CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts

Umar, Sadiq; Palasiewicz, Karol; Raemdonck, Katrien Van; Volin, Michael V.; Romay, Bianca; Ahmad, Imran; Tetali, Chandana; Sweiss, Nadera J.; Amin, M. Asif; Zomorrodi, Ryan K; Shahrara, Shiva

doi:10.1002/eji.202048681

Cited by 16 publications

(19 citation statements)

References 53 publications

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“…Pro-inflammatory macrophages also secrete angiogenic factors such as VEGF or TGF-a/b to increase new blood vessel formation (101), as well as influencing fibroblasts to secrete RANKL, leading to bone erosion (99). In this context, macrophages may also be able to directly differentiate into mature osteoclasts given the correct environmental cues such as CCL25/CCR9 to further increase bone erosion (102,103). This concept is supported by the identification of an osteoclastogenic macrophage subset in the synovial tissue of mice with collageninduced arthritis (104).…”

Section: Macrophage Subsets In Rheumatoid Arthritismentioning

confidence: 99%

Macrophages: The Good, the Bad, and the Gluttony

2021

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Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.

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Section: Macrophage Subsets In Rheumatoid Arthritismentioning

confidence: 99%

Macrophages: The Good, the Bad, and the Gluttony

2021

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“…In the joint cavity, synovial macrophages from the circulation can be used as osteoclasts precursors, but there is no evidence that resident synovial macrophages can differentiate into osteoclasts (161). Generally speaking, in the joint inflammation environment of RA, circulating monocytes will continue to transfer to the joint cavity and differentiate into osteoclasts to promote joint inflammation (161,162). Evidence showed that the monocytes that can differentiate into osteoclasts are CD14 positive but CD16 negative.…”

Section: The Macrophage-osteoclast Axis In Rheumatoid Arthritismentioning

confidence: 99%

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

et al. 2021

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Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role. Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment. Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity. Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases. In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts. Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases. These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments. And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.

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“…Additionally, GSH-Px can relieve inflammation-induced osteolytic bone destruction by breaking down LPS ( Islam et al, 2007 ; Li et al, 2020 ). Upregulating GSH-PX activity can inhibit pro-inflammatory factors associated with osteoclast maturation genes, such as iNOS, IL-1β, and tumor necrosis factor-alpha (TNF-α) ( Kruger et al, 2010 ; He et al, 2020 ; Li et al, 2020 ; Umar et al, 2021 ). GSH-Px may be the key link in the oxidative stress-inflammation reaction in postmenopausal osteoporosis with great potential research value.…”

Section: Antioxidant Enzymesmentioning

confidence: 99%

Three Classes of Antioxidant Defense Systems and the Development of Postmenopausal Osteoporosis

et al. 2022

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Osteoporosis is a common bone imbalance disease that threatens the health of postmenopausal women. Estrogen deficiency accelerates the aging of women. Oxidative stress damage is regarded as the main pathogenesis of postmenopausal osteoporosis. The accumulation of reactive oxygen species in the bone microenvironment plays a role in osteoblast and osteoclast apoptosis. Improving the oxidative state is essential for the prevention and treatment of postmenopausal osteoporosis. There are three classes of antioxidant defense systems in the body to eliminate free radicals and peroxides including antioxidant substances, antioxidant enzymes, and repair enzymes. In our review, we demonstrated the mechanism of antioxidants and their effect on bone metabolism in detail. We concluded that glutathione/oxidized glutathione (GSH/GSSG) conversion involved the PI3K/Akt-Nrf2/HO-1 signaling pathway and that the antioxidant enzyme-mediated mitochondrial apoptosis pathway of osteoblasts was necessary for the development of postmenopausal osteoporosis. Since the current therapeutic effects of targeting bone cells are not significant, improving the systemic peroxidation state and then regulating bone homeostasis will be a new method for the treatment of postmenopausal osteoporosis.

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CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts

Cited by 16 publications

References 53 publications

Macrophages: The Good, the Bad, and the Gluttony

Macrophages: The Good, the Bad, and the Gluttony

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases

Three Classes of Antioxidant Defense Systems and the Development of Postmenopausal Osteoporosis

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