Locally renewing resident synovial macrophages provide a protective barrier for the joint

Culemann, Stephan; Grüneboom, Anika; Nicolás-Ávila, José Ángel; Weidner, Daniela; Lämmle, Katrin F.; Rothe, Tobias; Quintana, Juan A.; Kirchner, Philipp; Krljanac, Branislav; Eberhardt, Martin; Ferrazzi, Fulvia; Kretzschmar, Elke; Schicht, Martin; Fischer, Kim; Gelse, Kolja; Faas, Maria M.; Pfeifle, R.; Ackermann, Jochen A.; Pachowsky, Milena; Renner, Nina; Simón, David; Haseloff, Reiner F.; Ekici, Arif B.; Bäuerle, Tobias; Blasig, Ingolf E.; Vera, Julio; Voehringer, David; Kleyer, Arnd; Paulsen, Friedrich; Schett, Georg; Hidalgo, Andrés; Krönke, Gerhard

doi:10.1038/s41586-019-1471-1

Cited by 415 publications

(493 citation statements)

References 36 publications

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“…MCP‐1 expression by synovial macrophages varies according to the expression of several of the cytokines investigated in our study (IL‐1β, IL‐6, IL‐4, IL‐10) . Following tissue injury, MCP‐1 contributes to the recruitment and accumulation of mononuclear cells in the synovial fluid and membrane, a process required to recover homeostasis . As such, MCP‐1 deficient mice cannot home macrophages to sites of injury and are prone to infection and chronic inflammation .…”

Section: Discussionmentioning

confidence: 85%

“…As such, MCP‐1 deficient mice cannot home macrophages to sites of injury and are prone to infection and chronic inflammation . IL‐4 and CSF‐1 can induce macrophage proliferation and are, therefore, key signaling components in regulating inflammation and its resolution …”

Section: Discussionmentioning

confidence: 99%

“…23 Following tissue injury, MCP-1 contributes to the recruitment and accumulation of mononuclear cells in the synovial fluid and membrane, 23 a process required to recover homeostasis. 12,14 As such, MCP-1 deficient mice cannot home macrophages to sites of injury and are prone to infection and chronic inflammation. 23,110 IL-4 and CSF-1 can induce macrophage proliferation and are, therefore, key signaling components in regulating inflammation and its resolution.…”

Section: Discussionmentioning

confidence: 99%

“…Under physiological conditions, macrophages are vital regulators of articular integrity, promoting joint health through the secretion of synovial fluid cytokines and growth factors essential for joint homeostasis, as well as the clearance of tissue debris, foreign material, and efferocytosis . Synovial macrophages also form a protective immunological barrier in the synovial lining, providing a tight‐junction‐mediated shield for intra‐articular structures . When these physiological functions become overwhelmed, synovial macrophages upregulate inflammation, recruiting lymphocytes, and neutrophils in response to increased demands for repair .…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Synovial macrophages also form a protective immunological barrier in the synovial lining, providing a tight-junction-mediated shield for intra-articular structures. 12 When these physiological functions become overwhelmed, synovial macrophages upregulate inflammation, recruiting lymphocytes, and neutrophils in response to increased demands for repair. 7,13,14 Sustained joint damage impedes the resolution of the inflammatory response and related cytokines and catabolic enzymes lead to joint degeneration.…”

Section: Introductionmentioning

confidence: 99%

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Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy

et al. 2020

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Synovial inflammation is a central feature of osteoarthritis (OA), elicited when local regulatory macrophages (M2‐like) become overwhelmed, activating an inflammatory response (M1‐like). Bone marrow mononuclear cells (BMNC) are a source of naïve macrophages capable of reducing joint inflammation and producing molecules essential for cartilage metabolism. This study investigated the response of BMNC to normal (SF) and inflamed synovial fluid (ISF). Equine BMNC cultured in autologous SF or ISF (n = 8 horses) developed into macrophage‐rich cultures with phenotypes similar to cells native to normal SF and became more confluent in ISF (~100%) than SF (~25%). BMNC cultured in SF or ISF were neither M1‐ nor M2‐like, but exhibited aspects of both phenotypes and a regulatory immune response, characterized by increasing counts of IL‐10+ macrophages, decreasing IL‐1β concentrations and progressively increasing IL‐10 and IGF‐1 concentrations. Changes were more marked in ISF and suggest that homeostatic mechanisms were preserved over time and were potentially favored by progressive cell proliferation. Collectively, our data suggest that intra‐articular BMNC could increase synovial macrophage counts, potentiating the macrophage‐ and IL‐10‐associated mechanisms of joint homeostasis lost during the progression of OA, preserving the production of cytokines involved in tissue repair (PGE2, IL‐10) generally impaired by frequently used corticosteroids.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy

et al. 2020

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Immunity‐on‐a‐Chip: Integration of Immune Components into the Scheme of Organ‐on‐a‐Chip Systems

Ramadan

Hazaymeh²,

Zourob

2023

Advanced Biology

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Studying the immune system in vitro aims to understand how, when, and where the immune cells migrate/differentiate and respond to the various triggering events and the decision points along the immune response journey. It becomes evident that organ‐on‐a‐chip (OOC) technology has a superior capability to recapitulate the cell‐cell and tissue‐tissue interaction in the body, with a great potential to provide tools for tracking the paracrine signaling with high spatial‐temporal precision and implementing in situ real‐time, non‐destructive detection assays, therefore, enabling extraction of mechanistic information rather than phenotypic information. However, despite the rapid development in this technology, integration of the immune system into OOC devices stays among the least navigated tasks, with immune cells still the major missing components in the developed models. This is mainly due to the complexity of the immune system and the reductionist methodology of the OOC modules. Dedicated research in this field is demanded to establish the understanding of mechanism‐based disease endotypes rather than phenotypes. Herein, we systemically present a synthesis of the state‐of‐the‐art of immune‐cantered OOC technology. We comprehensively outlined what is achieved and identified the technology gaps emphasizing the missing components required to establish immune‐competent OOCs and bridge these gaps.

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Inflammation‐Instructed Hierarchical Delivery of IL‐4/miR‐21 Orchestrates Osteoimmune Microenvironment toward the Treatment of Rheumatoid Arthritis

Deng

Yang

Liang

et al. 2021

Adv Funct Materials

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Dysregulated inflammation and failure in resolution account for the incidence and deterioration of rheumatoid arthritis (RA). IL‐4 and miR‐21 possess complementary functions in inhibiting inflammation and fostering resolution. Thus, inflammation‐instructed nanocomplexes (NCs) are herein developed to mediate hierarchical co‐delivery of miR‐21 and IL‐4 to orchestrate the osteoimmune microenvironment against RA. The NCs comprise a cationic inner core assembled from the membrane‐penetrating, helical polypeptide (PG) and miR‐21, an outer layer based on the acid‐responsive, charge reversal polymer (PLL‐CA), and surface‐adsorbed IL‐4. The negatively charged NCs enable prolonged blood circulation after systemic administration, and thus passively accumulate in the inflamed joint. In the slightly acidic microenvironment of inflamed synovium, PLL‐CA transforms from negative to positive, which sheds off to liberate IL‐4 extracellularly and facilitate the intracellular delivery of the PG/miR‐21 core into macrophages. Thus, the anti‐inflammatory miR‐21 cooperates with the proresolving IL‐4 to attenuate inflammation via NF‐κB inhibition, promote macrophage polarization to M2a/M2c phenotypes, propel resolution, and promote tissue repair against Zymosan A‐induced arthritis. This study provides an effective strategy toward the programmed delivery of drug/gene cargoes at different extracellular/intracellular locations, and the combined mechanism of anti‐inflammation and proresolution renders insights into the treatment of inflammatory diseases.

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Locally renewing resident synovial macrophages provide a protective barrier for the joint

Cited by 415 publications

References 36 publications

Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy

Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy

Immunity‐on‐a‐Chip: Integration of Immune Components into the Scheme of Organ‐on‐a‐Chip Systems

Inflammation‐Instructed Hierarchical Delivery of IL‐4/miR‐21 Orchestrates Osteoimmune Microenvironment toward the Treatment of Rheumatoid Arthritis

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