Mast cells in asthma – state of the art

Abstract

Summary Mast cells (MCs) play a central role in tissue homoeostasis, sensing the local environment through numerous innate cell surface receptors. This enables them to respond rapidly to perceived tissue insults with a view to initiating a co‐ordinated programme of inflammation and repair. However, when the tissue insult is chronic, the ongoing release of multiple pro‐inflammatory mediators, proteases, cytokines and chemokines leads to tissue damage and remodelling. In asthma, there is strong evidence of ongoing MC activation, and their mediators and cell–cell signals are capable of regulating many facets of asthma pathophysiology. This article reviews the evidence behind this.

Glucocorticoid and TNF signaling converge at A20 (TNFAIP3) to repress airway smooth muscle cytokine expression

“…More generally, our data also highlight the importance of negative feedback control of inflammation in ASM and suggest that selective cross-talk between GCs and NF-B may underpin steroid-mediated repression of TNF signaling. In that regard, whereas induction of NF-B is associated with asthma exacerbations, asthmatic inflammation is heterogeneous and integrates diverse signals from a diverse array of cytokines and cell types (9,18,33,48). It will be of significant future interest to determine whether GCs augment negative feedback mechanisms in the complex inflammatory milieu of the asthmatic airway.…”

Cistrome-based Cooperation between Airway Epithelial Glucocorticoid Receptor and NF-κB Orchestrates Anti-inflammatory Effects

“…Included in this set were: SERPINA1 (Fig. 7A), the gene that encodes for ␣1 antitrypsin, a major genetic cause of emphysema in humans (62); EDN2, whose disruption causes emphysema in mice (63); SOD2, which protects the airway epithelium from oxidative damage (64,65); SERPINA3, which encodes the ␣1 anti-chymotrypsin gene, a potent inhibitor of mast cell proteases that is implicated in asthma pathogenesis (66,67); FOXP4, which represses goblet cell differentiation and mucus secretion (68); and ABR (Fig. 7A), a RAC inhibitor whose deficiency worsens airway hyperresponsiveness and inflammation in murine allergic asthma models (69).…”

Matrix Metalloproteinase-1 Activation Contributes to Airway Smooth Muscle Growth and Asthma Severity

“…Mast cells, particularly activated, degranulated forms, are more common within ASM bundles of those with asthma (10)(11)(12) and generate proinflammatory cytokines including IL-4, IL-5, and IL-13, which regulate IgE production, eosinophilic inflammation, and profibrogenic cytokines, including transforming growth factor-b and basic fibroblast growth factor-2. Preformed serine proteases including tryptase, chymase, and carboxy-peptidase are secreted from granules and interact with various cell types via proteolytically activated receptors (PARs) (11).…”

“…Preformed serine proteases including tryptase, chymase, and carboxy-peptidase are secreted from granules and interact with various cell types via proteolytically activated receptors (PARs) (11). Collectively, mast cell mediators contribute to airway inflammation, hyperresponsiveness and remodeling causing bronchoconstriction, ASM cell proliferation, and inflammatory cell recruitment (13).…”