In particular, TSLP inhibits the production of the anti-inflammatory cytokine interleukin-10 (IL-10) by Treg lymphocytes, thus impairing the suppressive effects exerted by these cells on allergic proinflammatory pathways [70]

In particular, TSLP inhibits the production of the anti-inflammatory cytokine interleukin-10 (IL-10) by Treg lymphocytes, thus impairing the suppressive effects exerted by these cells on allergic proinflammatory pathways [70]. In addition to being implicated in the pathobiology of type 2 airway inflammation, TSLP appears to be involved in T2-low neutrophilic asthma, characterized by a pivotal pathogenic role played by Th17 lymphocytes [71]. airway remodeling [1,2]. A hallmark of asthma is the heterogeneity of airway inflammation, expressed by several phenotypes sustained by underlying different endotypes, which consist of complex cellular and molecular pathogenic mechanisms (Figure 1) [3,4,5]. The most frequent endotypes are grouped under the umbrella term type 2 (T2) asthma, which includes allergic and non-allergic traits, mostly outlined by eosinophilic inflammation [6,7]. Differently from type 2 airway inflammation, T2-low asthma can be featured by either neutrophilic or paucigranulocytic patterns [8,9,10]. Open in a separate window Figure 1 Putative role of TSLP in several asthma pathways. In allergic asthma, via activation of dendritic cells, TSLP promotes the differentiation of Th2 lymphocytes secreting IL-4, IL-5, IL-9, and IL-13, which target B cells, eosinophils, mast cells, and airway smooth muscle cells, respectively. IL-4 and IL-13 are also produced by basophils. In non-allergic eosinophilic asthma, TSLP stimulates ILC2 to release IL-5 and IL-13. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of neutrophil-activating Th17 NSI-189 lymphocytes. In paucigranulocytic asthma, TSLP NSI-189 mediates the complex crosstalks involving inflammatory cellular elements, such as mast cells, and airway structural cells including epithelial cells, fibroblasts, and smooth muscle cells. TSLP: thymic stromal lymphopoetin; Th: T helper; ILC2: group 2 innate lymphoid cells; IL: interleukin; TGF-: transforming NSI-189 growth factor-. This original figure was created by the authors using BioRender.com. In addition to chronic inflammation, all asthma endotypes are often characterized by airway structural NSI-189 changes, which span throughout the various layers of the bronchial wall [11]. These remodeling features include goblet cell metaplasia/hyperplasia, subepithelial fibrosis sustained by activation of fibroblasts and myofibroblasts, smooth muscle thickening, and neo-angiogenesis [11]. In T2-high asthma, the development, persistence, and amplification of eosinophilic inflammation are driven and orchestrated by multiple cellular elements including dendritic cells, T helper 2 (Th2) lymphocytes, group 2 innate lymphoid cells (ILC2), mast cells, basophils, and airway epithelial cells [12,13,14]. Within this endotypic context, a key pathophysiologic role is played by thymic stromal lymphopoietin (TSLP), an innate cytokine especially involved in type 2 eosinophilic inflammation, but also implicated in neutrophilic and paucigranulocytic asthma [15,16,17]. Indeed, TSLP stimulates dendritic cells to guide the differentiation of na?ve Th cells towards the Th2 lineage, but can also promote Th17 commitment [15]. Moreover, TSLP activates ILC2, mast cells, and basophils, induces eosinophil survival and transmigration, and also affects the functions of airway structural cells such as fibroblasts and airway smooth muscle cells [15]. Most patients with mild or moderate asthma are well controlled by inhaled corticosteroids (ICS), eventually integrated by the addition of long-acting 2-adrenergic agonists (LABA) within ICS/LABA fixed combinations [18]. Furthermore, asthmatics with more severe disease may need additional medications such as leukotriene modifiers, tiotropium, and even oral corticosteroids (OCS) [19,20]. Despite all these treatments, severe asthma can remain uncontrolled, thus requiring adjunctive biological therapies based on the use of monoclonal antibodies directed against immunoglobulins E (IgE), interleukin 5 (IL-5), IL-5 receptor, or interleukin-4 (IL-4) receptor [21,22,23,24,25,26]. These are excellent add-on treatments, but they could not be effective for all patients with severe T2-high asthma, and they do not Rabbit polyclonal to AIBZIP provide any benefit for T2-low asthmatic patients. In particular, the most relevant goals of biological therapies for severe asthma include the decreases in both exacerbation rate and OCS intake, as recently highlighted by the PONENTE NSI-189 trial (Study NCT03557307, https://clinicaltrials.gov/ website. Poster presentation at the American Academy of Allergy Asthma & Immunology, 26 FebruaryC1 March 2021). In addition to the already approved, above-mentioned anti-asthma.

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