Inflammatory phenotype of osteoarthritis and its potential therapies

:Parkinson’s disease (PD) is the second most common neurodegenerative disorder among elderly population, characterized by the progressive degeneration of dopaminergic neurons in the midbrain. To date, exact cause remains unknown and the mechanism of neurons death uncertain. It is typically considered as a disease of central nervous system (CNS). Nevertheless, numerous evidence has been accumulated in several past years testifying undoubtedly about the principal role of neuroinflammation in progression of PD. Neuroinflammation is mainly associated with presence of activated microglia in brain and elevated levels of cytokine levels in CNS. Nevertheless, active participation of immune system as well has been noted, such as, elevated levels of cytokine levels in blood, the presence of auto antibodies, and the infiltration of T cell in CNS. Moreover, infiltration and reactivation of those T cells could exacerbate neuroinflammation to greater neurotoxic levels. Hence, peripheral inflammation is able to prime microglia into pro-inflammatory phenotype, which can trigger stronger response in CNS further perpetuating the on-going neurodegenerative process.:In the present review, the interplay between neuroinflammation and the peripheral immune response in the pathobiology of PD will be discussed. First of all, an overview of regulation of microglial activation and neuroinflammation is summarized and discussed. Afterwards, we try to collectively analyze changes that occurs in peripheral immune system of PD patients, suggesting that these peripheral immune challenges can exacerbate the process of neuroinflammation and hence the symptoms of the disease. In the end, we summarize some of proposed immunotherapies for treatment of PD.

Download Full-text

Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity

Lupus ◽

10.1177/09612033211005014 ◽

2021 ◽

pp. 096120332110050

Author(s):

Rory C Monahan ◽

Liesbeth JJ Beaart-van de Voorde ◽

Jeroen Eikenboom ◽

Rolf Fronczek ◽

Margreet Kloppenburg ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Activity ◽

Lupus Erythematosus ◽

Neuropsychiatric Symptoms ◽

Anxiety And Depression ◽

Systemic Lupus ◽

Sf 36 ◽

Neuropsychiatric Sle ◽

Inflammatory Phenotype ◽

The Mean

Introduction We aimed to investigate risk factors for fatigue in patients with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms in order to identify potential interventional strategies. Methods Patients visiting the neuropsychiatric SLE (NPSLE) clinic of the Leiden University Medical Center between 2007–2019 were included. In a multidisciplinary consensus meeting, SLE patients were classified as having neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Fatigue was assessed with the SF-36 vitality domain (VT) since 2007 and the multidimensional fatigue inventory (MFI) and visual analogue scale (VAS) since 2011. Patients with a score on the SF-36 VT ≥1 standard deviation (SD) away from the mean of age-related controls of the general population were classified as fatigued; patients ≥2 SD away were classified as extremely fatigued. Disease activity was measured using the SLE disease activity index-2000. The influence of the presence of an inflammatory phenotype, disease activity and symptoms of depression and anxiety as measured by the hospital anxiety and depression scale (HADS) was analyzed using multiple regression analyses corrected for age, sex and education. Results 348 out of 371 eligible patients filled in questionnaires and were included in this study . The majority was female (87%) and the mean age was 43 ± 14 years. 72 patients (21%) had neuropsychiatric symptoms of an inflammatory origin. Fatigue was present in 78% of all patients and extreme fatigue was present in 50% of patients with an inflammatory phenotype vs 46% in the non-inflammatory phenotype. Fatigue was similar in patients with an inflammatory phenotype compared to patients with a non-inflammatory phenotype on the SF-36 VT (β: 0.8 (95% CI −4.8; 6.1) and there was less fatigue in patients with an inflammatory phenotype on the MFI and VAS (β: −3.7 (95% CI: −6.9; −0.5) and β: −1.0 (95% CI −1.6; −0.3)). There was no association between disease activity and fatigue, but symptoms of anxiety and depression (HADS) associated strongly with all fatigue measurements. Conclusion This study suggests that intervention strategies to target fatigue in (NP)SLE patients may need to focus on symptoms of anxiety and depression rather than immunosuppressive treatment.

Download Full-text

Association between alterations in plasma metabolome profiles and laminitis in intensively finished Holstein bulls in a randomized controlled study

Scientific Reports ◽

10.1038/s41598-021-92163-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sonja Christiane Bäßler ◽

Ákos Kenéz ◽

Theresa Scheu ◽

Christian Koch ◽

Ulrich Meyer ◽

...

Keyword(s):

Amino Acids ◽

Aromatic Amino Acids ◽

High Energy ◽

Metabolizable Energy ◽

Protein Diet ◽

Controlled Study ◽

Randomized Controlled ◽

Inflammatory Phenotype ◽

Dietary Nutrient ◽

Holstein Bulls

AbstractMetabolic consequences of an energy and protein rich diet can compromise metabolic health of cattle by promoting a pro-inflammatory phenotype. Laminitis is a common clinical sign, but affected metabolic pathways, underlying pathophysiology and causative relationships of a systemic pro-inflammatory phenotype are unclear. Therefore, the aim of this study was to elucidate changes in metabolome profiles of 20 months old Holstein bulls fed a high energy and protein diet and to identify novel metabolites and affected pathways, associated with diet-related laminitis. In a randomized controlled feeding trial using bulls fed a high energy and protein diet (HEP; metabolizable energy [ME] intake 169.0 ± 1.4 MJ/day; crude protein [CP] intake 2.3 ± 0.02 kg/day; calculated means ± SEM; n = 15) versus a low energy and protein diet (LEP; ME intake 92.9 ± 1.3 MJ/day; CP intake 1.0 ± 0.01 kg/day; n = 15), wide ranging effects of HEP diet on metabolism were demonstrated with a targeted metabolomics approach using the AbsoluteIDQ p180 kit (Biocrates Life Sciences). Multivariate statistics revealed that lower concentrations of phosphatidylcholines and sphingomyelins and higher concentrations of lyso-phosphatidylcholines, branched chain amino acids and aromatic amino acids were associated with an inflammatory state of diet-related laminitis in Holstein bulls fed a HEP diet. The latter two metabolites share similarities with changes in metabolism of obese humans, indicating a conserved pathophysiological role. The observed alterations in the metabolome provide further explanation on the underlying metabolic consequences of excessive dietary nutrient intake.

Download Full-text

The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation

International Journal of Molecular Sciences ◽

10.3390/ijms22094960 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4960

Author(s):

Natalia Guillén Díaz-Maroto ◽

Gemma Garcia-Vicién ◽

Giovanna Polcaro ◽

María Bañuls ◽

Nerea Albert ◽

...

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Cell Types ◽

Colorectal Tumor ◽

Cytotoxic Drugs ◽

Differential Sensitivity ◽

Paracrine Signaling ◽

Inflammatory Phenotype ◽

Heterotypic Interactions ◽

Carcinoma Associated Fibroblasts

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

Download Full-text

Evaluation of the role of CD47 in sickle cell disease

Journal of Hematopathology ◽

10.1007/s12308-020-00433-5 ◽

2021 ◽

Author(s):

Basmah Eldakhakhny ◽

Hadeel Al Sadoun ◽

Nehal Bin Taleb ◽

Dunya Ahmed Nori ◽

Nawal Helmi ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Annexin V ◽

Cell Disease ◽

Phagocytic Cells ◽

Surface Marker Expression ◽

Inflammatory Phenotype ◽

Healthy Control ◽

Cell Surface Marker Expression ◽

Pro Inflammatory Cytokines

AbstractCD47 is a self-marker expressed on the surface of RBCs and work to prevent the process of phagocytosis. SIRPα is the ligand of CD47 that is expressed on the surface of phagocytic cells, such as macrophages, to control the removal of dead/diseased cells. This study aimed to examine the expression of CD47 on RBCs and SIRPα on PBMC cells in SCD patients and the apoptosis of SCD RBCs. We also measured the levels of pro-inflammatory cytokines in SCD patients and correlated it with the cell surface marker expression of CD47 and SIRPα to determine whether CD47 and/or SIRPα played a role in promoting the pro-inflammatory phenotype in SCD. Whole blood samples were drawn from SCD patients, and healthy control and PBMC were isolated and stained with SIRPα. Change in CD47, apoptosis by annexin V marker, and pro-inflammatory cytokines were measured and correlation among these variants was determined. The expression of CD47 was significantly decreased and the apoptosis was increased in RBCs of SCD patients. A higher level of pro-inflammatory cytokines, IL-6 and IL-1β, was found in SCD patients and IL-1β was found to be inversely correlated with SIRPα expression. Our data showed that CD47 of erythrocytes of SCD samples is reduced and that the apoptosis is increased in those patients. Based on the role of CD47, we suggest that increased apoptosis in SCD would be impacted by the reduced level of CD47. An inverse relationship was found between SIRPα marker on PBMC and the increased production of pro-inflammatory cytokines in SCD.

Download Full-text

Microvesicles carrying LRP5 induce macrophage polarization to an anti‐inflammatory phenotype

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16723 ◽

2021 ◽

Author(s):

Aureli Luquero ◽

Gemma Vilahur ◽

Javier Crespo ◽

Lina Badimon ◽

Maria Borrell‐Pages

Keyword(s):

Macrophage Polarization ◽

Inflammatory Phenotype ◽

Anti Inflammatory

Download Full-text

Anti-Inflammatory and Immunomodulatory Effects of the Grifola frondosa Natural Compound o-Orsellinaldehyde on LPS-Challenged Murine Primary Glial Cells. Roles of NF-κβ and MAPK

Pharmaceutics ◽

10.3390/pharmaceutics13060806 ◽

2021 ◽

Vol 13 (6) ◽

pp. 806

Author(s):

Sarah Tomas-Hernandez ◽

Jordi Blanco ◽

Santiago Garcia-Vallvé ◽

Gerard Pujadas ◽

María José Ojeda-Montes ◽

...

Keyword(s):

Natural Compound ◽

Underlying Disease ◽

Grifola Frondosa ◽

Beneficial Effects ◽

Inflammatory Conditions ◽

Inflammatory Mechanism ◽

Inflammatory Phenotype ◽

Mice Brain ◽

Anti Inflammatory

In response to foreign or endogenous stimuli, both microglia and astrocytes adopt an activated phenotype that promotes the release of pro-inflammatory mediators. This inflammatory mechanism, known as neuroinflammation, is essential in the defense against foreign invasion and in normal tissue repair; nevertheless, when constantly activated, this process can become detrimental through the release of neurotoxic factors that amplify underlying disease. In consequence, this study presents the anti-inflammatory and immunomodulatory properties of o-orsellinaldehyde, a natural compound found by an in silico approach in the Grifola frondosa mushroom, in astrocytes and microglia cells. For this purpose, primary microglia and astrocytes were isolated from mice brain and cultured in vitro. Subsequently, cells were exposed to LPS in the absence or presence of increasing concentrations of this natural compound. Specifically, the results shown that o-orsellinaldehyde strongly inhibits the LPS-induced inflammatory response in astrocytes and microglia by decreasing nitrite formation and downregulating iNOS and HO-1 expression. Furthermore, in microglia cells o-orsellinaldehyde inhibits NF-κB activation; and potently counteracts LPS-mediated p38 kinase and JNK phosphorylation (MAPK). In this regard, o-orsellinaldehyde treatment also induces a significant cell immunomodulation by repolarizing microglia toward the M2 anti-inflammatory phenotype. Altogether, these results could partially explain the reported beneficial effects of G. frondosa extracts on inflammatory conditions.

Download Full-text

Short-chain fatty acids contribute to neuropathic pain via regulating microglia activation and polarization

Molecular Pain ◽

10.1177/1744806921996520 ◽

2021 ◽

Vol 17 ◽

pp. 174480692199652

Author(s):

Feng Zhou ◽

Xian Wang ◽

Baoyu Han ◽

Xiaohui Tang ◽

Ru Liu ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Thermal Hyperalgesia ◽

Short Chain Fatty Acids ◽

Antibiotic Administration ◽

Tnf Α ◽

Microglia Polarization ◽

Inflammatory Phenotype ◽

Phenotype Markers ◽

Anti Inflammatory

Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.

Download Full-text

FRI0421 RATES OF PROGRESSION DIFFER BETWEEN STRUCTURAL PHENOTYPES OF KNEE OSTEOARTHRITIS: A SECONDARY ANALYSIS FROM THE FNIH COHORT

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.1802 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 808.1-809

Author(s):

F. Roemer ◽

J. Collins ◽

T. Neogi ◽

M. Crema ◽

A. Guermazi

Keyword(s):

Subchondral Bone ◽

Radiographic Progression ◽

Conditional Logistic Regression ◽

Secondary Analysis ◽

Sensitivity Analyses ◽

Case Group ◽

Composite Outcome ◽

Bone Phenotype ◽

Increased Risk ◽

Inflammatory Phenotype

Background:Imaging plays an important role in determining structural disease severity and potential suitability of patients recruited to disease-modifying osteoarthritis drug (DMOAD) trials. It has been suggested that there may be three main structural phenotypes in OA, i.e., inflammation, meniscus/cartilage and subchondral bone. These may progress differently and may represent distinct tissue targets for DMOAD approaches.Objectives:To stratify the Foundation for National Institutes of Health Osteoarthritis Biomarkers Consortium (FNIH) cohort, a well-defined subsample of the larger Osteoarthritis Initiative (OAI) study, into distinct structural phenotypes based on semiquantitative MRI assessment and to determine their risk for progression over 48 months.Methods:The FNIH was designed as a case-control study with knees showing either 1) radiographic and pain progression (i.e., “composite” cases), 2) radiographic progression only (“JSL”), 3) pain progression only, and 4) neither radiographic nor pain progression. MRI of both knees was performed on 3 T systems at the four OAI clinical sites. Two musculoskeletal radiologists read the baseline MRIs according to the MOAKS scoring system. Knees were stratified into subchondral bone, meniscus/cartilage and inflammatory phenotypes1. A secondary, less stringent definition for inflammatory and meniscus/cartilage phenotype was used for sensitivity analyses. The relation of each phenotype to risk of being in the JSL or composite case group compared to those not having that phenotype was determined using conditional logistic regression. Only KL2 and 3 and those without root tears were included.Results:485 knees were included. 362 (75%) did not have any phenotype, while 95 (20%) had the bone phenotype, 22 (5%) the cartilage/meniscus phenotype and 19 (4%) the inflammatory phenotype. The bone phenotype was associated with a higher risk of the JSL and composite outcome (OR 1.81;[95%CI 1.14,2.85] and 1.65; 95%CI [1.04,2.61]) while the inflammatory (OR 0.96 [95%CI 0.38,2.42] and 1.25; 95%CI [0.48,3.25]) and the meniscus/cartilage phenotypes were not (OR 1.30 95%CI [0.55,3.07] and 0.99; 95%CI [0.40,2,49]).In sensitivity analyses, the bone phenotype and having two phenotypes (vs. none) were both associated with increased risk of experiencing the composite outcome (bone: OR 1.65; 95% CI 1.04, 2.61; 2 phenotypes: OR 1.87; 95% CI 1.11, 3.16.Conclusion:The bone phenotype was associated with increased risk of having both radiographic and pain progression together, or radiographic progression alone, whereas the inflammatory phenotype or meniscus/cartilage phenotype each individually were not associated with either outcome. Phenotypic stratification appears to provide insights into risk for structural or composite structure plus pain progression, and therefore may be useful to consider when selecting patients for inclusion in clinical trials.References:[1]Roemer FW, Collins J, Kwoh CK, et al. MRI-based screening for structural definition of eligibility in clinical DMOAD trials: Rapid OsteoArthritis MRI Eligibility Score (ROAMES). Osteoarthritis Cartilage 2020;28(1):71-81Disclosure of Interests:Frank Roemer: None declared, Jamie Collins Consultant of: Boston Imaging Core Lab (BICL), LLC., Tuhina Neogi Grant/research support from: Pfizer/Lilly, Consultant of: Pfizer/Lilly, EMD-Merck Serono, Novartis, Michel Crema: None declared, Ali Guermazi Consultant of: AventisGalapagos, Pfizer, Roche, AstraZeneca, Merck Serono, and TissuGene

Download Full-text

Serum C-reactive protein metabolite (CRPM) is associated with incidence of contralateral knee osteoarthritis

Scientific Reports ◽

10.1038/s41598-021-86064-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Anne-Christine Bay-Jensen ◽

Asger Bihlet ◽

Inger Byrjalsen ◽

Jeppe Ragnar Andersen ◽

Bente Juhl Riis ◽

...

Keyword(s):

Phase Iii ◽

Response To Treatment ◽

C Reactive Protein ◽

Two Phase ◽

Knee Oa ◽

Reactive Protein ◽

Inflammatory Phenotype ◽

The Mean ◽

Using Data

AbstractThe heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted in the field. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We investigated the level of blood CRPM in OA compared to RA using data from two phase III knee OA and two RA studies (N = 1591). Moreover, the association between CRPM levels and radiographic progression was investigated. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3–8.8] ng/mL, n = 781) compared to the RA patients (12.8 [9.5–16.0] ng/mL, n = 60); however, a significant subset of OA patients (31%) had CRPM levels (≥ 9 ng/mL) comparable to RA. Furthermore, OA patients (n = 152) with CRPM levels ≥ 9 ng/mL were more likely to develop contra-lateral knee OA assessed by X-ray over a two-year follow-up period with an odds ratio of 2.2 [1.0–4.7]. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.

Download Full-text