Macrophages: The Good, the Bad, and the Gluttony (original) (raw)
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Rheumatology
Objectives Myeloid cells with a monocyte/macrophage phenotype are present in large numbers in the RA joint, significantly contributing to disease; however, distinct macrophage functions have yet to be elucidated. This study investigates the metabolic activity of infiltrating polarized macrophages and their impact on pro-inflammatory responses in RA. Methods CD14+ monocytes from RA and healthy control (HC) bloods were isolated and examined ex vivo or following differentiation into ‘M1/M2’ macrophages. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT-PCR, western blot, Seahorse XFe technology, phagocytosis assays and transmission electron microscopy along with RNA-sequencing (RNA-seq) transcriptomic analysis. Results Circulating RA monocytes are hyper-inflammatory upon stimulation, with significantly higher expression of key cytokines compared with HC (P < 0.05) a phenotype which is maintained upon differentiation into mature ex vivo polariz...
Macrophages in rheumatoid arthritis
Arthritis research, 2000
The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains an efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage.
Macrophages in Synovial Inflammation
Frontiers in Immunology, 2011
Synovial macrophages are one of the resident cell types in synovial tissue and while they remain relatively quiescent in the healthy joint, they become activated in the inflamed joint and, along with infiltrating monocytes/macrophages, regulate secretion of proinflammatory cytokines and enzymes involved in driving the inflammatory response and joint destruction. Synovial macrophages are positioned throughout the sub-lining layer and lining layer at the cartilage-pannus junction and mediate articular destruction. Sub-lining macrophages are now also considered as the most reliable biomarker for disease severity and response to therapy in rheumatoid arthritis (RA). There is a growing understanding of the molecular drivers of inflammation and an appreciation that the resolution of inflammation is an active process rather than a passive return to homeostasis, and this has implications for our understanding of the role of macrophages in inflammation. Macrophage phenotype determines the cytokine secretion profile and tissue destruction capabilities of these cells. Whereas inflammatory synovial macrophages have not yet been classified into one phenotype or another it is widely known that TNFα and ILl , characteristically released by M1 macrophages, are abundant in RA while IL-10 activity, characteristic of M2 macrophages, is somewhat diminished. Here we will briefly review our current understanding of macrophages and macrophage polarization in RA as well as the elements implicated in controlling polarization, such as cytokines and transcription factors like NFκB, IRFs and NR4A, and pro-resolving factors, such as LXA4 and other lipid mediators which may promote a non-inflammatory, pro-resolving phenotype, and may represent a novel therapeutic paradigm.
Chronic Active Arthritis Driven by Macrophages Without Involvement of T Cells
Arthritis & Rheumatology
Objective. To develop a new chronic rheumatoid arthritis model that is driven by the innate immune system. Methods. Injection of a cocktail of 4 monoclonal antibodies against type II collagen, followed on days 5 and 60 by intraperitoneal injections of mannan (from Saccharomyces cerevisiae), was used to induce development of chronic arthritis in B10.Q mice. The role of the innate immune system as compared to the adaptive immune system in this arthritis model was investigated using genetically modified mouse strains. Results. A new model of chronic relapsing arthritis was characterized in B10.Q mice, in which a persistently active, chronic disease was found. This relapsing disease was driven by macrophages lacking the ability to mount a reactive oxygen species response against pathogens, and was associated with the classical/alternative pathway, but not the lectin pathway, of complement activation. The disease was independent of Fcc receptor type III, and also independent of the activity of adaptive immune cells (B and T cells), indicating that the innate immune system, involving complement activation, could be the sole driver of chronicity. Conclusion. Chronic active arthritis can be driven innately by macrophages without the involvement of T and B cells in the adaptive immune system. Rheumatoid arthritis (RA) is a common autoimmune disease, present in~1% of the population. It causes joint pain and degradation, and, if left untreated, can lead to cardiovascular disease and other comorbidities that result in disability and decreased quality of life. RA is in part dependent on genetics; among the genes that are reported to contribute to the development of RA are the major histocompatibility complex (MHC) class II region, protein tyrosine phosphatase N22, and neutrophil cytosolic factor 1 (NCF-1) (1-3). NCF-1 has an essential role in the NADPH oxidase 2 (NOX-2) complex, which in turn has an important role in the defense against pathogens through the production of reactive oxygen species (ROS). Besides being important for the defense against infectious organisms, ROS are believed to modify signaling within and between cells. ROS could regulate inflammation by 1) acting as a synaptic transmitter, which down-regulates the
Nature Medicine, 2020
Treatment-refractory rheumatoid arthritis (RA) is a major clinical challenge. Drug-free remission is uncommon but provides proof-of-concept that articular immune-homeostasis can be reinstated. Here we identify active cellular and molecular mechanisms of sustained remission in RA. Single-cell transcriptomics (32,000 cells) identified phenotypic changes in synovial tissue macrophages (STM) spanning health, early/active RA, treatment-refractory/active RA, and RA in sustained remission. Each clinical state is characterised by different frequencies of 9 discrete phenotypes of 4 distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas combined with deep-phenotypic, spatial and functional analyses of synovial biopsy FACSsorted STMs revealed two STM subpopulations (MerTK/TREM2 high and MerTK/FOLR2/LYVE1 pos) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. In response to damage signals these cells are potent producers of inflammation-resolving lipid mediators and are the only STMs that induce the repair response of synovial fibroblasts. A low proportion of MerTK pos STMs in remission RA is a prognostic biomarker predictive of flare after treatment cessation. Therapeutic enhancement of MerTK pos STM-subsets could encourage resolution of inflammation and reinstate synovial homeostasis in inflammatory arthritis.
Increased macrophage activation mediated through toll-like receptors in rheumatoid arthritis
Arthritis & Rheumatism, 2007
Objective. Macrophages are the major source of inflammation mediators that are important in the pathogenesis of rheumatoid arthritis (RA). This study was undertaken to analyze macrophages obtained from the joints of RA patients in order to characterize the expression of Toll-like receptor 2 (TLR-2) and TLR-4 and the responses to TLR ligation. Methods. Cells were isolated from the synovial fluid (SF) of RA patients or patients with other forms of inflammatory arthritis. Cell surface TLR-2 and TLR-4 expression and intracellular tumor necrosis factor ␣ (TNF␣) and interleukin-8 (IL-8) expression by CD14؉ macrophages were determined by flow cytometry. Peptidoglycan (PG) and lipopolysaccharide (LPS) were used as ligands for TLR-2 and TLR-4, respectively. Results. The expression of TLR-2 and TLR-4 was increased on CD14؉ macrophages from the joints of RA patients compared with that on control in vitrodifferentiated macrophages or control peripheral blood monocytes. Neither TLR-2 expression nor TLR-4 expression differed between RA and other forms of inflammatory arthritis. However, PG-and LPS-induced TNF␣ expression and IL-8 expression were greater with RA SF macrophages than with those obtained from the joints of patients with other forms of inflammatory arthritis or with control macrophages. PG-induced TNF␣ expression and IL-8 expression were highly correlated with TLR-2 expression in normal macrophages, but not with that in macrophages obtained from joints of RA patients or patients with other forms of inflammatory arthritis. Conclusion. TLR-2 and TLR-4 ligation resulted in increased activation of RA synovial macrophages compared with those from patients with other forms of inflammatory arthritis or compared with control macrophages. Factors other than the level of TLR-2 and TLR-4 expression contributed to the increased activation of RA SF macrophages. These observations support the notion of a potential role for activation through TLR-2 and TLR-4 in the inflammation and joint destruction of RA.
Rheumatology (Oxford, England), 2001
To document the change in synovial membrane macrophage and T-lymphocyte content in rheumatoid arthritis (RA) patients who achieve remission induced by disease-modifying anti-rheumatic drugs (DMARDs). Arthroscopic synovial biopsies were taken from four to seven sites around a knee joint in 13 patients with RA before and at regular intervals after commencing treatment with a DMARD. The cellular content of synovial membrane biopsies taken at regular intervals for a period of up to 3 yr after commencing treatment was quantitated by routine histopathology and immunohistochemical labelling with anti-macrophage (CD68) and anti-T lymphocyte (UCHL-1) antibodies. Synovial biopsies were quantitated with a validated semiquantitative scoring system and video image analysis. Nine patients obtained clinical remission, as defined by American College of Rheumatology (ACR) criteria. The changes that occurred in the synovial biopsies included a reduction in lining layer thickness, reduced vascularity ...
eLife, 2020
The resistance of synovial sublining macrophages to apoptosis has a crucial role in joint inflammation and destruction in rheumatoid arthritis (RA). However, the underlying mechanism is incompletely understood. Here we report that inactivation of the pro-apoptotic BCL-2 family protein BAD is essential for survival of synovial sublining macrophage in RA. Genetic disruption of Bad leads to more severe joint inflammation and cartilage and bone damage with reduced apoptosis of synovial sublining macrophages in collagen-induced arthritis (CIA) and TNFα transgenic (TNF-Tg) mouse models. Conversely, Bad3SA/3SA mice, in which BAD can no longer be inactivated by phosphorylation, are protected from collagen-induced arthritis. Mechanistically, phosphorylation-mediated inactivation of BAD specifically protects synovial sublining macrophages from apoptosis in highly inflammatory environment of arthritic joints in CIA and TNF-Tg mice, and in patients with RA, thereby contributing to RA pathology....
Identification of distinct polarized macrophage subsets in inflammatory arthritis
Journal of Translational Medicine, 2010
EHJG Aarntzen, W J Lesterhuis, M Van Rossum, GJ Adema, CF Figdor, CJA Punt and IJM De Vries clinical phenotypes of systemic sclerosis through a genome wide association strategy O2 Linking genotype to cell function in chronic inflammation: analysis of the IL-23/Th17 axis in spondylarthropathy M Roumier, M Coffre, H Law, C Salliot, M Dougados, E Bianchi and L Rogge O3 Cytosolic phospholipase A2α gene silencing in monocytes alters development of Th1 responses and reduces autoimmune arthritis G Courties, J Presumey, M Baron, V Escriou, P Van Lent, D Scherman, A Cantagrel, W Van den Berg, C Jorgensen, J-L Davignon and F Apparailly O4 RANKL expression in human T-lymphocytes requires cooperative signaling through the T-cell receptor and adhesion molecule CD2 BP Harvey and Z Kaymakcalan O5 Single-cell analysis techniques reveal a striking heterogeneity of human CD4 + T cell subsets M Coffre, K Placek, S Maiella, E Bianchi and L Rogge O6 Sustained T cell Rap1 activation protects against Experimental Autoimmune Encephalomyelitis (EAE) via modulation of T cell responses G Franco Salinas, S Krausz, W Dontje, PP Tak, D Baeten and K Reedquist O7 Skewed X-chromosomal inactivation impacts T regulatory cell function in systemic sclerosis JCA Broen, ILM Wolvers-Tettero, L Geurts-van Bon, MC Vonk, MJH Coenen, R Lafyatis, TRDJ Radstake and AW Langerak O8 Fra-1 regulates inflammatory and degenerative arthritis T Kireva, K Zwerina, W Baum, S Hayer, G Schett and J Zwerina POSTER PRESENTATIONS (P1-P73) P1 The neonatal Fc receptor is expressed by human lymphocytes K van Bilsen, J Bastiaans, WA Dik, EF De Haas, SG Baarsma, RW Kuipers, PM van Hagen P2 Differential association of two PTPN22 coding variants with Crohn's disease and ulcerative colitis LM Diaz-Gallo P3 Single-cell gene profiling analysis of human regulatory T cell subsets P9 Lack of adalimumab's complement dependent cytotoxicity on human cells expressing complement regulatory proteins KM Grebe, J Salfeld, Z Kaymakcalan P10 Efficacy of adalimumab in sarcoidosis LSJ Kamphuis, WK Lam-Tse, WA Dik, J Bastiaans, P van Biezen, PLA van Daele, DJ Kwekkeboom, RWAM Kuijpers, GS Baarsma, PM van Hagen, H Hooijkaas, JAM van Laar P11 Differences in virus prevalence and load in the hearts of patients with chronic dilated cardiomyopathy with and without immune-mediated inflammatory disease R Dennert, P van Paassen, C Bruggeman, P Wolffs, JW Cohen Tervaert, S Heymans P12 Inflammatory T-lymphocyte proliferation in morbid obesity K Van der Weerd, PM van Hagen, WA Dik, BS Schrijver, DH Schweitzer, AW Langerak, RM Kiewiet, MO Van Aken, JJM Van Dongen, AJ Van der Lelij, FJT Staal P13 Elevated soluble Flt1 mediates an anti-angiogenic state in patients with ANCA-associated vasculitis S Le Roux, R Pepper, A Dufay, M Néel, N Lamandé, M Rimbert,
International Journal of Molecular Sciences
Chronic inflammation is implicated in numerous human pathologies. In particular, low-grade inflammation is currently recognized as an important mechanism of osteoarthritis (OA), at least in some patients. Among the signs of the inflammatory process are elevated macrophage numbers detected in the OA synovium compared to healthy controls. High macrophage counts also correlate with clinical symptoms of the disease. Macrophages are central players in the development of chronic inflammation, pain, cartilage destruction, and bone remodeling. However, macrophages are also involved in tissue repair and remodeling, including cartilage. Therefore, reduction of macrophage content in the joints correlates with deleterious effects in OA models. Macrophage population is heterogeneous and dynamic, with phenotype transitions being induced by a variety of stimuli. In order to effectively use the macrophage inflammatory circuit for treatment of OA, it is important to understand macrophage heterogenei...