Eosinophilic inflammation: An Appealing Target for Pharmacologic Treatments in Severe Asthma

Abstract

Severe asthma is characterized by different endotypes driven by complex pathologic mechanisms. In most patients with both allergic and non-allergic asthma, predominant eosinophilic airway inflammation is present. Given the central role of eosinophilic inflammation in the pathophysiology of most cases of severe asthma and considering that severe eosinophilic asthmatic patients respond partially or poorly to corticosteroids, in recent years, research has focused on the development of targeted anti-eosinophil biological therapies; this review will focus on the unique and particular biology of the eosinophil, as well as on the current knowledge about the pathobiology of eosinophilic inflammation in asthmatic airways. Finally, current and prospective anti-eosinophil therapeutic strategies will be discussed, examining the reason why eosinophilic inflammation represents an appealing target for the pharmacological treatment of patients with severe asthma.

Keywords: biologic drugs; eosinophil; severe asthma; type 2 inflammation.

Figure 1

Eosinophil structure, granules, surface receptors, exosomes and EETs. Eosinophils are supplied by a large number of proteins, receptors and enzymes that allow them to interact with the microenvironment and express a number of receptors on their surface, including receptors for cytokines, chemokines and lipid mediators, which are involved in cell growth, survival, adhesion, migration and activation. In addition to receptors, adhesion molecules such as integrins are expressed on the cell surface, which allows eosinophils to migrate and react to several stimuli. The effects of eosinophils are largely achieved due to the content of their granules. Primary granules include Charcot-Leyden/galectin-10 protein, a characteristic eosinophilic protein implicated in asthma and parasitic infections, as well as a constituent part of so-called eosinophilic extracellular traps, whose other major constituents are nuclear or mitochondrial DNA strands. Specific or secondary granules contain four main cationic proteins: MBP, ECP, EPX and EDN. In addition, some of the content of the granules is released through particular vesicles called sombrero vesicles. Each of them has different effects, clarified in the text. Lipid bodies contain prostaglandins, thromboxane and leukotrienes, which participate in allergic inflammation, fibrosis and thrombosis. Finally, eosinophils are able to release exosomes that fuse with the cell membrane, which are involved in epithelial damage. CLC/Gal-10: Charcot-Leyden crystal proteins; ECP: eosinophil cationic protein; MBP: major basic proteins; EPX: eosinophil peroxidase; EDN: eosinophil-derived neurotoxin; MHC class II: Mayor histocompatibility complex-II; EET: eosinophilic extracellular traps. See the text for further explanation.

Figure 2

Following different stimulations, eosinophils can release the contents of the granules by classical exocytosis, compound exocytosis, piecemeal degranulation (PMD) or cytolysis. Conventional exocytosis consists of the release of granule content by fusion of the granule itself to the cellular membrane (panel A). Compound exocytosis is another type of exocytosis in which granules in which granules merge with each other before interacting with the cellular membrane (panel B). Piecemeal degranulation is the progressive and selective release of vesicles from specific granules and the unloading of their contents after the fusion with the cellular membrane (panel C). Cytolysis is a non-apoptotic form of cell death with rupture of the nuclear and plasma membrane, subsequent release of nuclear DNA and deposition of specific intact granules in the extracellular space. After cytolysis, there may be the release of eosinophilic extracellular traps (EETs), giving this peculiar form of cell death the characteristic name of EETosis (panel D).

Figure 3

The centrality of the eosinophil in the pathophysiology of T2 asthma. The main effect can be summarized in four peculiar activities: airway damage, airway remodeling, airway hyperresponsiveness, and mucus production. When activated eosinophils reach the airways, they release specific granules whose contents have cytotoxic properties that can cause direct damage to the airways. The content of these granules, especially MBP and EPO, is also able to stimulate mast cells and basophils to release histamine, which contributes to bronchial hyperresponsiveness together with the direct action triggered by the release of IL-13 and leukotrienes by the eosinophil itself. IL-13 also increases mucus secretion by promoting the differentiation of goblet cells. Airway remodeling is associated with smooth muscle cell hyperplasia and fibroblast proliferation, which are promoted by TGF-β released both as a result of epithelial damage and as an exosomal content of eosinophils. TGF-β is also responsible for structural changes to the extracellular matrix, by increasing the production of collagen and glycosaminoglycans. IL-13: interleukin-13; MBP: mayor basic protein; EPO: eosinophil peroxidase; TGF-β: transforming growth factor-β.