Since the discovery of T helper 17 (Th17) cells, an increasing body of evidence indicates that these cells play a major role in the development and progression of inflammatory and autoimmune diseases . Importantly, it has been shown that there is an inverse relationship between Th17 and regulatory T cells (Treg). The Treg cell type has anti-inflammatory properties, maintains tolerance to self-components and can cause quiescence of autoimmune diseases . Th17 cells represent a pro-inflammatory subset, whereas Treg cells have an antagonist effect and their developmental pathways are reciprocally interconnected . Generation of effector T cells or Tregs from naive precursors is referred to as T-cell differentiation – a process heavily influenced by the prevailing environmental inputs present during T-cell activation. The relative dominance of these populations can determine the difference between autoimmune pathology and tolerance. As a matter of fact, an interleukin (IL)-17 increase has been observed in different autoimmune diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, systemic lupus erythematosus and multiple sclerosis .
As outlined by Baeten and Kuchroo, IL-17 is now considered a key mediator of chronic tissue inflammation, and for its involvement in several autoimmune diseases it has become the target for new therapeutic approaches. Recent evidence obtained both in knockout animal models (IL-17 knockout mice) as well as human experimental data has indicated that IL-17 plays a critical role in the pathogenesis of psoriatic disease. Th17 cells have been detected in dermal infiltrates of psoriatic lesions as well as in synovial fluid of psoriatic arthritis patients.
IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. In psoriasis, IL-17 production by CD4+ T cells is induced by IL-23secreted by dendritic cells in the dermis of patients. As a matter of fact, an antibody that selectively binds and neutralizes IL-17 has been proven to be therapeutically effective in the treatment of psoriasis .
In recent years, IL-12 and IL-23 have become targets for newer biologic therapy agents, such as briakinumab and ustekinumab, which function by targeting the common p40 subunit of IL-12 and IL-23 . Ustekinumab is a human monoclonal antibody that binds to the shared p40 protein subunit of human IL-12 and IL-23 with high affinity and specificity, thereby preventing interaction with their cell surface IL-12R beta 1 receptor.
When the IL-23 receptor is activated, it promotes the development of Th17 cells, characterized by the production of IL-17A, IL-17F, and IL-22 . New biologic therapies of psoriasis include antibodies to IL-23. Human antibody specific for the IL-12 p40 subunit, which prevents interaction with IL-12R beta 1, has been shown to rapidly downregulate Th1 cytokines, chemokines, and IL-12/IL-23 and agents that specifically target these cytokines improved psoriasis in early clinical trials .
Baeten and Kuchroo recall that IL-23R is a receptor crucial for the development and stability of Th17 cells, and that a variety of innate and acquired immune cells – other than canonical Th17 – can produce IL-17A in response to IL-23; therefore addressing the central role of IL-23 in the activation of cells producing IL-17A.
The authors also describe the rationale of developing programs of antibody to IL-17A in multiple sclerosis and ankylosing spondylitis, and that non-Th17 immune cells can release IL-17A in response to IL-23, suggesting that the IL-23→IL-17 axis may have a pathogenic role independent of canonical Th17 cells in ankylosing spondylitis.
Of note, IL-17 has recently been associated with the development and progression of atherosclerotic lesions. Atherosclerosis is a low-grade, chronic inflammatory disease underlying different types of arterial wall lesions, from flat stable phenotypes to ulcerated complicated ones [9-12].
Development of these plaques was considered until few years ago to be the result of cytokines released in the microenvironment of the plaques, stimulating thrombotic complications or consolidating the fibrous cap of stable plaques . These effects were assigned to a Th1/Th2 imbalance.
Recent evidence indicates, however, that another, more important mechanism is influencing the atherosclerosis progression – the Th17/Treg imbalance. Th17 cells produce IL-17 as well as TNF- α and IL-6. Previous reports showed a remarkable Th17/Treg functional imbalance in patients with acute coronary syndrome and unstable carotid atherosclerotic plaques [14,15]. These data were confirmed in mice experimental models .
Moreover the increase of IL-17 serum levels in patients bearing atherosclerotic plaques was paralleled by increase in IL-6 and TNF- α levels too, so that it was concluded that the increased peripheral blood Th17 cells and Th17-associated cytokines are positively associated with the severity and progression of carotid plaques .
Recent data in the literature seem to delineate a hierarchical cytokines framework that promotes several chronic inflammatory diseases. In fact, as suggested in the paper by Baeten and Kuchroo, IL-17 inhibition may be effective in the treatment of psoriasis, multiple sclerosis and ankylosing spondylitis but ineffective for Crohn’s disease.
The study of the immunological and pathological pathways taking place in specific organs, and the knowledge of cellular sources of different cytokines should be very relevant to the development of new therapeutic approaches that target selectively the resolution of tissue-specific chronic inflammatory processes.
Rita Businaro, MD, PhD; Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy; email: email@example.com
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Cover image credit: The IL-17 family of cytokines. Schematic representation of the different IL-17 cytokines and their receptors. The main signaling events downstream the activation of the IL-17A receptor are summarized. From: The IL-17 Family of Cytokines in Psoriasis: IL-17A and Beyond by Nicolò Costantino Brembilla et al. Front. Immunol., 02 August 2018.