scholarly journals A roadmap to target interleukin-6 in osteoarthritis

Rheumatology ◽  
2020 ◽  
Vol 59 (10) ◽  
pp. 2681-2694
Author(s):  
Renske Wiegertjes ◽  
Fons A J van de Loo ◽  
Esmeralda N Blaney Davidson
Keyword(s):  
Synovial Fluid ◽  
Disease Incidence ◽  
Joint Inflammation ◽  
Protective Role ◽  
Future Perspective ◽  
Current Evidence ◽  
Joint Pathology ◽  
Matrix Degrading Enzymes ◽  
Review Current

Abstract Joint inflammation is present in the majority of OA patients and pro-inflammatory mediators, such as IL-6, are actively involved in disease progression. Increased levels of IL-6 in serum or synovial fluid from OA patients correlate with disease incidence and severity, with IL-6 playing a pivotal role in the development of cartilage pathology, e.g. via induction of matrix-degrading enzymes. However, IL-6 also increases expression of anti-catabolic factors, suggesting a protective role. Until now, this dual role of IL-6 is incompletely understood and may be caused by differential effects of IL-6 classic vs trans-signalling. Here, we review current evidence regarding the role of IL-6 classic- and trans-signalling in local joint pathology of cartilage, synovium and bone. Furthermore, we discuss targeting of IL-6 in experimental OA models and provide future perspective for OA treatment by evaluating currently available IL-6 targeting strategies.

scholarly journals An Overview of Adipose Tissue ACE2 Modulation by Diet and Obesity. Potential Implications in COVID-19 Infection and Severity

2021 ◽  
Vol 22 (15) ◽  
pp. 7975
Author(s):  
Saioa Gómez-Zorita ◽  
Iñaki Milton-Laskibar ◽  
Laura García-Arellano ◽  
Marcela González ◽  
María P. Portillo
Keyword(s):  
Adipose Tissue ◽  
Protective Role ◽  
Inflammatory Factors ◽  
Current Evidence ◽  
Disease Outcomes ◽  
Lower Activation ◽  
Two Factors ◽  
Obese Subjects ◽  
Ace2 Gene

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce.

scholarly journals Prostacyclin-IP signaling and prostaglandin E2-EP2/EP4 signaling both mediate joint inflammation in mouse collagen-induced arthritis

2006 ◽  
Vol 203 (2) ◽  
pp. 325-335 ◽  
Author(s):  
Tetsuya Honda ◽  
Eri Segi-Nishida ◽  
Yoshiki Miyachi ◽  
Shuh Narumiya
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
The Other ◽  
Receptor Subtype ◽  
Significant Suppression ◽  
Wild Type ◽  
Collagen Induced Arthritis

Prostaglandin (PG)I2 (prostacyclin [PGI]) and PGE2 are abundantly present in the synovial fluid of rheumatoid arthritis (RA) patients. Although the role of PGE2 in RA has been well studied, how much PGI2 contributes to RA is little known. To examine this issue, we backcrossed mice lacking the PGI receptor (IP) to the DBA/1J strain and subjected them to collagen-induced arthritis (CIA). IP-deficient (IP−/−) mice exhibited significant reduction in arthritic scores compared with wild-type (WT) mice, despite anti-collagen antibody production and complement activation similar to WT mice. IP−/− mice also showed significant reduction in contents of proinflammatory cytokines, such as interleukin (IL)-6 in arthritic paws. Consistently, the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced IL-6 production and induced expression of other arthritis-related genes. On the other hand, loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA. However, a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4. Our results show significant roles of both PGI2-IP and PGE2-EP2/EP4 signaling in the development of CIA, and suggest that inhibition of PGE2 synthesis alone may not be sufficient for suppression of RA symptoms.

scholarly journals Number of individual ACPA reactivities in synovial fluid immune complexes, but not serum anti-CCP2 levels, associate with inflammation and joint destruction in rheumatoid arthritis

2018 ◽  
Vol 77 (9) ◽  
pp. 1345-1353 ◽  
Author(s):  
Azita Sohrabian ◽  
Linda Mathsson-Alm ◽  
Monika Hansson ◽  
Ann Knight ◽  
Jörgen Lysholm ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Synovial Fluid ◽  
Disease Activity ◽  
Immune Complexes ◽  
Magnetic Beads ◽  
Joint Destruction ◽  
Joint Pathology ◽  
A New Technique ◽  
Laboratory Measures

IntroductionIndividual patients with rheumatoid arthritis (RA) show divergent specific anti-citrullinated protein/peptide antibodies (ACPA) patterns, but hitherto no individual ACPA specificity has consistently been linked to RA pathogenesis. ACPA are also implicated in immune complexes (IC)-associated joint pathology, but until now, there has been no method to investigate the role of individual ACPA in RA IC formation and IC-associated pathogenesis.MethodsWe have developed a new technique based on IC binding to C1q-coated magnetic beads to purify and solubilise circulating IC in sera and synovial fluids (SF) from 77 patients with RA. This was combined with measurement of 19 individual ACPA in serum, SF and in the IC fractions from serum and SF. We investigated whether occurrence of individual ACPA as well as number of ACPA in these compartments was related to clinical and laboratory measures of disease activity and inflammation.ResultsThe majority of individual ACPA reactivities were enriched in SF as compared with in serum, and levels of ACPA in IC were regulated independently of levels in serum and SF. No individual ACPA reactivity in any compartment showed a dominating association to clinical and laboratory measures of disease activity and severity. Instead, the number of individual ACPA reactivities in the IC fraction from SF associated with a number of markers of joint destruction and inflammation.ConclusionsOur data highlight the polyclonality of ACPA in joint IC and the possibility that a broad ACPA repertoire in synovial fluid IC might drive the local inflammatory and matrix-degrading processes in joints, in analogy with antibody-induced rodent arthritis models.

scholarly journals Chronic rapamycin treatment causes diabetes in male mice

2014 ◽  
Vol 307 (4) ◽  
pp. R434-R443 ◽  
Author(s):  
Christine E. Schindler ◽  
Uttara Partap ◽  
Bonnie K. Patchen ◽  
Steven J. Swoap
Keyword(s):  
Glucose Intolerance ◽  
Mammalian Target Of Rapamycin ◽  
Protective Role ◽  
Metabolic Effects ◽  
Current Evidence ◽  
Male Mice ◽  
Rapamycin Treatment ◽  
Female Mice ◽  
Glucose Levels

Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2plays a protective role against the development of rapamycin-induced diabetes.

scholarly journals Lung Microbiome in Asthma: Current Perspectives

2019 ◽  
Vol 8 (11) ◽  
pp. 1967 ◽  
Author(s):  
Konstantinos Loverdos ◽  
Georgios Bellos ◽  
Louiza Kokolatou ◽  
Ioannis Vasileiadis ◽  
Evangelos Giamarellos ◽  
...  
Keyword(s):  
Respiratory Diseases ◽  
Human Microbiome ◽  
Current Evidence ◽  
Host Immune System ◽  
Prevention Strategies ◽  
Chronic Respiratory Diseases ◽  
Lung Microbiome ◽  
Modes Of Interaction ◽  
Review Current

A growing body of evidence implicates the human microbiome as a potentially influential player actively engaged in shaping the pathogenetic processes underlying the endotypes and phenotypes of chronic respiratory diseases, particularly of the airways. In this article, we specifically review current evidence on the characteristics of lung microbiome, and specifically the bacteriome, the modes of interaction between lung microbiota and host immune system, the role of the “lung–gut axis”, and the functional effects thereof on asthma pathogenesis. We also attempt to explore the possibilities of therapeutic manipulation of the microbiome, aiming at the establishment of asthma prevention strategies and the optimization of asthma treatment.

scholarly journals Protective Role of mTOR in Liver Ischemia/Reperfusion Injury: Involvement of Inflammation and Autophagy

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Tao Zhang ◽  
Jianrong Guo ◽  
Jian Gu ◽  
Ke Chen ◽  
Huili Li ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mammalian Target Of Rapamycin ◽  
Graft Function ◽  
Protective Role ◽  
Liver Graft ◽  
Current Evidence ◽  
Liver Ischemia ◽  
Pathological Conditions

Liver ischemia/reperfusion (IR) injury is a common phenomenon after liver resection and transplantation, which often results in liver graft dysfunction such as delayed graft function and primary nonfunction. The mammalian target of rapamycin (mTOR) is an evolutionarily highly conserved serine/threonine protein kinase, which coordinates cell growth and metabolism through sensing environmental inputs under physiological or pathological conditions, involved in the pathophysiological process of IR injury. In this review, we mainly present current evidence of the beneficial role of mTOR in modulating inflammation and autophagy under liver IR to provide some evidence for the potential therapies for liver IR injury.

Collagenase activity in anterior cruciate ligament: protective role of the synovial sheath

1990 ◽  
Vol 69 (3) ◽  
pp. 902-906 ◽  
Author(s):  
D. Amiel ◽  
E. Billings ◽  
F. L. Harwood
Keyword(s):  
Anterior Cruciate Ligament ◽  
Synovial Fluid ◽  
Cruciate Ligament ◽  
Protective Role ◽  
Collagenase Activity ◽  
Treatment Groups ◽  
Active Collagenase ◽  
Anterior Cruciate ◽  
Biochemical Assessment

To evaluate the protective role of the synovial sheath of the anterior cruciate ligament (ACL), we have developed a synovectomy model that exposes the ACL substance to the intra-articular environment with and without hemarthrosis. Histology and the level of collagenase activity were studied to assess intrinsic ligament alterations. The treatment groups studied were as follows: ACLs of sham-operated knees receiving arthrotomy only, ACLs of knees receiving arthrotomy and acute hemarthrosis, ACLs of knees that underwent synovectomy, and ACLs of knees that underwent both synovectomy and acute hemarthrosis. All animals were killed 10 days postoperatively for gross, histological, and biochemical assessment. Histologically at 10 days ACLs experiencing synovectomy and ACLs having synovectomy plus hemarthrosis revealed marked hypocellular areas. Biochemical results indicate that synovectomy is the treatment mainly responsible for the observed increase in ACL collagenase activity. Hemarthrosis alone clearly had no effect, although hemarthrosis coupled with synovectomy appeared to further increase the amount of active collagenase present in the ACLs. This study indicates that, with exposure of the ACL substance to the synovial fluid or with hemarthrosis after synovectomy, there is an increase in the degradative activity of the ACL. The protective role of the synovial sheath suggests that the synovial sheath injury associated with acute ACL rupture may allow for exposure of the ligament substance to the degradative effects of the synovial environment and associated hemarthrosis.

scholarly journals Non-alcoholic fatty liver disease, Mediterranean diet and 10-year cardiovascular disease incidence: the mediating role of adiponectin. Highlights from the ATTICA prospective (2002–2012) study

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Kouvari ◽  
D.B Panagiotakos ◽  
C Chrysohoou ◽  
C Boutari ◽  
E.N Georgousopoulou ◽  
...  
Keyword(s):  
Mediterranean Diet ◽  
Disease Incidence ◽  
Protective Role ◽  
Inverse Association ◽  
Alcoholic Fatty Liver ◽  
Low Carbohydrate ◽  
Stratified Analysis ◽  
Cardiovascular Disease Incidence ◽  
Alcoholic Fatty Liver Disease

Abstract Background/Introduction The most updated set of guidelines (EASL-EASD-EASO 2016) suggests Mediterranean diet as a promising dietary pattern for non-alcoholic fatty liver disease (NAFLD) management. Purpose The association between NAFLD and adherence to Mediterranean diet as well as their interaction on 10-year fatal/non fatal cardiovascular disease incidence were evaluated. Methods Study population included 1,514 men and 1,528 women (>18 years old) in our city in Greece, free of CVD recruited during the 2001–2002 period. Liver steatosis and fibrosis assessment indices were calculated at baseline and specific cut-offs were used to capture NAFLD. Level of adherence to Mediterranean diet was assessed through MedDietScore. National and international food databases were used to estimate total daily carbohydrate intake. The cut-off point of 35% of total daily energy intake was set to define low vs. high carbohydrate intake. Circulating adiponectin level was measured at baseline (4.0 (2.0) μg/mL). Results MedDietScore was inversely associated with NAFLD indices of both steatosis and fibrosis yet only in Triglycerides-Glucose index [Odds Ratio (OR)3rd vs. 1st MedDietScore tertile = 0.53, 95% Confidence Interval (95% CI) (0.29, 0.95)] persisted in multi-adjusted models including adjustments for metabolic syndrome components, energy intake and overall and central obesity. This was more evident in men (p for sex interaction = 0.03). The protective role of Mediterranean diet was retained irrespective to the total carbohydrate content; however, sex-based stratified analysis revealed that in woman subsample only Mediterranean diet with low carbohydrate content (i.e. <35%) had an independent protective role against NAFLD presence [OR3rd vs. 1st MedDietScore tertile = 0.79, 95% CI (0.40, 0.96)]. NAFLD predicted CVD [Hazard Ratio (HR) = 3.01, 95% CI (2.28, 3.95)] in crude model as well as in multi-adjusted model [HR=1.37, 95% CI (1.10, 2.10)]. NAFLD effect on CVD remained significant only in MedDietScore below median [HR=1.38, 95% CI (1.00, 1.93)] whereas it was essentially null [HR=1.00, 95% CI (0.38, 2.63)] among subjects with lower score. Mediation analysis revealed that adiponectin was the strongest mediator of the examined associations. In particular, per 1 mg/dL serum adiponectin about 21% lower likelihood to have NAFLD was observed. Stratified analysis using the median value of adiponectin level (4.1 mg/dL) revealed that the inverse association between Mediterranean diet and NAFLD reached the level of significance only in case of adiponectin levels over the median values (OR (3rd vs. 1st MedDietScore tertile) = 0.69 95% CI (0.35, 0.98)). Conclusion Beyond the inverse association between Mediterranean diet and NAFLD several novelties were revealed; low-carbohydrate Mediterranean diet was more protective against NAFLD in women while an adiponectin-related mechanism was revealed. Funding Acknowledgement Type of funding source: Other. Main funding source(s): This work was supported by a research grant from Hellenic Atherosclerosis Society. The ATTICA study is supported by research grants from the Hellenic Cardiology Society [HCS2002] and the Hellenic Atherosclerosis Society [HAS2003]

scholarly journals Expanding Regulatory T Cells Alleviates Chikungunya Virus-Induced Pathology in Mice

2015 ◽  
Vol 89 (15) ◽  
pp. 7893-7904 ◽  
Author(s):  
Wendy W. L. Lee ◽  
Teck-Hui Teo ◽  
Zhisheng Her ◽  
Fok-Moon Lum ◽  
Yiu-Wing Kam ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Chikungunya Virus ◽  
Interleukin 2 ◽  
Joint Inflammation ◽  
Chikv Infection ◽  
Joint Pathology ◽  
Alternative Approach ◽  
Control Virus

ABSTRACTChikungunya virus (CHIKV) infection is a reemerging pandemic human arboviral disease. CD4+T cells were previously shown to contribute to joint inflammation in the course of CHIKV infection in mice. The JES6-1 anti-IL-2 antibody selectively expands mouse regulatory T cells (Tregs) by forming a complex with IL-2. In this study, we show that the IL-2 JES6-1-mediated expansion of Tregs ameliorates CHIKV-induced joint pathology. It does so by inhibiting the infiltration of CD4+T cells due to the induction of anergy in CHIKV-specific CD4+effector T cells. These findings suggest that activation of Tregs could also become an alternative approach to control CHIKV-mediated disease.IMPORTANCEChikungunya virus (CHIKV) has reemerged as a pathogen of global significance. Patients infected with CHIKV suffer from incapacitating joint pain that severely affects their daily functioning. Despite the best efforts, treatment is still inadequate. While T cell-mediated immunopathology in CHIKV infections has been reported, the role of regulatory T cells (Tregs) has not been explored. The JES6-1 anti-interleukin 2 (IL-2) antibody has been demonstrated to selectively expand mouse Tregs by forming a complex with IL-2. We reveal here that IL-2 JES6-1-mediated expansion of Tregs ameliorates CHIKV-induced joint pathology in mice by neutralizing virus-specific CD4+effector T (Teff) cells. We show that this treatment abrogates the infiltration of pathogenic CD4+T cells through induction of anergy in CHIKV-specific CD4+Teff cells. This is the first evidence where the role of Tregs is demonstrated in CHIKV pathogenesis, and its expansion could control virus-mediated immunopathology.

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