Abstract

Introduction

The mammalian inflammatory response is a double‐edged sword. Although immune responses are necessary for efficient pathogen clearance, symbiosis with commensal microbes, wound repair and overall tissue homeostasis, these responses can become dysregulated and initiate a chronic reaction that lacks resolution 1. This condition, referred to as chronic low‐grade inflammation, can fester for long periods of time and adversely contribute to, or possibly even cause, many diseases associated with the aging including obesity 2, type 1 diabetes (T1D) 2, rheumatoid arthritis (RA) 3, systemic lupus erythematosus (SLE) 4, neurodegeneration 5, and cardiovascular diseases (CVD) 6. In many of these cases chronic inflammatory symptoms, such as elevations in inflammatory cytokines and autoantibodies in the serum, can serve as a prognostic indicator of later disease manifestation and overall morbidity and mortality 7.

As the world's elderly population continues to grow at an alarming rate, there is tremendous need to predict which individuals are at the highest risk for developing many of the disorders mentioned above. However, because chronic inflammation does not typically cause obvious clinical symptoms, and screening for inflammatory markers is not a test performed during routine medical exams, the potentially predictive power of one's chronic inflammatory state is not currently being harnessed. This is in part due to the fact that elevated inflammatory factors in the serum are not markers specific to chronic inflammation, and thus their diagnostic value is currently limited. Further, until a better understanding of the mechanisms underlying this deleterious condition is obtained, therapeutic inhibition of chronic inflammation will remain challenging.

In this article, we review our current understanding of the known causes of chronic low‐grade inflammation with a focus on factors distinct from chronic infection. We will also focus on cells of the immune system, although we recognize that non‐immune cells also contribute to this state. We also discuss recent evidence that mammalian microRNAs and long noncoding RNAs (lncRNAs) have evolved to regulate chronic inflammatory states including those that occur during the aging process, and describe how they provide both diagnostic and therapeutic opportunities moving forward.

Causes of chronic inflammation

During chronic inflammation the resolution phase of the inflammatory response does not occur. This can be a result of either a persisting stimulus and/or the perturbation of molecular mechanisms involved in the resolution of inflammation. Thus, normal “healthy” immune responses can progress to chronic inflammatory states in instances where either of these events takes place.

Immune responses involve a resolution phase where the inflammatory response is shut down once the stimulus, such as a pathogen, is cleared. Mechanisms of resolution have been an intense area of study in recent years, and many important steps in this process have been discovered. Specialized cell types, such as T regulatory cells (Tregs), carry out critical immune repressive functions that are essential in preventing autoimmunity 8. At the molecular level, the cytokine IL‐10 9, 10, the signaling molecule A20 11, the signaling receptor PD1 12, the signaling molecule CTLA4 13, and the secreted factor IL1RA 14 are all examples of molecules that have evolved to balance and ultimately shut down immune cell activation. In some cases, these pathways are already being exploited therapeutically for such applications as cancer therapy. For instance, antibody disruption of the PD1 pathway, which enhances the immune response against tumors, is proving to be an effective therapy for melanoma 15. Further, as we will describe below, specific miRNAs such as miR‐146a have also evolved to keep immune responses in check.

Initial causes of some forms of chronic inflammatory states are also incompletely understood, yet their identification and prevention is key to avoiding the disease process. Recently, several distinct contributing factors have been described (Fig. ​(Fig.1)1) and include the following: (i) chronic inflammation can be primarily initiated by immune responses to self‐tissues. The recognition of self‐antigens by the immune system can result in diseases such as RA 16, SLE 17, multiple sclerosis (MS) 18, and T1D 19, and this self‐recognition may or may not have a microbial component; (ii) in other instances, the immune response appears to be a secondary event that emerges in response to damage associated molecular patterns (DAMPs) that are produced following a breakdown in tissue homeostasis where the ensuing immune response driven by DAMPs alters tissue function 20. Examples of diseases associated with DAMPs include obesity – where nutrient excess and hypertrophic adipocytes are the primary drivers 21, CVD – where lipoprotein buildup initially seeds the pathology 22, and certain neurodegenerative disorders such as Alzheimer's disease (AD) – mediated by protein aggregation 5; (iii) contributions by the microbiota are also documented in some types of chronic inflammation, as their metabolites can influence both gut and peripheral tissues 23. Obesity has been associated with alterations to the gut microbiota composition 24; (iv) finally, the aging process itself leads to changes in immune system phenotypes and correlates with increasing inflammatory status as we grow older 25. In this section, we will expand on each of these aspects of chronic inflammation.

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Figure 1

Mechanisms, anatomical locations, and disease types involving chronic inflammation. Chronic inflammation can be initiated by autoantigens or in response to damage associated molecular patterns (DAMPs). Furthermore, the microbiota – via the action of their metabolites, etc. – as well as the aging process itself have been shown to be involved in certain types of chronic inflammation.

The regulatory potential of noncoding RNAs in the immune system

With the long‐term goal of being able to prevent or reverse the pathological outcomes of chronic inflammatory states, much work has gone into understanding how these debilitating conditions are initially triggered, as we have just discussed. Further, we have developed a good understanding of various mechanisms that provide resolution to immune responses following necessary and protective responses to infection. This knowledge has led to the emergence of a wide range of possible therapeutic targets that are either currently being exploited clinically or still being tested and developed to reduce inflammation. Examples of therapeutic targets include anti‐TNFα treatment for inflammatory arthritis 48, anti‐IL‐1 as a therapy for gout 49, anti‐IL1R as treatment for a wide range of inflammatory diseases 50, anti‐PD1 and anti CTLA4 for cancer treatment 15, and steroids for a variety of inflammatory conditions 51.

However, while these approaches hold much promise, they are based almost exclusively on targeting, activating, or inhibiting cellular protein factors that we know are involved in chronic inflammatory responses. Yet, approximately 3/4 of the human genome is transcribed into RNA, with only about 1% of these transcripts encoding proteins. Thus, most of the RNA diversity in our cells is made up of ncRNA. In recent years, it has become clear that different types of ncRNAs play important regulatory roles, not only in the immune system, but in all mammalian organ systems. In particular, miRNAs and lncRNAs have emerged as critical regulators of immune system development and function 52, 53, 54, including several new studies that have linked specific miRNA and lncRNA species to the control of chronic inflammatory conditions (Table 1). The role of lncRNAs in the immune system is reviewed further by Heward and Lindsay 54.

MicroRNAs, immune responses, and the regulation of cellular physiology

MicroRNAs modulate immune cell differentiation and responses

MicroRNAs are small, single‐stranded ncRNAs that were first discovered in C. elegans 55 approximately one decade before they were appreciated in mammalian cells 56, 57. Since then, research involving miRNAs has exploded over the past 10–15 years and much has been learned regarding their biogenesis, expression patterns and functions at the molecular, cellular and organismal levels. miRNAs clearly function to repress gene expression and influence virtually all organ systems in vertebrates 58. Much of this has been extensively reviewed elsewhere 59. However, there are certain fundamental attributes of miRNAs that make them ideally suited to regulate chronic inflammatory conditions.

Through their ability to modulate gene expression networks by adjusting the levels of dosage sensitive target genes, miRNAs are able to shift thresholds that dictate whether a cellular response will occur or not, how strong it will be, and if it will be resolved (Fig. ​(Fig.2)2) 60. For instance, miR‐146a is induced in response to TLR signaling and forms a negative feedback loop that inhibits Traf6 and Irak1, two critical upstream TLR‐signaling mediators that promote macrophage activation (Fig. ​(Fig.2A).2A). While miR‐146a is a repressor of immune cell signaling 61, miR‐155 and miR‐181a are activators of inflammation. miR‐155 is induced in activated myeloid cells and represses both Socs1 and Ship1 to enhance cytokine production by dendritic cells and macrophages (Fig. ​(Fig.2B)2B) 62. miR‐155 has also been shown to enable CD8+ T cells to respond to limiting doses of γ‐chain cytokines, which enables robust immune responses in lymphoreplete hosts 63. T cell receptor (TCR) signaling strength is regulated by miR‐181a, which modulates expression of several phosphatases that inhibit TCR‐induced signaling pathways resulting in activation of T cell genes (Fig. ​(Fig.2C)2C) 64. Thus, miRNAs can both enhance or hinder signaling pathways that control innate and adaptive immune responses that underlie inflammation.

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Figure 2

Mechanisms of miRNA function in the immune system. miRNAs can have various functions within the immune system and can act in different manners. A: For example, miR‐146a acts as an anti‐inflammatory miRNA via feedback inhibition of an inflammatory pathway. B: miR‐155, on the other hand, is a pro‐inflammatory miRNA that acts in a feed‐forward manner bolstering the immune response. C: miR‐181a is also a pro‐inflammatory miRNA that acts by inhibiting phosphatases that block the activation of T cell genes thus activating T cells. D: Finally, the miR‐17~92 cluster is involved in promoting the differentiation of a subset of inflammatory T cells called T follicular helpers cells (T_FH).

Further, miRNAs have also been shown to confer robustness to cellular states. In these scenarios, specific miRNAs play important roles in determining the extent to which differentiation occurs. For example, the miR‐17~92 cluster of miRNAs repress Pten and Phlpp2, inhibitors of Icos signaling in activated T cells, resulting in the skewing of cells into T follicular helper cells (Tfh cells) (Fig. ​(Fig.2D)2D) 65. In the absence of the miR‐17~92 cluster, these proteins are at higher levels and reduce the amount of Tfh cells produced during inflammatory responses. Another example is miR‐155, a miRNA that is necessary for both T cell homeostasis and optimal differentiation of multiple T cell types including Th17 66, 67, Tfh 68, Th2 69, and Th1 cells 70. In these cases, miR‐155 appears to be working through repression of multiple targets including Jarid2, Socs1, Ship1, Ets1, Peli1, Fosl2 (and possibly others). However, additional work is needed to determine if unique target/s are used by miR‐155 depending on the Th cell type produced. Because T cells are central regulators of inflammatory responses, their modulation by miRNAs is of significant relevance to chronic inflammatory states, as described below.

Additionally, several miRNAs have been implicated in regulating macrophage lineage skewing during inflammatory responses. Macrophages can be skewed toward either pro‐inflammatory subtypes (M1), or toward more reparative and less inflammatory subtypes (M2). miR‐ 125 has been shown to repress M1 skewing while promoting the M2 fate 71, 72. miR‐223 has also been implicated in macrophage skewing where miR‐223 promotes macrophage polarization toward the M2 subtype 73. Additionally, miR‐223 has been implicated in control of granulocyte activation, and miR‐223‐/‐ mice display overactive immune responses and develop inflammatory lung pathology 74.

Further highlighting the importance of miRNAs in human systems, greater numbers of miRNAs have emerged throughout evolution, in addition to increased target diversity 75. This suggests that miRNAs are among the regulatory mechanisms that enable increased human complexity despite a genome size that is similar to less complex organisms. This appears to include critical roles in establishing proper inflammatory set points and facilitating optimal responses and resolution by our immune system. In the next section, we will assess our current understanding of how miRNAs influence distinct types of chronic inflammatory conditions.

Functional roles for miRNAs during chronic inflammation

MicroRNAs are involved in inflammaging

As described above, the aging process itself is associated with inflammatory phenotypes. Early studies in C. elegans have functionally linked miRNAs to lifespan, perhaps offering a first clue that miRNAs are involved in different aspects of the aging process. For instance, lin‐4 loss‐of‐function mutants have shortened lifespans while lin‐14 loss‐of‐function mutants have increased lifespans 84. Additionally, mouse studies have shown that certain miRNAs alter expression patterns with aging. For example, in the mouse brain miR‐22 and miR‐101a are up‐regulated in aged mice 85. These studies reveal that miRNAs can both affect the aging process as well as be affected by it.

Recently, the roles of miRNAs in age‐dependent inflammatory phenotypes have started to be explored. In particular, it has been discovered that mice lacking miR‐146a develop an age‐dependent, chronic inflammatory disease that is spontaneous, life‐shortening, associated with inflammatory cytokines and autoantibodies, and that involves a variety of hematopoietic abnormalities and/or malignancies typically associated with the aging process 68. Further, the condition has been shown to involve activated lymphocytes and be largely dependent upon NF‐kB 86.

Our group and others have recently explored this miR‐146a deficiency phenotype further and found that it involves the spontaneous development of T follicular helper cells that play a pivotal role in facilitating germinal center (GC) B cell development, production of high affinity, class‐switched antibodies, and formation of B cell memory 68. Consistent with this, both Tfh and GC B cells begin to spontaneously arise in younger miR‐146a‐/‐ animals, and this precedes most other phenotypes in this model. Upon reaching middle age, these animals begin to produce anti‐dsDNA autoantibodies as a consequence of their deregulated GC response, and begin to display inflammation in a variety of different peripheral tissues. Of relevance, this phenotype was largely dependent on T cell expression of miR‐155 indicating that these two miRNAs counter‐regulate chronic inflammation. Although more work remains, it is plausible that these autoantibodies contribute to tissue stress and ultimately the onset of disease upon reaching old age (Fig. ​(Fig.33).

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Figure 3

Sequential threshold model of age‐dependent diseases linked to miRNA regulated chronic inflammation. During youth, the immune system has little chronic inflammation; however, as the aging process occurs, levels of inflammatory cells, such as T follicular helper cells (T_FH) and germinal center B cells (GCB), start to rise. Once the levels of these cells reach a certain threshold, they trigger increased inflammation and the production of autoantibodies. As levels of autoantibodies rise this might trigger tissue damage, which can accumulate and result in the clinical manifestation of chronic inflammatory diseases.

MicroRNAs are emerging biomarkers and therapeutic targets in chronic inflammation

As miRNAs have been functionally connected to the development of chronic inflammation, it follows that alterations to miRNA levels could be a reasonable way to detect the presence of chronic inflammatory states in patients. miRNAs are currently being used as diagnostics for at least some types of diseases, including some forms of chronic inflammation such as colitis and IBD 90, 91. With some diseases, miRNAs can even be used for both diagnosis and prognosis 92. The appeal of using miRNAs as diagnostic markers comes from the high sensitivity that miRNA biomarkers possess as well as the ability to use miRNA profiles to stratify distinct downstream disease outcomes. The hope is that miRNAs associated with chronic inflammation can be used to diagnose chronic inflammation before clinical manifestations appear. This would allow for preventative treatment of diseases that stem from chronic, low‐grade inflammatory states.

Recently, the identification of miRNAs in blood serum as well as other biological fluids has opened the door for diagnosis of various diseases using these samples obtained through non‐invasive methods. Serum miRNAs can either exist cell‐free in association with the RISC complex or within small lipid vesicles such as exosomes 93. Recently, there has been significant interest in utilizing these extracellular miRNAs as biomarkers because of their specificity and sensitivity of detection. Specific secreted miRNAs in the serum can be used to diagnose chronic inflammatory diseases such as IBD 94 where each disease has a unique profile of secreted miRNAs. This could also be an approach to diagnosing other forms of chronic inflammatory states, such as those described above.

The presence of extracellular miRNAs raises questions regarding the biological role of these secreted miRNAs. One current theory of the role of extracellular miRNAs, especially those within exosomes, is that they constitute a novel form of intercellular communication 95, 96. This idea is supported by several reports providing evidence that secreted miRNAs are functionally passed between various cell types including immune cells 97, 98, 99. It is possible that these extracellular miRNAs could play a role in the development, advancement, or inhibition of chronic inflammatory states. However, further investigation is needed to determine the role of extracellular miRNAs during chronic inflammation and diseases derived from this condition.

miRNAs have also begun to emerge as therapeutic targets. Currently, several anti‐miRNA therapeutics are in clinical trials: most notably antisense inhibitors of miR‐122 are being used to combat HCV infections 100, 101. The therapeutic targeting of miRNAs is discussed in further detail in Li and Rana's 2014 review 100. Based on the success of these approaches, it is our view that miRNAs that regulate chronic inflammation, such as miR‐155 or miR‐146a, could also be targeted therapeutically with optimal doses of anti‐miRs or miRNA mimics. Ideally, chronic inflammatory disease could be diagnosed early using miRNA detection in blood serum samples, and then possibly treated with specific cocktails targeting the particular miRNAs that are dysregulated. However, there are some barriers to utilizing miRNAs as therapies. One of the biggest hurdles is targeting the miRNA therapeutics to the cells of interest. Exosomes and other lipid carriers have received a lot of attention lately as possible ways by which miRNAs and other therapies may be delivered to specific cell types 102. However, there is still additional understanding that is required before these approaches can be effectively used in the clinic to provide specificity and sufficient dosing.

Long non‐coding RNAs are involved in chronic inflammation

MicroRNAs are currently the best characterized ncRNAs involved in chronic inflammation; however, there are also other emerging classes of ncRNAs, such as lncRNAs, that are also involved (Table 1) 54. LncRNAs appear to function through a variety of different molecular mechanisms, and most commonly play a scaffolding role to promote proper recruitment and positioning of protein regulators both in the nucleus and in the cytoplasm. Loss‐of‐function approaches have found that lncRNAs regulate the biology of both innate and adaptive immune cells during inflammatory responses. For example, there have recently been reports linking macrophage lncRNAs and obesity 103, as well as other studies that have implicated certain lncRNAs in macrophage and DC inflammatory functions 104. LncRNA have also been connected to the regulation of T cell homing and differentiation into effector subtypes 105. These and other classes of ncRNAs must be further characterized to better understand their roles in chronic inflammation. The role of lncRNAs in the immune system is reviewed further by Heward and Lindsay 54.

Conclusions and outlook

The association of chronic inflammation with a variety of diseases emphasizes the importance of gaining a deeper understanding of the underlying mechanisms behind this phenomenon. In this review, we have highlighted factors that contribute to chronic inflammation emphasizing the newly identified roles of miRNAs and other ncRNAs. As we move forward, it will be essential to consider contributions by both coding and noncoding factors in order to formulate an optimal approach for diagnosing, treating, and/or preventing diseases associated with chronic inflammation.

Despite the potential that ncRNAs pose as therapeutic reagents or targets, there are significant barriers that must be overcome in order to achieve therapeutic efficacy. Cell‐specific delivery of reagents to manipulate ncRNAs remains a significant challenge. Although progress has been made on cell targeting therapies utilizing lipid vesicles and nonlipid carriers containing antisense miRNAs or miRNA mimics, this remains a substantial challenge facing the field of ncRNA therapy. Additionally, delivery of effective doses of ncRNAs or their inhibitors is also a major hurdle for therapy. For diseases brought on by chronic inflammation, it may also be difficult to determine when to begin treatment, although the use of ncRNA biomarkers in patients’ biofluids should held to indicate when treatment should begin. Despite these barriers, the manipulation of ncRNAs represents a potential way to treat chronic inflammatory diseases, and hopefully surmounting these barriers will lead to more efficacious uses of ncRNAs as therapeutics.

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