Activin-A in the regulation of immunity in health and disease. (November 2019)

• Record Type: Journal Article
• Authors: Morianos, Ioannis; Papadopoulou, Gina; Semitekolou, Maria; Xanthou, Georgina
• Is Part Of: Journal of autoimmunity. Volume 104(2019)
• Publication Date: 2019-11
• Subjects: Cytokines -- Activin-A -- Inflammation -- Immune regulation -- Infection -- Autoimmunity -- Allergy -- Cancer; SMAD mothers against decapentaplegic -- MAPK mitogen activated protein kinase -- ERK extracellular signal-regulated kinase -- JNK c-Jun N-terminal kinase -- BAMBI pseudoreceptor BMP and activin membrane-bound inhibitor homolog -- LPS Lipopolysaccharides -- BM bone marrow -- IFN-γ interferon γ -- IL interleukin -- GM-CSF granulocyte-macrophage colony-stimulating factor -- MAF C-maf proto-oncogene -- IGF1 insulin-like growth factor 1 -- SERPINB2 Plasminogen activator inhibitor 2 -- F13A1 coagulation factor XIII A chain -- PGE2 Prostaglandin E2 -- HIF-1α hypoxia-inducible factor 1-alpha -- ARDS acute respiratory distress syndrome -- BMP bone morphogenic protein -- GDF growth and differentiation factor -- ActRI activin-A receptor type I -- ACVR1A activin receptor type-1A -- ALK2 activin receptor like kinase 2 -- ACVR1B activin receptor type-1B -- ALK4 activin receptor like kinase 4 -- ALK7 activin receptor like kinase 7 -- ActRIIA activin receptor type IIA -- ActRIIB activin receptor type IIB -- FS follistatin -- I-SMAD inhibitory SMAD -- R-SMAD receptor-regulated SMAD -- TLR toll like receptor -- MMP-2 matrix metalloproteinase-2 -- NO nitric oxide -- DC dendritic cell -- moDC monocyte derived dendritic cell -- PB peripheral blood -- cDC conventional dendritic cell -- PHA phytohemagglutinin -- PAP pulmonary alveolar proteinosis -- TFH T follicular helper -- Treg T regulatory -- YAP Yes-Associated Protein -- NK natural killer -- fMLP N-formyl-L-methionyl-L-leucyl-phenylalanine -- CNS central nervous system -- CSF cerebrospinal fluid -- pPROM preterm premature rupture of the membranes -- HCV hepatitis C virus -- HBV hepatitis B virus -- HCMV human cytomegalovirus -- HRV human rhinovirus infection -- BEC bronchial epithelial cell -- NFAT nuclear factor of activated T cells -- AHR airway hyperresponsiveness -- BAL bronchoalveolar lavage -- OVA ovalbumin -- HDM house dust mite -- SA severe asthma -- MMA mild-moderate asthmatics -- HC healthy controls -- α-SMA a-smooth muscle actin -- VEGF vascular endothelial growth factor -- VEGFR1 VEGF receptor-1 -- Tr1 Type-1 regulatory -- TGF-β transforming growth factor β -- SF synovial fluid -- RA rheumatoid arthritis -- FLS fibroblast-like synoviocyte -- DMBA 7, 12-dimethylbenz[a]anthracene -- TPA 12-O-tetradecanoylphorbol 13-acetate -- DETC dendritic epidermal γδ T cell -- HPV human papillomavirus -- LLC Lewis Lung Carcinoma -- CFA Complete Freund's Adjuvant -- SLE systemic lupus erythematosus -- BAFF B-cell activating factor -- APRIL A proliferation-inducing ligand -- LPS lipopolysaccharide; Autoimmunity -- Periodicals; Autoimmune diseases -- Periodicals; Autoantibodies -- Periodicals; Autoimmune Diseases -- Periodicals; Auto-immunité -- Périodiques; Maladies auto-immunes -- Périodiques; Electronic journals; 616.978005
• DOI: 10.1016/j.jaut.2019.102314
• Languages: English
• ISSNs: 0896-8411

Abstract

Abstract: The TGF-β superfamily of cytokines plays pivotal roles in the regulation of immune responses protecting against or contributing to diseases, such as, allergy, autoimmunity and cancer. Activin-A, a member of the TGF-β superfamily, was initially identified as an inducer of follicle-stimulating hormone secretion. Extensive research over the past decades illuminated fundamental roles for activin-A in essential biologic processes, including embryonic development, stem cell maintenance and differentiation, haematopoiesis, cell proliferation and tissue fibrosis. Activin-A signals through two type I and two type II receptors which, upon ligand binding, activate their kinase activity, phosphorylate the SMAD2 and 3 intracellular signaling mediators that form a complex with SMAD4, translocate to the nucleus and activate or silence gene expression. Most immune cell types, including macrophages, dendritic cells (DCs), T and B lymphocytes and natural killer cells have the capacity to produce and respond to activin-A, although not in a similar manner. In innate immune cells, including macrophages, DCs and neutrophils, activin-A exerts a broad range of pro- or anti-inflammatory functions depending on the cell maturation and activation status and the spatiotemporal context. Activin-A also controls the differentiation and effector functions of Th cell subsets, including Th9 cells, TFH cells, Tr1 Treg cells and Foxp3 + Treg cells. Moreover, activin-A affects B cell responses, enhancing mucosal IgA secretion and inhibiting pathogenic autoantibody production. Interestingly, an array of preclinical and clinical studies has highlighted crucial functions of activin-A in the initiation, propagation and resolution of human diseases, including autoimmune diseases, such as, systemic lupus erythematosus, rheumatoid arthritis and pulmonary alveolar proteinosis, in allergic disorders, including allergic asthma and atopic dermatitis, in cancer and in microbial infections. Here, we provide an overview of the biology of activin-A and its signaling pathways, summarize recent studies pertinent to the role of activin-A in the modulation of inflammation and immunity, and discuss the potential of targeting activin-A as a novel therapeutic approach for the control of inflammatory diseases. Highlights: This review presents a comprehensive overview of the biology and functions of activin-A, a TGF-β superfamily member. The role of activin-A and its signaling pathways in the regulation of inflammation and immunity is outlined. Activin-A's cross-regulation with other inflammatory mediators and the implications for the pathophysiology of human diseases are discussed. The potential use of activin-A as an effective means for the suppression of exuberant inflammatory responses in immune disorders is contemplated.