Synovial macrophages in cartilage destruction and regeneration – lessons learnt from osteoarthritis and synovial chondromatosis

2021 ◽  
Author(s):  
Yingjie Li ◽  
Yinghong Zhou ◽  
Yifan Wang ◽  
Ross Crawford ◽  
Yin Xiao
Keyword(s):  
Chondrogenic Differentiation ◽  
Macrophage Polarization ◽  
Synovial Chondromatosis ◽  
Cartilage Destruction ◽  
Macrophage Phenotype ◽  
Immune Effector ◽  
Effector Cells ◽  
Innate Immune Effector ◽  
And Function ◽  
Physical And Chemical

Abstract Inflammation is a critical process in disease pathogenesis and the restoration of tissue structure and function, for example, in joints such as the knee and temporomandibular. Within the innate immunity process, the body’s first defense response in joints when physical and chemical barriers are breached is the synovial macrophages, the main innate immune effector cells, which are responsible for triggering the initial inflammatory reaction. Macrophage is broadly divided into three phenotypes of resting M0, pro-inflammatory M1-like (referred to below as M1), and anti-inflammatory M2-like (referred to below as M2). The synovial macrophage M1-to-M2 transition can affect the chondrogenic differentiation of mesenchymal stem cells (MSCs) in joints. On the other hand, MSCs can also influence the transition between M1 and M2. Failure of the chondrogenic differentiation of MSCs can result in persistent cartilage destruction leading to osteoarthritis (OA). However, excessive chondrogenic differentiation of MSCs may cause distorted cartilage formation in the synovium, which is evidenced in the case of synovial chondromatosis (SC). This review summarizes the role of macrophage polarization in the process of both cartilage destruction and regeneration, and postulates that the transition of macrophage phenotype in an inflammatory joint environment may play a key role in determining the fate of joint cartilage.

scholarly journals Effects of Eltrombopag on In Vitro Macrophage Polarization in Pediatric Immune Thrombocytopenia

2020 ◽  
Vol 22 (1) ◽  
pp. 97
Author(s):  
Alessandra Di Paola ◽  
Giuseppe Palumbo ◽  
Pietro Merli ◽  
Maura Argenziano ◽  
Chiara Tortora ◽  
...  
Keyword(s):  
Immune Thrombocytopenia ◽  
Macrophage Polarization ◽  
Macrophage Phenotype ◽  
Activated Macrophages ◽  
T Helper ◽  
T Helper 1 ◽  
Alternatively Activated Macrophages ◽  
Effector Cells ◽  
Anti Inflammatory

Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibodies-mediated platelet destruction, a prevalence of M1 pro-inflammatory macrophage phenotype and an elevated T helper 1 and T helper 2 lymphocytes (Th1/Th2) ratio, resulting in impairment of inflammatory profile and immune response. Macrophages are immune cells, present as pro-inflammatory classically activated macrophages (M1) or as anti-inflammatory alternatively activated macrophages (M2). They have a key role in ITP, acting both as effector cells, phagocytizing platelets, and, as antigen presenting cells, stimulating auto-antibodies against platelets production. Eltrombopag (ELT) is a thrombopoietin receptor agonist licensed for chronic ITP to stimulate platelet production. Moreover, it improves T and B regulatory cells functions, suppresses T-cells activity, and inhibits monocytes activation. We analyzed the effect of ELT on macrophage phenotype polarization, proposing a new possible mechanism of action. We suggest it as a mediator of macrophage phenotype switch from the M1 pro-inflammatory type to the M2 anti-inflammatory one in paediatric patients with ITP, in order to reduce inflammatory state and restore the immune system function. Our results provide new insights into the therapy and the management of ITP, suggesting ELT also as immune-modulating drug.

scholarly journals 671 Biological impacts of standard of care chemotherapies on immune effector cells from AML patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A699-A699
Author(s):  
Dmitry Zhigarev ◽  
Alexander MacFarlane ◽  
Christina Drenberg ◽  
Reza Nejati ◽  
Asya Varshavsky ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Phenotype ◽  
Second Line ◽  
Color Flow ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
And Function

BackgroundAcute myeloid leukemia (AML) is a heterogeneous group of malignant bone marrow diseases, characterized by massive and uncontrolled proliferation of myeloid precursor cells, which alters normal blood cell ratios. This disease is common to older adults and collectively displays one of the lowest 5-year overall survival rates (<25%) among all cancers, currently representing the deadliest form of leukemia. Improved treatments are clearly needed, and immunotherapies are attractive candidate therapies to explore.There are currently several standard chemotherapeutic treatment schemes for AML, which could be divided into two major groups: (1) cytotoxic chemotherapy (“7+3” or daunorubicin-cytarabine) and (2) hypomethylating agents (HMAs). HMAs include both 5-azacytidine and decitabine, which are cytidine analogs that inhibit DNA methyltransferase, resulting in the hypomethylation of DNA and inducing expression of silenced gene loci. Currently, HMAs are routinely delivered in combination with the Bcl-2 inhibitor venetoclax.The goals of this study are to determine how these standard first line therapies can affect the frequency and functional integrity of effector immune cells in patients' blood and establish when the phenotype and function of immune cells are restored to identify time windows when second line immunotherapies could be most effective.MethodsMore than 100 blood samples were obtained from 33 previously untreated AML patients. More than 50 measurable biomarkers were analyzed using 14-color flow cytometry to assess immune phenotypes of T and NK cells in peripheral blood of AML patients prior to treatment and at up to four timepoints after initiation of treatment with HMA or chemotherapy.ResultsWe found several significant changes in immune cell phenotype and function that occur in response to these therapies. Treatment with HMAs was strikingly less impactful on immune cells in patients compared to previously published in vitro studies. Nevertheless, HMA treatment increased perforin levels in T and NK cells, inhibited IFN-gamma secretion by CD8+ T cells, and changed expression of several checkpoint molecules. While chemotherapy caused fewer phenotypic changes it dramatically decreased the total number of immune cells. We also determined viable, functional and phenotypical recovery periods for immune effector cells after the treatments.ConclusionsOur results are important for introducing new second line immunotherapies to these chemotherapeutic regimens for treating AML and to improve overall understanding of immune cell behavior under conditions of anti-tumor treatment.AcknowledgementsSupported by grants from Janssen and the U.S./Israel Binational Science Foundation.Ethics ApprovalThe study was approved by the Fox Chase Cancer Center Institutional Review Board, approval number 17-8010, and all patients provided informed consent before taking part in the study.

scholarly journals There Is Strength in Numbers: Quantitation of Fc Gamma Receptors on Murine Tissue-Resident Macrophages

2021 ◽  
Vol 22 (22) ◽  
pp. 12172
Author(s):  
Christof Vorsatz ◽  
Niklas Friedrich ◽  
Falk Nimmerjahn ◽  
Markus Biburger
Keyword(s):  
Immune Complexes ◽  
Expression Patterns ◽  
Fcγ Receptors ◽  
Immune Effector ◽  
Effector Cells ◽  
Effector Functions ◽  
Immune Effector Cells ◽  
Innate Immune Effector ◽  
Murine Liver ◽  
Murine Tissue

Many of the effector functions of antibodies rely on the binding of antibodies/immune complexes to cellular Fcγ receptors (FcγRs). Since the majority of innate immune effector cells express both activating and inhibitory Fc receptors, the outcome of the binding of immune complexes to cells of a given population is influenced by the relative affinities of the respective IgG subclasses to these receptors, as well as by the numbers of activating and inhibitory FcγRs on the cell surface. A group of immune cells that has come into focus more recently is the various subsets of tissue-resident macrophages. The central functions of FcγRs on tissue macrophages include the clearance of opsonized pathogens, the removal of small immune complexes from the circulation and the depletion of antibody-opsonized cells in the therapy of autoimmunity and cancer. Despite these essential functions of FcγRs on tissue-resident macrophages, an in-depth quantification of FcγRs is lacking. Thus, the aim of our current study was to quantify the various Fcγ receptors on macrophages in murine liver, lung, kidney, brain, skin and spleen. Our study identified a pronounced heterogeneity between FcγR expression patterns of the different tissue macrophages, which may reflect their specialized functions within their unique niches in different organ environments.

scholarly journals The right microbial stimulus can direct innate immune effector cells to specific organ sites to clear pathology

2019 ◽  
Author(s):  
Shirin Kalyan ◽  
Mark Bazett ◽  
Ho Pan Sham ◽  
Momir Bosiljcic ◽  
Beryl Luk ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune ◽  
Immune Memory ◽  
Immune Effector ◽  
Effector Cells ◽  
Adaptive Immune ◽  
Immune Effector Cells ◽  
Innate Immune Effector ◽  
Organ Site ◽  
Tissue Site

ABSTRACTRecent developments in understanding how the functional phenotype of the innate immune system is programmed has led to paradigm-shifting views on immunomodulation. These advances have overturned two long-held dogmas: only adaptive immunity confers immunological memory and innate immunity lacks specificity. This work describes the novel observation that innate immune effector cells can be recruited to specific tissues of the body where pathology is present by using a microbial-based immune stimulus that consists of an inactivated pathogen that typically resides or causes infection in that target tissue site. We demonstrate this principle using experimental models of cancer and infection for which different subcutaneously delivered microbial-based treatments were shown to induce the recruitment of immune effector cells to specific diseased organs. Amelioration of disease in a given organ niche was dependent on matching the correct microbial stimulus for the affected organ site but was independent of the nature of the pathology. This observation intriguingly suggests that the immune system, upon pathogen recognition, tends to direct its resources to the compartment in which the pathogen has previously been encountered and would be the most likely source of infection. Importantly, this phenomenon provides a novel means to therapeutically target innate immune effector cells to sites of specific disease localization to potentially treat a wide spectrum of pathologies, including cancer, infection, and chronic inflammatory disorders.AUTHOR SUMMARYVaccines that target adaptive immune memory have revolutionized medicine. This study describes a novel strategy that works as a modified innate immune “vaccine” that exploits the trained response of innate immune effector cells to clear pathology in a specific tissue site. Unlike memory of the adaptive immune system, which functions like a lock and key, innate immune memory is more akin to a reflex response – like experienced muscle or neural cells that are changed by a stimulus to respond more efficiently upon re-exposure. This change in behavior through experience is the definition of learning. Our study suggests that this innate immune learning occurs at different levels. Emergency hematopoiesis trains new innate immune cells in the bone marrow to respond quickly and effectively to a non-specific threat; whereas, pathogen-specific training occurs at sites where cells making up the immunologic niche have had interactions with a particular pathogen and have been trained to respond more robustly to it upon re-presentation in the context of a danger signal. The speed with which new immune cells are trained in the bone marrow in response to an imminent microbial threat and their subsequent recruitment to the target organ site where that microbe typically resides suggests there are ways the immune system communicates to coordinate this rapid response that are yet to be fully delineated. These findings provide a novel highly proficient way to harness the potent effector functions of the innate immune system to address a wide range of immune-based diseases.

scholarly journals Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Shiming Ye ◽  
Melvin I. Fox ◽  
Nicole A. Belmar ◽  
Mien Sho ◽  
Debra T. Chao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Antitumor Activity ◽  
Tumor Cells ◽  
Tumor Xenograft ◽  
Immune Effector ◽  
Effector Cells ◽  
Innate Immune Effector ◽  
Receptor Monoclonal Antibody

Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

Role and function of macrophages in the metabolic syndrome

2012 ◽  
Vol 442 (2) ◽  
pp. 253-262 ◽  
Author(s):  
Prerna Bhargava ◽  
Chih-Hao Lee
Keyword(s):  
Metabolic Syndrome ◽  
Metabolic Diseases ◽  
Inflammatory Responses ◽  
Metabolic Stress ◽  
Innate Immune ◽  
Signalling Pathways ◽  
Immune Effector ◽  
Effector Cells ◽  
The Metabolic Syndrome ◽  
And Function

Macrophages are key innate immune effector cells best known for their role as professional phagocytes, which also include neutrophils and dendritic cells. Recent evidence indicates that macrophages are also key players in metabolic homoeostasis. Macrophages can be found in many tissues, where they respond to metabolic cues and produce pro- and/or anti-inflammatory mediators to modulate metabolite programmes. Certain metabolites, such as fatty acids, ceramides and cholesterol crystals, elicit inflammatory responses through pathogen-sensing signalling pathways, implicating a maladaptation of macrophages and the innate immune system to elevated metabolic stress associated with overnutrition in modern societies. The outcome of this maladaptation is a feedforward inflammatory response leading to a state of unresolved inflammation and a collection of metabolic pathologies, including insulin resistance, fatty liver, atherosclerosis and dyslipidaemia. The present review summarizes what is known about the contributions of macrophages to metabolic diseases and the signalling pathways that are involved in metabolic stress-induced macrophage activation. Understanding the role of macrophages in these processes will help us to develop therapies against detrimental effects of the metabolic syndrome.

Mechanobiology of Macrophages: How Physical Factors Coregulate Macrophage Plasticity and Phagocytosis

2019 ◽  
Vol 21 (1) ◽  
pp. 267-297 ◽  
Author(s):  
Nikhil Jain ◽  
Jens Moeller ◽  
Viola Vogel
Keyword(s):  
Inflammatory Diseases ◽  
Apoptotic Cell ◽  
Macrophage Polarization ◽  
New Drugs ◽  
Physical Factors ◽  
Macrophage Phenotype ◽  
Pathological Conditions ◽  
Macrophage Plasticity ◽  
And Function ◽  
Made In

In addition to their early-recognized functions in host defense and the clearance of apoptotic cell debris, macrophages play vital roles in tissue development, homeostasis, and repair. If misregulated, they steer the progression of many inflammatory diseases. Much progress has been made in understanding the mechanisms underlying macrophage signaling, transcriptomics, and proteomics, under physiological and pathological conditions. Yet, the detailed mechanisms that tune circulating monocytes/macrophages and tissue-resident macrophage polarization, differentiation, specification, and their functional plasticity remain elusive. We review how physical factors affect macrophage phenotype and function, including how they hunt for particles and pathogens, as well as the implications for phagocytosis, autophagy, and polarization from proinflammatory to prohealing phenotype. We further discuss how this knowledge can be harnessed in regenerative medicine and for the design of new drugs and immune-modulatory drug delivery systems, biomaterials, and tissue scaffolds.

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