Noncoding RNAs, cytokines, and inflammation-related diseases

Chronic inflammation is involved in the onset and development of many diseases, including obesity, atherosclerosis, type 2 diabetes, osteoarthritis, autoimmune and degenerative diseases, asthma, periodontitis, and cirrhosis. The inflammation process is mediated by chemokines, cytokines, and different inflammatory cells. Although the molecules and mechanisms that regulate this primary defense mechanism are not fully understood, recent findings offer a putative role of noncoding RNAs, especially microRNAs (miRNAs), in the progression and management of the inflammatory response. These noncoding RNAs are crucial for the stability and maintenance of gene expression patterns that characterize some cell types, tissues, and biologic responses. Several miRNAs, such as miR-126, miR-132, miR-146, miR-155, and miR-221, have emerged as important transcriptional regulators of some inflammation-related mediators. Additionally, little is known about the involvement of long noncoding RNAs, long intergenic noncoding RNAs, and circular RNAs in inflammation-mediated processes and the homeostatic imbalance associated with metabolic disorders. These noncoding RNAs are emerging as biomarkers with diagnosis value, in prognosis protocols, or in the personalized treatment of inflammation-related alterations. In this context, this review summarizes findings in the field, highlighting those noncoding RNAs that regulate inflammation, with emphasis on recognized mediators such as TNF-α, IL-1, IL-6, IL-18, intercellular adhesion molecule 1, VCAM-1, and plasminogen activator inhibitor 1. The down-regulation or antagonism of the noncoding RNAs and the administration of exogenous miRNAs could be, in the near future, a promising therapeutic strategy in the treatment of inflammation-related diseases.—Marques-Rocha, J. L., Samblas, M., Milagro, F. I., Bressan, J., Martínez, J. A., Marti, A. Noncoding RNAs, cytokines, and inflammation-related diseases. Inflammation is a complex protective process that requires a cross-talk between different types of immune cells to remove or neutralize harmful stimuli (1). In the classic view, the inflammatory process is induced by an invasion of foreign pathogens of biologic origin or by tissue damage. Neutrophils, dendritic cells, and macrophages express almost all types of TLRs participating in the transmission of a signal from the plasma membrane through a multistep cascade to responsive transcription factors. Members of the TLR family have emerged as the primary evolutionarily conserved sensors of pathogen-associated molecular patterns (1). Binding of the TLRs to their respective ligands initiates a wide spectrum of responses, from phagocytosis to production of a variety of cytokines, which in turn shape and enhance the inflammatory and adaptive immune responses. Typical transcription factors that activate inflammatory mediators are NF-κB (2), activator protein 1 (3), signal transducer and activator of transcription (STAT) (4), CCAAT enhancer binding protein (C/EBP) (5), and Ets-like gene 1 (6). The interactions between transcription factors that compete for binding sites in the promoter regions of specific target genes are highly complex. Usually the multistep signaling leads to a prompt transcription of genes resulting in accumulation of specific mRNAs coding for TNF-α, IL-1, IL-6, IL-8, monocyte chemotactic protein 1 (MCP-1), and other cytokines involved in inflammation (7). Some cytokines may elicit a broad inflammatory response, while others act on specific cell types. The activation, proliferation, and recruitment phenomena of specific differentiated immune cells are involved in resolving the nonhomeostatic state [for a review, see Shi (8)]. Thus, macrophages stimulate the inflammatory responses of neutrophils, fibroblasts, and endothelial cells (2). Other sentinel cells may present antigens to the T-helper cells, which play a central role in coordinating immune responses, such as clonal expansion of T cells and B cell responses (9). Acute inflammation is an important part of the immune response, but chronic inappropriate inflammation can cause metabolic disorders (10). For example, chronic low-grade inflammation has been repeatedly associated with the onset and prevalence of metabolic syndrome (11, 12). The International Diabetes Federation estimates that one quarter of the world’s adult population has metabolic syndrome (13). This phenomenon is defined by a combination of interconnected cardiometabolic alterations that include the presence of arterial hypertension, insulin resistance, dyslipidemia, cardiovascular disease, and abdominal obesity (11). With the pathologic enlargement of the adipose tissue in obesity, the blood supply to adipocytes may be reduced, with subsequent hypoxia leading to a an elevated production of proinflammatory mediators [TNF-α and IL-6, plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein (CRP)] and increased infiltration of immune cells, particularly adipose tissue macrophages (14, 15). These altered signals mediate multiple processes, including insulin sensitivity (16), oxidative stress (17), energy metabolism, blood coagulation, and inflammatory responses (12). These pathologic conditions predispose to diabetes mellitus, hepatic steatosis, atherosclerosis, plaque rupture, and atherothrombosis (11). However, to date, the available information is controversial and does not necessarily imply an unequivocal causal role. The data obtained by functional genomics techniques indicate that several hundreds of genes participate in the inflammatory response and that their coordinated expression is tightly regulated [reviewed in Jura and Koj (18)]. Nevertheless, the involved pathways and the regulatory mechanisms are not completely understood. In the last few years, there has been a growing interest in the role of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in the development of several inflammation-related diseases (Table 1). These noncoding RNAs have emerged as important transcriptional regulators in both physiologic and pathophysiological conditions (19–21). In physiologic homeostasis, these nucleic acids may participate in cell differentiation, proliferation, apoptosis, hematopoiesis, limb morphogenesis, and important metabolic pathways, such as insulin secretion, triglyceride and cholesterol biosynthesis, and oxidative stress (20, 22, 23). Given their fundamental biologic roles, it is not surprising that miRNAs expression is tightly controlled and that its dysregulation can lead to disease onset