Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation

Manferdini, Cristina; Paolella, Francesca; Gabusi, Elena; Gambari, Laura; Piacentini, A.; Filardo, Giuseppe; Fleury-Cappellesso, Sandrine; Barbero, Andrea; Murphy, Mary; Lisignoli, Gina

doi:10.1016/j.joca.2017.01.011

Cited by 117 publications

(100 citation statements)

References 51 publications

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“…2C). In addition, when male and female data were combined, chow-fed ApoE −/− /LysM-PTP1B exhibited a significant increase in circulating levels of the eicosanoid, prostaglandin E2 (PGE 2 ) (Figure 3F), which has been recently implicated as essential in switching macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype by stimulating IL-10 release [16], [17]. Although not significant, a similar trend was observed when the groups were separated by gender (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to its role as a pro-inflammatory molecule, recent research has implicated PGE 2 to behave as an immunomodulator, acting on four distinct G-protein coupled receptors (GPCRs, EP1-4) to both, inhibit and stimulate, the synthesis of pro- and anti-inflammatory cytokines, respectively. Importantly, PGE 2 has been found to be essential in switching macrophages from a pro-inflammatory M1 to an anti-inflammatory M2 phenotype and does so through an IL-10 dependent mechanism [16], [17]. In addition, deletion of PTP1B enhances the expression of COX2, which is upstream of PGE 2 release [26], and was found to be protective against endothelial dysfunction in a model of Type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

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Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE −/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

Thompson

Morrice

Grant

et al. 2017

Molecular Metabolism

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ObjectiveCardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD.MethodsWe generated novel macrophage-specific PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B). Mice were fed standard or pro-atherogenic diet, and body weight, adiposity (echoMRI), glucose homeostasis, atherosclerotic plaque development, and molecular, biochemical and targeted lipidomic eicosanoid analyses were performed.ResultsMyeloid-PTP1B knockout mice on atherogenic background (ApoE−/−/LysM-PTP1B) exhibited a striking improvement in glucose homeostasis, decreased circulating lipids and decreased atherosclerotic plaque lesions, in the absence of body weight/adiposity differences. This was associated with enhanced phosphorylation of aortic Akt, AMPKα and increased secretion of circulating anti-inflammatory cytokine interleukin-10 (IL-10) and prostaglandin E2 (PGE2), without measurable alterations in IR phosphorylation, suggesting a direct beneficial effect of myeloid-PTP1B targeting.ConclusionsHere we demonstrate that inhibiting the activity of PTP1B specifically in myeloid lineage cells protects against atherosclerotic plaque formation, under atherogenic conditions, in an ApoE−/− mouse model of atherosclerosis. Our findings suggest for the first time that macrophage PTP1B targeting could be a therapeutic target for atherosclerosis treatment and reduction of CVD risk.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE −/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

Thompson

Morrice

Grant

et al. 2017

Molecular Metabolism

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“…PGE 2 , frequently considered a marker of inflammation, also exhibits anti-inflammatory and anabolic properties, including chondrocyte protection and activation of pro-resolving macrophages. 21,62,[102][103][104] In fact, PGE 2 generated during the early stages of inflammation upregulates the synthesis of specialized pro-resolving molecules involved in inflammation resolution and tissue repair. 21 Increasing concentrations of PGE 2 in both SF and ISF could result from the metabolism of arachidonic acid from phagocytosed dead cells, especially considering the absence of inflammatory triggers in SF.…”

Section: Discussionmentioning

confidence: 99%

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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“…Due to this association with cell division, Ki‐67 has been used to identify proliferating cells of the inflamed synovium . The observation of leukocytic synovial infiltration with the presence of CD68 positive macrophages has also been well described in the literature …”

mentioning

confidence: 95%

“…17 The observation of leukocytic synovial infiltration with the presence of CD68 positive macrophages has also been well described in the literature. 18,19 Therefore, the following research questions were asked: (i) Is there a correlation between the histopathologic synovitis score and the immunohistochemical markers CD15 (neutrophils), Ki-67 (proliferating cells), and CD68 (macrophages), respectively? (ii) Do histopathologic synovitis score and immunohistochemical markers correlate with the histologic degree of cartilage degeneration in the lateral compartment of the knee?…”

mentioning

confidence: 99%

Varus knee osteoarthritis: Elevated synovial CD15 counts correlate with inferior biomechanical properties of lateral‐compartment cartilage

Koller

Waldstein

Krenn

et al. 2017

Journal Orthopaedic Research

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The study analyzed the influence of synovitis on the histological and biomechanical properties of lateral-compartment cartilage. In a prospective cohort study, 84 patients (100 knees) with varus deformity of the knee were included. Osteochondral samples from the distal lateral femur underwent biomechanical and histologic analysis. Synovial tissue was sampled for histological (chronic synovitis score) and immunohistochemical evaluation of the degree of synovitis. CD15 (neutrophils), Ki-67 (dividing cells), and CD68 (macrophages) were tested in all synovial samples. While the histological synovitis score did not correlate with the degree of cartilage degeneration (histological OARSI grades), both CD15 (r = 0.297, p = 0.006) and Ki-67 (r = 0.249, p = 0.023) correlated with histological OARSI grades. There was a weak negative correlation of CD15 with biomechanical properties of cartilage of the distal lateral femur (aggregate modulus (Ha): r = -0.125; p = 0.257; dynamic modulus (DM): r = -0.216; p = 0.048). No correlations were observed for Ki-67 and CD68. In addition, biomechanical properties were inferior in knees with a CD15 of >8/high power field compared to knees with a CD15 of ≤8/high power field (Ha: p = 0.031, d = 0.46; DM: p = 0.005, d = 0.68). The study demonstrates an association of increased inflammatory activity with advanced cartilage degeneration. Lateral-compartment cartilage in knees with elevated synovial CD15 counts has a reduced ability to withstand compressive loads. CD15 might serve as an indicator for inferior biomechanical cartilage properties. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:841-846, 2018.

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Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation

Cited by 117 publications

References 51 publications

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE −/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

Myeloid protein tyrosine phosphatase 1B (PTP1B) deficiency protects against atherosclerotic plaque formation in the ApoE −/− mouse model of atherosclerosis with alterations in IL10/AMPKα pathway

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

Varus knee osteoarthritis: Elevated synovial CD15 counts correlate with inferior biomechanical properties of lateral‐compartment cartilage

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