Thymic stromal lymphopoietin and alarmins as possible therapeutical targets for asthma

Abstract

Purpose of reviewOverview of epithelial cytokines, particularly thymic stromal lymphopoietin (TSLP), released by the airway epithelium and the effects of their inhibition on the outcomes of patients with asthma. Recent findingsThe epithelial cytokines are early mediators at the top of the inflammatory cascade and are attractive therapeutic targets to prevent exacerbations and improve lung function in patients with type 2 and nontype 2 asthma. SummaryClinical trials demonstrated that tezepelumab, an anti-TSLP monoclonal antibody, is a promising alternative treatment for asthma that is effective also in nontype 2 asthma. The PATHWAY and NAVIGATOR trials have assessed its effects in improving outcomes on broad clinically diverse populations. The identification of biomarkers will help to predict potential responders and help in asthma treatment personalization.

The lung-gut crosstalk in respiratory and inflammatory bowel disease

“…Thymic stromal lymphopoietin (TSLP), is critical to induce the activation of both innate and adaptive immune responses in asthma. It can activate the STAT5 signaling pathway, and mediate eosinophils recruitment and type 2 cytokines secretion by ILC2 or Th2 cells ( Lin et al., 2016 ; Salvati et al., 2021 ). IL-6, one of the main inflammatory cytokines during infectious respiratory diseases, is the main activating factor of Th17 cells subset which can drive Th17 inflammatory response in multiple organs ( Vargas-Rojas et al., 2011 ; Lin et al., 2016 ) and regulate the number and phenotype of microbe-responsive regulatory T cells in the gut ( Yan et al., 2021 ).…”

Therapeutical Targets in Allergic Inflammation

“…Recently, the FDA has approved tezepelumab as maintenance therapy for severe asthma. This is the first approved monoclonal antibody targeting thymic stromal lymphopoietin (TSLP), an epithelial cytokine released by the airway epithelium that acts as early mediator at the top of the allergic inflammatory cascade in asthma [ 72 , 73 , 74 ].…”

Alarming inflammation: The TGFβ1–Nrp1 pathway upregulates the IL‐33 axis in lung ILC2s

“…On the contrary, the IL‐33 axis is undergoing extensive studies in asthma, especially considering the central role of this pathway in childhood asthma. Anti‐IL‐33 mAbs (itepekimab, etokimab, and tozorakimab) and anti‐ST2 mAbs (astegolimab and melrilimab) have been developed and are under clinical investigation 5 . Itepekimab increased disease control and slightly improved lung function in moderate‐to‐severe asthma without any appreciable differences when compared to dupilumab, an anti‐IL‐4Rɑ monoclonal antibody, 6 while astegolimab reduced exacerbations in patients with severe asthma independently from blood eosinophil counts 7 .…”

“…Anti-IL-33 mAbs (itepekimab, etokimab, and tozorakimab) and anti-ST2 mAbs (astegolimab and melrilimab) have been developed and are under clinical investigation. 5 Itepekimab increased disease control and slightly improved lung function in moderate-to-severe asthma without any ap- monoclonal antibody, 6 while astegolimab reduced exacerbations in patients with severe asthma independently from blood eosinophil counts. 7 Given the pleiotropic immunomodulatory functions of IL-33, the possibility to interfere with lung ILC2s' activation without blocking this cytokine is intriguing (Figure 1).…”