Modulation of Signaling Mediated by TSLP and IL-7 in Inflammation, Autoimmune Diseases, and Cancer

Abstract

Thymic Stromal Lymphopoietin (TSLP) and Interleukin-7 (IL-7) are widely studied cytokines within distinct branches of immunology. On one hand, TSLP is crucially important for mediating type 2 immunity at barrier surfaces and has been linked to widespread allergic and inflammatory diseases of the airways, skin, and gut. On the other hand, IL-7 operates at the foundations of T-cell and innate lymphoid cell (ILC) development and homeostasis and has been associated with cancer. Yet, TSLP and IL-7 are united by key commonalities in their structure and the structural basis of the receptor assemblies they mediate to initiate cellular signaling, in particular their cross-utilization of IL-7Rα. As therapeutic targeting of TSLP and IL-7 via diverse approaches is reaching advanced stages and in light of the plethora of mechanistic and structural data on receptor signaling mediated by the two cytokines, the time is ripe to provide integrated views of such knowledge. Here, we first discuss the major pathophysiological roles of TSLP and IL-7 in autoimmune diseases, inflammation and cancer. Subsequently, we curate structural and mechanistic knowledge about receptor assemblies mediated by the two cytokines. Finally, we review therapeutic avenues targeting TSLP and IL-7 signaling. We envision that such integrated view of the mechanism, structure, and modulation of signaling assemblies mediated by TSLP and IL-7 will enhance and fine-tune the development of more effective and selective approaches to further interrogate the role of TSLP and IL-7 in physiology and disease.

The Salivary Microbiota, Cytokines, and Metabolome in Patients with Ankylosing Spondylitis Are Altered and More Proinflammatory than Those in Healthy Controls

“…Correspondingly, the inhibition of IL-6 transsignaling, wherein the complex of IL-6 and sIL-6R can stimulate cells that do not express IL-6R (such as endothelial cells and smooth muscle cells), is sufficient to block disease in mouse models of inflammatory bowel disease and RA ( 40 ). IL-10 is primarily an anti-inflammatory cytokine ( 37 ); IL-27 is a negative regulator of IL-12 ( 38 ); TSLP is a “master switch” for allergic inflammation ( 41 ); and MMP-3 can degrade extracellular matrix proteins and aggravate the inflammatory response ( 42 ). Importantly, increased MMP-3 levels have also been observed in supraspinous ligament samples from AS patients, whereas the degradation of extracellular matrix components is a pathological feature of chronic arthritis ( 43 ).…”

Expression and clinical significance of IL7R, NFATc2, and RNF213 in familial and sporadic multiple sclerosis

“…The identi cation of IL7R has made great strides in understanding the MS genetic risk factors (28). Increasing evidence has shown that this gene also promotes oligodendrocyte survival and myelination (29). Lei et al, have used metronidazole-induced demyelination in a transgenic zebra sh line in which oligodendrocytes expressed green uorescent protein (GFP).…”

Tezepelumab: A Potential New Biological Therapy for Severe Refractory Asthma

“…Short TSLP is constitutively present in many tissues where it plays a homeostatic role, whilst the production of the long isoform can be induced by proinflammatory stimuli and is increased in asthmatic patients [ 31 ]. The long variant of TSLP exerts its biological functions by selectively binding to its cognate receptor (TSLPR), and this interaction is promoted by the electrostatic attraction occurring between the positive charges of TSLP surface and the negative charges of TSLPR [ 32 , 33 ]. The resulting TSLP/TSLPR binary molecular aggregate in turn recruits the α subunit of the IL-7 receptor (IL-7Rα).…”

“…The resulting TSLP/TSLPR binary molecular aggregate in turn recruits the α subunit of the IL-7 receptor (IL-7Rα). As a consequence, the assembly of the extracellular ternary complex TSLP/TSLPR/IL-7Rα leads to activation of an intracellular signaling network including Janus kinases 1 and 2 (JAK1/2), signal transducers and activators of transcription 3 and 5 (STAT3/5), as well as nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPK), and phosphoinositide 3 kinase (PI3K) ( Figure 2 ) [ 31 , 32 , 33 ]. These signaling pathways lead to activation of genes encoding Th2 cytokines such as IL-4, IL-5, IL-9, and IL-13.…”