Michael Roth discusses soluble circulating cytokine receptors in chronic inflammatory lung diseases, which he describes as the under-estimated regulators of inflammation and remodelling
Chronic inflammatory lung diseases including asthma and the smoker’s lung (COPD) are the most frequent non-transmissible chronic diseases of the lung. None of them can be cured by any of the existing medication and therapies, only symptom control is possible. According to the American Thoracic Society, a major obstacle to cure these diseases is the lack of knowledge on the mechanisms that maintain the lung’s tissue structure. Chronic inflammation is still regarded as the major pathology and tissue remodelling resulting from the long-lasting disease. However, more and more studies suggest that both pathologies can occur independent of each other and they can initiate each other.
In asthma, pro-inflammatory cytokines and growth factors are in the focus of research including transforming growth factor (TGF)-β1, thymic stromal lymphopoietin (TSLP), interleukin (IL)-4, IL-5, IL-13, and IL-33. All these cytokines stimulate B-cells to switch antibody production towards IgE, activate mast cells, and attract eosinophil to infiltrate the airways. New asthma drugs were developed to either neutralise specific T2 cytokines or block their receptors.
In COPD a similar set of cytokines is investigated: Tumour necrosis factor (TNF)-α, TGF-β1, IL-6, IL-8, CXCL9 (C-X-C motif ligand 9), CXCL10, CXCL11, CCL2 (C-C motif chemokine ligand 2), and CXCL12. Currently, several animal studies are investigating if neutralising antibodies to some of these cytokines may reduce tissue damage caused by cigarette smoke. However, none of these have entered the clinical trial phase.
All cytokines activate their target cells by binding to their specific receptor proteins that are expressed on the outside of the cell membrane. Upon binding, these receptors undergo conformational changes, which most often results in their phosphorylation and this phosphate group is handed down a line of subsequent signalling proteins. Thereby, they finally activate or inhibit cell type specific responses such as inflammation, or remodelling, or cell proliferation, or cell differentiation. This process, however, can be interrupted by soluble cytokine receptors, which are generated by either mRNA splicing, or by shedding an existing membrane bound receptor through unknown enzymes.
Soluble receptors have also been described for growth factors such as TGF-β. Soluble TGF-β receptors-I, -II and -III have been reported in other diseases, where they blocked TGF-β signalling, and thereby reduced remodelling or tissue repair. A very similar scenario applies to TNF-α and its soluble receptors sTNF-R1 and –R2 in chronic utricaria. Both TNF-α and TGF-β1 are major regulators of inflammation and tissue remodelling in asthma and COPD. However, no study has investigated the ratio of TNF-α or TGF-β1 and their soluble receptors in these conditions.
In regards to type-2 cytokine, IL-4 binds to either a heterodimer receptor complex (type I), formed by the IL-4 receptor subunit-α (IL4Rα), the cytokine receptor common γ-chain (γc), or to a heterodimer (type II) consisting of one IL4Rα and one IL-13 receptor-α 1 subunit (IL13Rα1). In contrast, IL-13 can only bind and activate IL13Rα1. Type-I and type-II receptors are cell type specifically expressed. However, the therapeutic application of neutralizing anti-IL-4 (dupilumab, DupixentTM) and anti-IL-13 antibodies did not achieve the expected benefits in patients. More specific anti-IL-4 antibodies (AMG 317) are also assessed in clinical trials for their application to allergic diseases. Thus, newly developed strategies aim to block the IL-4 and IL-13 receptors. Furthermore, truncated forms of the IL4Rα subunit (pitrakinra) are tested for asthma therapy. It is assumed that such truncated receptor protein will bind IL-4 and prevent its binding to the cell surface receptor. However, as IL4Rα and IL13Rα1 signal through the same intracellular pathways it has to be proven that blocking one of them is sufficient to reduce inflammation sufficiently.
Neutralising anti-IL-5 antibodies (Mepolizumab, Reslizumab, Benralizumab) and anti-IL-5 receptor-α subunit antibodies were also tested for allergic diseases including asthma. It is hoped that neutralising IL-5 or inhibiting its receptor will reduce eosinophil infiltration and degranulation, which is a main pathology in allergic asthma. Therapy with neutralizing IL-5 halved exacerbation rates and oral steroid use but did not improve health-related quality of life scores or lung function significantly.
Blocking cytokine receptors for reducing inflammation and remodelling might cause unwanted side effects in long-term therapy. Many of the membrane bound cytokine receptors can be shed and enter into the circulation as soluble receptors. The function of most of these soluble receptors is not well known, and it is indicated that they have an important role to maintain healthy. Over 20 years ago, such a system was described for IL-6 and its receptors. The IL-6 receptor unit-1 (IL6Rα) was not only expressed on the cell membrane, but was under normal conditions present as a soluble short version (sIL6Rα) in the blood. Reduced sIL6Rα in the serum was an indicator for inflammation. Blocking sIL6Rα reduced inflammation, but under non-disease condition, it prevented fat burning and caused obesity.
Therefore, the therapeutic application of inhibitors to sIL6Rα became difficult and required additional monitoring. Until today, the physiological mechanism that controls sIL6Rα synthesis either by splicing or by shedding from the cell membrane remains unclear. Thus, measuring IL-6 itself as an indicator for inflammation was insufficient, only the ratio of IL-6 and its soluble receptor indicated if IL-6 will induce fever, and inflammation.
In the late 90’s, the soluble IL-4 receptor was reported in the serum of patients with infection or inflammation, and it was shown to reduce inflammation. A similar anti-inflammatory effect was reported for the soluble IL-5 receptor. In contrast, the soluble IL-13 receptor caused signalling after ligand binding. Thus, blocking cytokine receptors without knowing their function under normal physiological conditions may cause unwanted side effects. Therefore, we need to understand the role of soluble cytokine receptor in physiology before we block them.
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