scholarly journals AB0075 SYNOVIAL TISSUE MACROPHAGES ARE DOMINANTLY ALTERNATIVELY ACTIVATED IN PATIENTS WITH MATURE OSTEOARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1337.2-1338
Author(s):  
G. Laskarin ◽  
T. Kehler ◽  
D. Legović ◽  
V. Šantić ◽  
B. Ćurko-Cofek ◽  
...  
Keyword(s):  
T Cells ◽  
Knee Osteoarthritis ◽  
Synovial Tissue ◽  
Tnf Alpha ◽  
Lymphocyte Infiltration ◽  
Activated Macrophages ◽  
Tissue Samples ◽  
Arginase 1 ◽  
Immunofluorescence Labeling ◽  
Alternatively Activated

Background:Macrophages are abundant inflammatory cell type in the synovial membrane of knee osteoarthritis (OA) (1). Their quantity is associated with radiographic severity of knee OA and joint symptoms (2), while their functions are set in response to micro-environmental signals (3). Classically activated macrophages M1 support T helper 1 (Th1) driven pro-inflammatory reactions, while alternatively activated macrophages M2 strengthen Th2 inflammatory processes (3).Objectives:To investigate activation status of synovial tissue macrophages in patients with mature OA in terms of M1 / M2 polarization.Methods:Synovial tissue samples (6) with abundant lymphocyte infiltration were obtained during aloarthroplasty. Double immunofluorescence labeling was performed on paraffin-embedded synovial tissue sections using primary rabbit anti-macrophage CD68 mAb in combination with mouse anti-human antibodies directed toward CD3, arginase-1, TNF-alpha and IL-15. CD206 and CD163 were single labelled.Results:CD68+ macrophages mostly co-expressed arginase-1 (4/6 samples), indicating their M2 orientation. Macrophages were placed in lining synovial tissue and nearby tissue-resident CD3+ cells. M2 markers CD206 and CD163 were found in the area of macrophage interaction with T cells. CD68+ cells co-expressing TNF-alpha or IL-15 M1 markers were in minority in these synovial tissues. Lymphocyte infiltration was less abundant in remaining (2/6) synovial tissue samples.Conclusion:Mature synovial tissue macrophages, equipped dominantly with arginase-1 are M2 oriented and might support Th2 immune response in surrounding T cells.References:[1]Grieshaber-Bouyer R, Kämmerer T, Rosshirt N, Nees TA, Koniezke P, Tripel E, Schiltenwolf M, Kirsch J, Hagmann S, Moradi B. Divergent Mononuclear Cell Participation and Cytokine Release Profiles Define Hip and Knee Osteoarthritis. J Clin Med. 2019;8(10):piiE1631.[2]Haraden CA, Huebner JL, Hsueh MF, Li YJ, Kraus VB. Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation. Arthritis Res Ther. 2019;21(1):146.[3]Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G. Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS One. 2013;8(11):e80908.Acknowledgments:University of Rijeka supported the research by the grants No. Uni-ri-biomed-18-110 and No. Uni-ri-biomed-18-160.Disclosure of Interests:None declared

Alternatively activated macrophages engage in homotypic and heterotypic interactions through IL-4 and polyamine-induced E-cadherin/catenin complexes

Blood ◽  
2009 ◽  
Vol 114 (21) ◽  
pp. 4664-4674 ◽  
Author(s):  
Jan Van den Bossche ◽  
Pieter Bogaert ◽  
Jolanda van Hengel ◽  
Christopher J. Guérin ◽  
Geert Berx ◽  
...  
Keyword(s):  
Allergic Airway Inflammation ◽  
Interleukin 4 ◽  
Cell Contact ◽  
Cellular Interactions ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Arginase 1 ◽  
Heterotypic Interactions ◽  
Alternatively Activated ◽  
E Cadherin

Abstract Alternatively activated macrophages (AAMs), triggered by interleukin-4 (IL-4) and IL-13, play a modulating role during Th2 cytokine-driven pathologies, but their molecular armament remains poorly characterized. Here, we established E-cadherin (Cdh1) as a selective marker for IL-4/IL-13–exposed mouse and human macrophages, which is STAT6-dependently induced during polarized Th2 responses associated with Taenia crassiceps helminth infections or allergic airway inflammation. The IL-4–dependent, arginase-1/ornithine decarboxylase–mediated production of polyamines is important for maximal Cdh1 induction, unveiling a novel mechanism for IL-4–dependent gene transcription. At the macrophage surface, E-cadherin forms a functional complex with the catenins that accumulates at sites of cell contact. Macrophage-specific deletion of the Cdh1 gene illustrates the implication of E-cadherin in IL-4–driven macrophage fusion and heterotypic interactions with CD103+ and KLRG1+ T cells. This study identifies the E-cadherin/catenin complex as a discriminative, partly polyamine-regulated feature of IL-4/IL-13–exposed alternatively activated macrophages that contributes to homotypic and heterotypic cellular interactions.

scholarly journals Extraintestinal Helminth Infection Limits Pathology and Proinflammatory Cytokine Expression during DSS-Induced Ulcerative Colitis: A Role for Alternatively Activated Macrophages and Prostaglandins

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Yadira Ledesma-Soto ◽  
Blanca E. Callejas ◽  
César A. Terrazas ◽  
Jose L. Reyes ◽  
Arlett Espinoza-Jiménez ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Activity Index ◽  
Disease Activity Index ◽  
Helminth Parasites ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Arginase 1 ◽  
Alternatively Activated

Chronic inflammation of the intestinal mucosa is characteristic of inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease. Helminth parasites have developed immunomodulatory strategies that may impact the outcome of several inflammatory diseases. Therefore, we investigated whetherTaenia crassicepsinfection is able to decrease the inflammatory effects of dextran sulfate sodium- (DSS-) induced ulcerative colitis in BALB/c and C57BL/6 mice. Preinfection significantly reduced the manifestations of DSS-induced colitis, as weight loss and shortened colon length, and decreased the disease activity index independently of the genetic background of the mice.Taeniainfection decreased systemic levels of proinflammatory cytokines while increasing levels of IL-4 and IL-10, and the inflammatory infiltrate into the colon was also markedly reduced. RT-PCR assays from colon showed thatT. crassiceps-infected mice displayed increased expression of Arginase-1 but decreased expression of iNOS compared to DSS-treated uninfected mice. The percentages of T regulatory cells were not increased. The adoptive transfer of alternatively activated macrophages (AAMФs) from infected mice into mice with DSS-induced colitis reduced the severity of colon inflammation. Administration of indomethacin abrogated the anticolitic effect ofTaenia. Thus,T. crassicepsinfection limits the pathology of ulcerative colitis by suppressing inflammatory responses mechanistically associated with AAMФs and prostaglandins.

scholarly journals Utilization of Host Polyamines in Alternatively Activated Macrophages Promotes Chronic Infection byBrucella abortus

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Tobias Kerrinnes ◽  
Maria G. Winter ◽  
Briana M. Young ◽  
Vladimir E. Diaz-Ochoa ◽  
Sebastian E. Winter ◽  
...  
Keyword(s):  
Chronic Infection ◽  
Intracellular Survival ◽  
Interleukin 4 ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Content Type ◽  
Arginase 1 ◽  
Long Course ◽  
Multiple Drugs ◽  
Alternatively Activated

ABSTRACTTreatment of intracellular bacterial pathogens with antibiotic therapy often requires a long course of multiple drugs. A barrier to developing strategies that enhance antibiotic efficacy against these pathogens is our poor understanding of the intracellular nutritional environment that maintains bacterial persistence. The intracellular pathogenBrucella abortussurvives and replicates preferentially in alternatively activated macrophages (AAMs); however, knowledge of the metabolic adaptations promoting exploitation of this niche is limited. Here we show that one mechanism promoting enhanced survival in AAMs is a shift in macrophage arginine utilization from production of nitric oxide (NO) to biosynthesis of polyamines, induced by interleukin 4 (IL-4)/IL-13 treatment. Production of polyamines by infected AAMs promoted both intracellular survival ofB. abortusand chronic infection in mice, as inhibition of macrophage polyamine synthesis or inactivation of the putative putrescine transporter encoded bypotIHGFreduced both intracellular survival in AAMs and persistence in mice. These results demonstrate that increased intracellular availability of polyamines induced by arginase-1 expression in IL-4/IL-13-induced AAMs promotes chronic persistence ofB. abortuswithin this niche and suggest that targeting of this pathway may aid in eradicating chronic infection.

scholarly journals SIRPα sequesters SHP-2 to promote IL-4/13 signaling and alternative activation of macrophages

2021 ◽  
Author(s):  
Lei Shi ◽  
Koby Kidder ◽  
Zhen Bian ◽  
Samantha Kuon Ting Chiang ◽  
Corbett Ouellette ◽  
...  
Keyword(s):  
Wound Healing ◽  
Ex Vivo ◽  
Experimental Colitis ◽  
Alternative Activation ◽  
Activated Macrophages ◽  
Negative Regulators ◽  
Impaired Wound Healing ◽  
Alternatively Activated Macrophages ◽  
Arginase 1 ◽  
Alternatively Activated

The Th2 cytokines IL-4 and IL-13 through activation of their shared receptor IL-4Rα direct macrophage alternative activation to promote immunosuppression and wound healing. However, the mechanisms that control macrophage responses to IL-4/13 are not fully understood. Apart from driving JAK-STAT and PI3K-Akt pathways to polarize macrophages toward the alternative phenotype, the activated IL-4/13 receptors recruit negative regulators SHP-1 and SHP-2, which dephosphorylate IL-4Rα and decrease its signaling. Here we report that SIRPα spatially restricts SHP-2 and, by such, promotes IL-4/13 signaling and macrophage alternative activation. SIRPα executes this regulation via its cytoplasmic ITIMs/ITSMs that undergo phosphorylation by IL-4/13-induced, Src kinase-activated Brutons tyrosine kinase (Btk), resulting in recruitment of SHP-2 and preclusion of SHP-2 from binding to and inhibiting IL-4/13 receptors. Despite that this regulation occurs independent of CD47, extracellular CD47 ligation of SIRPα facilitates its cytoplasmic phosphorylation and SHP-2 sequestration, leading to stronger IL-4/13 signaling and enhanced macrophage expression of IL-10, TGFβ, CD206, arginase-1, etc. Conversely, deficiency of SIRPα allows SHP-2 to freely bind to γC or IL-13Rα1 and through which dephosphorylate IL-4Rα, dampening its signaling. Consistent with these findings, impaired wound healing in Sirpα-/- mice under experimental colitis correlated with a deficit of immunosuppressive macrophages in the colon, a condition that was corrected by transfusion of ex vivo-produced SIRPαhigh alternatively activated macrophages.

scholarly journals Chronic Helminth Infection Induces Alternatively Activated Macrophages Expressing High Levels of CCR5 with Low Interleukin-12 Production and Th2-Biasing Ability

2002 ◽  
Vol 70 (7) ◽  
pp. 3656-3664 ◽  
Author(s):  
Miriam Rodríguez-Sosa ◽  
Abhay R. Satoskar ◽  
Rodrigo Calderón ◽  
Lorena Gomez-Garcia ◽  
Rafael Saavedra ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 12 ◽  
Prostaglandin E ◽  
Activated Macrophages ◽  
Chronic Infections ◽  
Alternatively Activated Macrophages ◽  
Acute Infections ◽  
Helminth Infections ◽  
Alternatively Activated

ABSTRACT Helminth infections induce Th2-type biased immune responses. Although the mechanisms involved in this phenomenon are not yet clearly defined, antigen-presenting cells (APC) could play an important role in this process. Here, we have used peritoneal macrophages (F4/80+) recruited at different times after challenge with Taenia crassiceps as APC and tested their ability to regulate Th1/Th2 differentiation. Macrophages from acute infections produced high levels of interleukin-12 (IL-12) and nitric oxide (NO), paralleled with low levels of IL-6 and prostaglandin E2 (PGE2) and with the ability to induce strong antigen-specific CD4+ T-cell proliferation in response to nonrelated antigens. In contrast, macrophages from chronic infections produced higher levels of IL-6 and PGE2 and had suppressed production of IL-12 and NO, associated with a poor ability to induce antigen-specific proliferation in CD4+ T cells. Failure to induce proliferation was not due to a deficient expression of accessory molecules, since major histocompatibility complex class II, CD40, and B7-2 were up-regulated, together with CD23 and CCR5 as infection progressed. These macrophages from chronic infections were able to bias CD4+ T cells to produce IL-4 but not gamma interferon (IFN-γ), contrary to macrophages from acute infections. Blockade of B7-2 and IL-6 and inhibition of PGE2 failed to restore the proliferative response in CD4+ T cells. Furthermore, studies using STAT6−/− mice revealed that STAT6-mediated signaling was essential for the expansion of these alternatively activated macrophages. These data demonstrate that helminth infections can induce different macrophage populations that have Th2-biasing properties.

Adaptation of Human CD4+ T Cells to Pathophysiological Hypoxia: A Transcriptome Analysis

2009 ◽  
Vol 36 (12) ◽  
pp. 2655-2669 ◽  
Author(s):  
TIMO GABER ◽  
THOMAS HÄUPL ◽  
GRIT SANDIG ◽  
KAROLINA TYKWINSKA ◽  
MONIQUE FANGRADT ◽  
...  
Keyword(s):  
T Cells ◽  
Synovial Tissue ◽  
Cd4 T Cells ◽  
Protein Modification ◽  
Quantitative Polymerase Chain Reaction ◽  
Low Oxygen ◽  
Rheumatoid Synovium ◽  
Tissue Samples ◽  
Oxygen Levels ◽  
Hypoxic Conditions

Objective.Inflamed tissues are usually characterized by low oxygen levels. We investigated whether pathophysiological hypoxia (pO2 < 1%) as found in the rheumatoid synovium modulates the transcriptome of human CD4+ T cells.Methods.We analyzed the extent to which hypoxia influences the transcriptome in the rheumatoid synovium according to a gene cluster reflecting adaptation to low oxygen levels. Hypoxia-inducible factor-1α (HIF-1α) was detected in the rheumatoid synovium using immunohistochemistry. Isolated human CD4+ T cells were exposed to hypoxia and analyzed using microarray analysis, quantitative polymerase chain reaction, and immunoblot detection.Results.In rheumatoid arthritis (RA) synovial tissue samples, hypoxia modulates the transcription profile. This profile is similar, but not identical, to that found in isolated CD4+ T cells incubated under hypoxic conditions. We show that HIF-1α is expressed in synovial tissue samples and in hypoxic CD4+ cells; and that hypoxia directly affects differential gene expression in human T cells with up to 4.8% modulation of the transcriptome. Functional genome analysis revealed substantial effects of hypoxia on immune response, transcriptional regulation, protein modification, cell growth and proliferation, and cell metabolism.Conclusion.Severe hypoxia, a feature of joint inflammation, considerably modulates the transcriptome of cells found in the rheumatoid synovium. Human CD4+ T cells adapt to hypoxic conditions mainly by HIF-1-driven effects on the transcriptome reflecting a profound influence on immune functions. Thus, hypoxia must be taken into account when therapeutically targeting inflammation.

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