joint inflammation, suggesting that IL-17A is critical for the induction of pathological bone resorption through direct activation of osteoclast precursors. Moreover, IL-17A induced a second myeloid population CD11b+Gr1high neutrophil-like cells, which was associated with cutaneous pathology including epidermal hyperplasia, parakeratosis and Munro's microabscesses formation.ConclusionsCollectively, these data support that IL-17A can play a key role in the pathogenesis of inflammation-associated arthritis and/or skin disease, as observed in PsA.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 586-586
Author(s):  
Lequn Li ◽  
Jin sub Kim ◽  
Vassiliki A Boussiotis

Abstract Abstract 586 A major challenge of the immune system is to fight pathogens and tumor antigens while preserving tolerance to self-antigen. T regulatory cells (Treg) are critical extrinsic regulators of immune tolerance and maintenance of lymphoid homeostasis. Recently it was determined that, when used as cell-based immunosuppressive therapy, Treg have a potent effect in preventing GvHD in patients undergoing allogeneic stem cell transplantation. However, several studies suggest that the Treg phenotype is not at end stage of differentiation. Treg can express and produce effector cytokines including IFN-γ and IL-17 under certain conditions, particularly in the context of inflammatory milieu, suggesting that Treg may convert into inflammatory mediators. IL-1β and TNF-α are critical inflammatory cytokines that have been implicated in GvHD. The precise role and the mechanism(s) via which these cytokines may affect development of GvHD remain unclear. In the presence study, we sought to determine whether IL-1β and TNF-α regulate the properties of Treg and specifically whether these cytokines affect Treg expansion and/or conversion into IL-17 producing cells. CD4+CD25+Treg cells were isolated from B6 mice and were stimulated with anti-CD3-plus-anti-CD28 mAbs in the presence of either media, IL-1β or TNF-α. Addition of either cytokine induced Treg proliferation as determined by CFSE. Assessment of intracellular IL-17 expression by flow cytometry and IL-17 production by ELISA revealed that IL-1β but not TNF-α induced conversion of Treg into IL-17 producing cells, suggesting that conversion was mediated via pathways distinct from those that regulate cell cycle progression. To evaluate conversion of Treg to IL-17 producers during antigen stimulation and to determine the role of IL-1β in this process, we used neutral culture conditions in which no exogenous cytokines were supplied. Treg cells isolated from Foxp3GFP-KI mouse were added to cultures of naive conventional CD4+ T cells (Tc) in the presence of APC and anti-CD3 mAb. We found that these conditions preferentially induced conversion of Treg to IL-17 producing cells. To determine the role of IL-1β in this conversion process, we used IL-1β neutralizing antibody. Addition of anti-IL-1β neutralizing antibody reduced IL-17 production to almost undetectable levels. Because it has exogenous IL-6 can induce IL-17 production by both Treg and Tc, we evaluated whether endogenous IL-6 was involved in the conversion of Treg into IL-17 producing cells in our system. Addition of a combination of IL-6 neutralizing and IL-6 receptor blocking antibodies did not affect IL-17 production, suggesting that the conversion process of Treg into IL-17 producing cells was dependent on endogenous IL-1β rather than IL-6. To determine whether IL-1β was mandatory for this process, we used T cells from IL-1R deficient mice. Individual culture of IL−1R−/− Tc or IL-1R−/− Treg with wild type (wt) APC and co-culture of IL-1R−/− Tc and IL-1R−/− Treg with wt APC did not result in detectable IL-17 production. Similarly, no IL-17 production was observed when wt instead of IL-1R−/− Tc were used. In contrast, substitution of IL-1R−/− Treg with wt Treg resulted in abundant IL-17 production. To investigate the in vivo biological relevance of our findings we adoptively transferred Treg cells from either congenic B6.PL mice or IL-1R1−/− mice into IL-1R1−/− recipients, which were then immunized with KLH in IFA. Three days after immunization both IL-1R−/− Treg and IL-1R−/− Tc cells were incapable of producing detectable levels of IL-17 or expressing RORγt, the key transcriptional factor of IL-17. In contrast, a significant percentage of IL-17 and RORγt positive cells were detected within the adoptively transferred Thy1.1+ Treg population. Mechanistic analysis revealed that IL-1β induced activation of p38 and JNK in Treg and addition of pharmacologic inhibitors specific for these MAPKs abrogated IL-17 production. Our studies reveal that although Treg have primarily immunosuppressive functions they may also facilitate pro-inflammatory responses as they can be converted into IL-17 producing cells by IL-1β. These observations may have significant implications on clinical strategies that employ Treg for control of GvHD and suggest that further intervention might be required to prevent attainment of pro-inflammatory properties by Treg while maintaining their suppressive function. Disclosures: No relevant conflicts of interest to declare.


Rheumatology ◽  
2002 ◽  
Vol 41 (3) ◽  
pp. 329-337 ◽  
Author(s):  
H. Matsuno ◽  
K. Yudoh ◽  
R. Katayama ◽  
F. Nakazawa ◽  
M. Uzuki ◽  
...  

2022 ◽  
Author(s):  
Charalampos Papadopoulos ◽  
Eleftheria Spourita ◽  
Konstantinos Mimidis ◽  
George Kolios ◽  
Ioannis Tentes ◽  
...  

Non-alcoholic steatohepatitis (NASH) constitutes a significant cause of deaths, liver transplantations and economic costs worldwide. Despite extended research, investigations on the role of erythrocytes are scarce. Red blood cells from experimental animals and human patients with NASH, present phosphatidylserine exposure which is then recognized by Kupffer cells. This event leads to erythrophagocytosis, and amplification of inflammation through iron disposition. In addition, it has been shown that erythrocytes from NASH patients release the chemokine MCP1, leading to increased TNF-α release from macrophages RAW 264.7. However, erythrophagocytosis can also be caused by reduced CD47 levels. In addition, increased MCP1 release could be either signal-induced, or caused by higher MCP1 levels on the erythrocyte membrane. Finally, erythrocyte efferocytosis could provide additional inflammatory metabolites. In this study, we measured the erythrocyte membrane levels of CD47 and MCP1 by ELISA, and cholesterol and sphingosine with thin-layer chromatography. 18 patients (8 men, 10 women aged 56.7+/-11.5 years) and 14 healthy controls (7 men, 7 women aged 39.3+/-15.5 years) participated in our study. The erythrocyte CD47 levels were decreased in the erythrocyte membranes of NASH patients (844+/-409 pg/ml) compared to healthy controls (2969+/-1936 pg/ml) with P(Healthy>NAFLD)=99.1%, while the levels of MCP1 were increased in NASH patients (389+/-255 pg/ml), compared to healthy controls (230+/-117 pg/ml) with P(Healthy<NAFLD)=88.9%. Moreover, in erythrocyte membranes there was a statistically significant accumulation of sphingosine and cholesterol in NASH patients, compared to healthy controls. Our results imply that erythrocytes release chemotactic (find me signals) MCP1, while containing reduced (do not eat me signals) CD47. These molecules can lead to erythrophagocytosis. Next, increased (goodbye signals) sphingosine and cholesterol could augment inflammation by metabolic reprogramming.


2019 ◽  
Author(s):  
Jun Tang ◽  
Tiantian Luo ◽  
Junjun Geng ◽  
Bo Zhang ◽  
Yin Niu ◽  
...  

Abstract Background: Neuroinflammation is a major detrimental role of secondary brain injury after spontaneously intracerebral hemorrhage (ICH). Neutrophil infiltration plays a key role in the pathophysiology of ICH, but the coming resource and mechanism is unknown. This study aims to investigate whether spleen-derived neutrophil infiltration accelerated neuroinflammation and the role of C1q classical pathway.Methods: Male C57 mice were subjected to collagenase-induced ICH. If necessary, splenectomy was performed 2 weeks prior to ICH induction or anti-C1q neutralizing antibody (50mg/kg) was injected intravenously into the tail vein 15 minutes prior. Immunohistochemistry, Propidium Iodide staining, western blotting, ELISA and qRT-PCR were used to study the change of molecular proteins, neuronal cells and inflammatory factors. 7.0T animal MRI was used to assess hydrocephalus.Results: At 0h, 6h, 12h, 24h and 48h post ICH induction, we found a significant increasing tendency of microglia activation and neutrophil infiltration around hematoma and that C1q upregulation was correlated with neuronal decrease, which peaked at 24h after ICH. Here, we demonstrated spleen atrophy and upregulation of neutrophil in spleen 24h after ICH. Splenectomy prior to ICH mice resulted in significant decrease of microglia and neutrophil infiltration compared with that in group of sham-splenectomy. Moreover, both anti-C1q antibody and splenectomy significantly attenuated neutrophil infiltration and neuron death, restored synapse VGAT, alleviated hydrocephalus and inflammatory factors, such as IL-1β, TNF-α and IL-6 after ICH.Conclusion: The study demonstrated that spleen is a major source of brain neutrophil infiltration after ICH. C1q-targeted inhibition of classic complement pathway could prevent spleen-derived neutrophil infiltration and attenuate ICH induced neuroinflammation, which provides a novel therapeutic approach for hemorrhagical stroke.


2008 ◽  
Vol 294 (4) ◽  
pp. F945-F955 ◽  
Author(s):  
Kar Neng Lai ◽  
Joseph C. K. Leung ◽  
Loretta Y. Y. Chan ◽  
Moin A. Saleem ◽  
Peter W. Mathieson ◽  
...  

We have previously documented that human mesangial cell (HMC)-derived TNF-α is an important mediator involved in the glomerulo-tubular communication in the development of interstitial damage in IgA nephropathy (IgAN). With the strategic position of podocytes, we further examined the role of mesangial cells in the activation of podocytes in IgAN. There was no binding of IgA from patients with IgAN to podocytes. Podocytes cultured with IgA from patients with IgAN did not induce the release of growth factors or cytokines. Furthermore, podocytes did not express mRNA of known IgA receptors. In contrast, IgA-conditioned medium (IgA-HMC medium) prepared by culturing HMC with IgA from patients with IgAN for 48 h significantly increased the gene expression and protein synthesis of TNF-α by podocytes with a 17-fold concentration above that of IgA-HMC medium. The upregulation of TNF-α expression by podocyte was only abolished by a neutralizing antibody against TNF-α but not by other antibodies. Exogenous TNF-α upregulated the synthesis of TNF-α by podocytes in an autocrine fashion. IgA-HMC medium prepared with IgA from patients with IgAN also significantly upregulated the expression of both TNF-α receptor 1 and 2 in podocytes. Our in vitro finding suggests podocytes may play a contributory role in the development of interstitial damage in IgAN by amplifying the activation of tubular epithelial cells with enhanced TNF-α synthesis after inflammatory changes of HMC.


2019 ◽  
Vol 8 (1) ◽  
pp. 110 ◽  
Author(s):  
Shang-Hung Lin ◽  
Ji-Chen Ho ◽  
Sung-Chou Li ◽  
Jia-Feng Chen ◽  
Chang-Chun Hsiao ◽  
...  

In psoriatic arthritis (PsA), progressive bone destruction is mediated by monocyte-derived osteoclasts. MicroRNAs (miRNAs) regulate many pathophysiological processes; however, their function in PsA patient monocytes has not been examined. This study aims to address whether specific miRNAs in CD14+ monocytes and monocyte-derived osteoclasts cause active osteoclastogenesis in PsA patients. Candidate miRNAs related to monocyte activation (miR-146a-5p, miR-146b-5p and miR-155-5p) were measured in circulatory CD14+ monocytes collected from 34 PsA patients, 17 psoriasis without arthritis (PsO) patients, and 34 normal controls (NCs). CD14+ monocytes were cultured with media containing TNF-α and RANKL to differentiate into osteoclasts. Osteoclast differentiation and bone resorption were measured by TRAP immunostaining and dentin slice resorption, respectively. The results showed that the miR-146a-5p expression was higher in PsA patient-derived CD14+ monocytes compared to PsO and NCs. Activation and bone resorption were selectively enhanced in osteoclasts from PsA patients, but both were abrogated by RNA interference against miR-146a-5p. More importantly, after clinical improvement using biologics, the increased miR-146a-5p expression in CD14+ monocytes from PsA patients was selectively abolished, and associated with blood CRP level. Our findings indicate that miR-146a-5p expression in CD14+ monocytes derived from PsA patients correlates with clinical efficacy, and induction of osteoclast activation and bone resorption.


2014 ◽  
Vol 92 (2) ◽  
pp. 132-139 ◽  
Author(s):  
Zhiqiang Ye ◽  
Yuxian Chen ◽  
Rongkai Zhang ◽  
Haitao Dai ◽  
Chun Zeng ◽  
...  

Osteoarthritis (OA) is a chronic degenerative joint disorder. Previous studies have shown abnormally increased apoptosis of chondrocytes in patients and animal models of OA. TNF-α and nitric oxide have been reported to induce chondrocyte ageing; however, the mechanism of chondrocyte apoptosis induced by IL-1β has remained unclear. The aim of this study is to identify the role of the c-Jun N-terminal kinase (JNK) – c-Jun pathway in regulating induction of Bim, and its implication in chondrocyte apoptosis. This study showed that Bim is upregulated in chondrocytes obtained from the articular cartilage of OA patients and in cultured mouse chondrocytes treated with IL-1β. Upregulation of Bim was found to be critical for chondrocyte apoptosis induced by IL-1β, as revealed by the genetic knockdown of Bim, wherein apoptosis was greatly reduced in the chondrocytes. Moreover, activation of the JNK–c-Jun pathway was observed under IL-1β treatment, as indicated by the increased expression levels of c-Jun protein. Suppression of the JNK–c-Jun pathway, using chemical inhibitors and RNA interference, inhibited the Bim upregulation induced by IL-1β. These findings suggest that the JNK–c-Jun pathway is involved in the upregulation of Bim during OA and that the JNK–c-Jun–Bim pathway is vital for chondrocyte apoptosis.


2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Michal A. Rahat ◽  
Mirna Safieh ◽  
Elina Simanovich ◽  
Eliran Pasand ◽  
Tal Gazitt ◽  
...  

Abstract Background Angiogenesis plays a central role in the pathophysiology of rheumatic diseases. Patients with psoriatic arthritis (PsA) demonstrate increased vascularity over patients with rheumatoid arthritis (RA), with unknown mechanisms. Methods We evaluated the serum levels of several pro- and anti-angiogenic factors in 62 PsA patients with active disease, 39 PsA patients in remission, 33 active RA patients, and 33 healthy controls (HC). Additionally, we used an in vitro co-culture system of fibroblast (HT1080) and monocytic-like (MM6) cell lines, to evaluate how their interactions affect the secretion of angiogenic factors and angiogenesis promoting abilities using scratch and tube formation assays. Results PsA patients, regardless of disease activity, exhibited higher levels of EMMPRIN/CD147, IL-17, and TNF-α relative to RA patients or HC. Factors, such as IL-6, and the ratio between CD147 and thrombospondin-1, exhibited elevated levels in active PsA patients relative to PsA patients in remission. Secretion of CD147, VEGF, and MMP-9 was increased in vitro. CD147 neutralization with an antibody reduced these levels and the ability of endothelial cells to form tube-like structures or participate in wound healing. Conclusions CD147 plays a role in mediating angiogenesis in PsA, and the therapeutic possibilities of neutralizing it merit further investigation.


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