Abstract
The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.
Highlights
Reviewed by: Martin Stacey, University of Leeds, United Kingdom Bernahrd Ryffel, Centre National de la Recherche Scientifique (CNRS), France
In 2010, the current nomenclature was adopted, from which IL-1F5 was designated as IL-36Ra, IL-1F6 was designated as IL-36a, IL-1F8 was designated as IL-36b, and IL-1F9 was designated as IL-36g (9) (Table 1)
This first study determined that IL-36g enhances the activation of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling through the orphan receptor IL-1 Receptor-Related protein 2 (IL-1Rrp2) – a receptor that is highly expressed in epithelial cells and in embryonic tissue
Summary
After the discovery of this subfamily of cytokines, functional studies, aimed to understand the biology of IL-36 cytokines, as well as their role in inflammation were performed using in vitro platforms. Regarding why the binding of proinflammatory IL-36 cytokines to IL-1Rrp[2] induces the recruitment of IL-1ARcP whereas the ligation of IL-36Ra to IL-1Rrp[2] does not, one report identified the existence of two structural loops present in human IL-36g – one between bstrands 11 and 12 and one between b-strands 4-5 – that appear to be involved in the recruitment of IL-1RAcP to the IL-1Rrp2/IL36g complex and the consequent induction of downstream signaling (Figure 4D) (57). Even though the baseline expression of IL-1Rrp[2] at the transcript level is lower in lung tissue compared to that in the skin, instillation of recombinant cleaved IL-36a (73) and IL-36g (41, 74) into the lungs of healthy mice results in rapid induction of cytokine production and neutrophil recruitment in the alveolar space, highlighting that IL-36 cytokines exert potent pro-inflammatory effects in the lungs. The Gram-positive pathogen Spn is the most common cause of community acquired pneumonia worldwide (79) and poses a major threat to public health given its ability to cause pneumococcal invasive diseases and the emergence of multidrug resistant clones and serotypes not covered in the current
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