Interferon and Alternative Activation of Monocyte/Macrophages in Systemic Sclerosis–Associated Pulmonary Arterial Hypertension
| Autor: | Romy B. Christmann, Alsya J. Affandi, Giuseppina Farina, Robert Lafyatis, Everett Hayes, Sarah A. Pendergrass, Cristina Padilla, Michael L. Whitfield, Harrison W. Farber |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Adult
Myxovirus Resistance Proteins Sialic Acid Binding Ig-like Lectin 1 CD14 medicine.medical_treatment Hypertension Pulmonary Immunology Lipopolysaccharide Receptors Receptors CCR1 Inflammation Biology Peripheral blood mononuclear cell Article Rheumatology GTP-Binding Proteins medicine Immunology and Allergy Macrophage Humans Pharmacology (medical) Familial Primary Pulmonary Hypertension Receptors Immunologic Interleukin 4 Aged Interleukin-13 Membrane Glycoproteins Scleroderma Systemic Monocyte Janus Kinase 2 Macrophage Activation Middle Aged Interleukin-13 Receptor alpha1 Subunit Cytokine medicine.anatomical_structure Gene Expression Regulation Interleukin 13 Interferons Interleukin-4 medicine.symptom |
| Popis: | Systemic sclerosis (SSc) is characterized by vascular injury, autoimmunity, and fibrosis in multiple organs, resulting in multifaceted clinical manifestations with high morbidity and mortality (1). Pulmonary arterial hypertension (PAH), one of the leading causes of mortality in SSc, is associated with elevated expression of markers of vascular damage as well as inflammation, suggesting that SSc-related PAH might be secondary to the inflammatory process (2). We recently showed that peripheral blood mononuclear cells (PBMCs) from patients with limited cutaneous SSc (lcSSc) with associated PAH had increased expression of a cluster of genes, including IL13RA1, ICAM1, and others (3), compared with PBMCs from lcSSc patients without PAH and compared with PBMCs from controls. Strikingly, a gradient of expression of these genes was apparent, showing higher gene expression in lcSSc patients without PAH than in controls and even higher expression in lcSSc patients with PAH than in lcSSc patients without PAH. In addition, several of the genes overexpressed by PBMCs have been previously associated with monocyte/macrophage cell types, suggesting that this cell type might be particularly important in mediating inflammation in lcSSc and lcSSc-related PAH (3). Our group previously demonstrated that PBMCs from patients with diffuse cutaneous SSc (dcSSc) overexpress a cluster of interferon (IFN)-regulated genes, including Siglec1 (4), a surface protein found exclusively on macrophages and monocyte-derived dendritic cells. However, unlike altered gene expression associated with lcSSc-related PAH, increased Siglec1 expression by PBMCs in dcSSc does not correlate well with the Modified Rodnan Skin Thickness Score (MRSS) (4,5). In contrast, genes with elevated expression in lcSSc patients with PAH are not known to be regulated by IFN, suggesting that monocytes from lcSSc patients with PAH might be activated by another, non–type I IFN, cytokine. Monocytes can be activated through several pathways, the best defined of which are classical and alternative activation pathways (6-8). The classical activation pathway is mediated by IFNγ and/or lipopolysaccharide (LPS), enhancing microbicidal and tumoricidal capacity (7). The alternative activation pathway is mediated by IL-4 and/or IL-13. The main cellular effects of this pathway are activation of endocytosis, inhibition of nitric oxide production with consequent enhanced arginase activity, and induction of tissue remodeling and fibrosis (8). Although arginase is a well-known marker of alternative activation in mice, it is not regulated by IL-4/IL-13 in human monocytes, whereas expression of MRC1 (c-type mannose receptor 1) is highly induced by IL-4/IL-13 in human monocytes and is thus thought to represent a strong marker of alternative activation of monocyte/macrophages in humans (8). To better understand monocyte/macrophage activation in the pathogenesis of lcSSc and lcSSc-related PAH, we explored the relationship between IFN-regulated genes, the recently described cluster of genes associated with lcSSc-related PAH, and the alternative activation pathway. We observed that IFN-regulated genes and biomarker genes represent distinct, although related, clusters. We found that the expression of markers of IFN activation, including Siglec1, expressed only by CD14+ cells, and MX1, expressed by both CD14+ and CD14− cells, was increased in all SSc patient subsets. Expression of MRC1 was found to be highly increased in lcSSc patients with PAH, was highly induced in vitro by IL-13, and correlated with pulmonary artery pressure and PAH-related mortality. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|