Systemic sclerosis (SSc) is a multi-system autoimmune disease with tissue fibrosis prominent in the skin and lung. In this review, we briefly describe the autoimmune features (mainly autoantibody production and cytokine profiles) and the potential pathogenic contributors including genetic/epigenetic predisposition, and environmental factors. We look in detail at the cellular and molecular bases underlying tissue-fibrosis which include trans-differentiation of fibroblasts (FBs) to myofibroblasts (MFBs). We also state comprehensively the pro-inflammatory and pro-fibrotic cytokines relevant to MFB trans-differentiation, vasculopathy-associated autoantibodies, and fibrosis-regulating microRNAs in SSc. It is conceivable that tissue fibrosis is mainly mediated by an excessive production of TGF-β, the master regulator, from the skewed Th2 cells, macrophages, fibroblasts, myofibroblasts, and keratinocytes. After binding with TGF-β receptors on MFB, the downstream Wnt/β-catenin triggers canonical Smad 2/3 and non-canonical Smad 4 signaling pathways to transcribe collagen genes. Subsequently, excessive collagen fiber synthesis and accumulation as well as tissue fibrosis ensue. In the later part of this review, we discuss limited data relevant to the role of long non-coding RNAs (lncRNAs) in tissue-fibrosis in SSc. It is expected that these lncRNAs may become the useful biomarkers and therapeutic targets for SSc in the future. The prospective investigations in the development of novel epigenetic modifiers are also suggested.

Polymorphonuclear neutrophils (PMNs) are traditionally regarded as professional phagocytic and acute inflammatory cells that engulf the microbial pathogens. However, accumulating data have suggested that PMNs are multi-potential cells exhibiting many important biological functions in addition to phagocytosis. These newly found novel activities of PMN include production of different kinds of cytokines/chemokines/growth factors, release of neutrophil extracellular traps (NET)/ectosomes/exosomes and trogocytosis (membrane exchange) with neighboring cells for modulating innate, and adaptive immune responses. Besides, PMNs exhibit potential heterogeneity and plasticity in involving antibody-dependent cellular cytotoxicity (ADCC), cancer immunity, autoimmunity, inflammatory rheumatic diseases, and cardiovascular diseases. Interestingly, PMNs may also play a role in ameliorating inflammatory reaction and wound healing by a subset of PMN myeloid-derived suppressor cells (PMN-MDSC). Furthermore, PMNs can interact with other non-immune cells including platelets, epithelial and endothelial cells to link hemostasis, mucosal inflammation, and atherogenesis. The release of low-density granulocytes (LDG) from bone marrow initiates systemic autoimmune reaction in systemic lupus erythematosus (SLE). In clinical application, identification of certain PMN phenotypes may become prognostic factors for severe traumatic patients. In the present review, we will discuss these newly discovered biological and pathobiological functions of the PMNs.

Systemic lupus erythematosus (SLE) is an archetype of systemic autoimmune disease, characterized by the presence of diverse autoantibodies and chronic inflammation. There are multiple factors involved in lupus pathogenesis, including genetic/epigenetic predisposition, sexual hormone imbalance, environmental stimulants, mental/psychological stresses, and undefined events. Recently, many authors noted that “inflammaging”, consisting of immunosenescence and inflammation, is a common feature in aging people and patients with SLE. It is conceivable that chronic oxidative stresses originating from mitochondrial dysfunction, defective bioenergetics, abnormal immunometabolism, and premature telomere erosion may accelerate immune cell senescence in patients with SLE. The mitochondrial dysfunctions in SLE have been extensively investigated in recent years. The molecular basis of normoglycemic metabolic syndrome has been found to be relevant to the production of advanced glycosylated and nitrosative end products. Besides, immunosenescence, autoimmunity, endothelial cell damage, and decreased tissue regeneration could be the results of premature telomere erosion in patients with SLE. Herein, the molecular and cellular bases of inflammaging and cardiovascular complications in SLE patients will be extensively reviewed from the aspects of mitochondrial dysfunctions, abnormal bioenergetics/immunometabolism, and telomere/telomerase disequilibrium.