Sounding the alarmins-The role of alarmin cytokines in asthma

Abstract

The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

Keywords: alarmin cytokines; asthma; clinical trials; eosinophilia; exacerbation.

FIGURE 1

Release mechanisms of airway epithelial cell‐derived alarmins. Immune responses in AEC are initiated through PRR recognition of highly conserved motifs of invading pathogens including lipopolysaccharides, peptidoglycans, viral DNA, and bacterial flagellin. For example, in allergic asthmatic airways, Der p2, a sensitizing protein of house dust mite allergen, activates TLR‐4 to release epithelial‐derived alarmins ultimately driving type 2 airway inflammation. CLRs (e.g., dectin‐1 and MRs) recognize allergen carbohydrate motifs causing alarmin secretion from AEC. Allergen‐derived serine proteases activate PAR‐2 receptors causing alarmin release from AEC, and they also target the protease sensor region of IL‐33 generating a hyperactive shorter IL‐33 isoform with 30‐60X the biological activity of IL‐33_FL. Airway epithelial cell = AEC; C‐type lectin receptor = CLR; full‐length IL‐33 = IL‐33_FL; mannose receptors = MR; nucleotide‐binding oligomerization domain (NOD)‐like receptors = NLR; Pattern recognition receptor = PRR; pathogen‐associated molecular pattern = PAMP; protease‐activated receptors = PAR; retinoic acid‐inducible gene‐I (RIG‐I)‐like receptors = RLR; Toll‐like receptor = TLR.

FIGURE 2

Overview of the pathobiology and pathophysiology of the alarmin cytokines in asthmatic airways leading to clinical sequelae. Triggered release of alarmin cytokines from airway epithelium targets a variety of structural cells as well as innate and adaptive immune cells, leading to the release of mediators contributing to airway remodeling, airway hyperresponsiveness, and inflammation.

FIGURE 3

Allergen‐induced airway responses attenuated by blockade of TSLP. In mild allergic asthmatics that develop allergen‐induced early‐ and late‐phase bronchoconstriction, enhanced airway responsiveness, and increased levels of eosinophils and FeNO in airways, treatment with anti‐TSLP MAb significantly attenuates these airway responses.

FIGURE 4

Effects of TSLP on the dendritic cell/T cell axis. TSLP induces the maturation of dendritic cells leading to the upregulation of co‐stimulatory molecules important for the polarization of T cells to a T2 phenotype and macrophages to M2 phenotype. TSLP also induces dendritic cells to drive lymphopoiesis and ILC2 activation.

FIGURE 5

Potential mechanisms of the alarmin cytokines in human airways causing bronchoconstriction and airway remodeling. Data generated from human cells studied in vitro and ex vivo have been summarized to illustrate the effects of alarmin stimulation in structural cells that are known to contribute to airway remodeling, and in immune cells that are known to contain spasmogens.