Allergy Asthma Immunol Res.  2018 Mar;10(2):106-120. 10.4168/aair.2018.10.2.106.

Can Controlling Endoplasmic Reticulum Dysfunction Treat Allergic Inflammation in Severe Asthma With Fungal Sensitization?

• Jeong JS
• Kim SR
• Lee YC

• KMID: 2402970
• DOI: http://doi.org/10.4168/aair.2018.10.2.106

Abstract

Severe asthma is a heterogeneous disease entity to which diverse cellular components and pathogenetic mechanisms contribute. Current asthma therapies, including new biologic agents, are mainly targeting T helper type 2 cell-dominant inflammation, so that they are often unsatisfactory in the treatment of severe asthma. Respiratory fungal exposure has long been regarded as a precipitating factor for severe asthma phenotype. Moreover, as seen in clinical definitions of allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS), fungal allergy-associated severe asthma phenotype is increasingly thought to have distinct pathobiologic mechanisms requiring different therapeutic approaches other than conventional treatment. However, there are still many unanswered questions on the direct causality of fungal sensitization in inducing severe allergic inflammation in SAFS. Recently, growing evidence suggests that stress response from the largest organelle, endoplasmic reticulum (ER), is closely interconnected to diverse cellular immune/inflammatory platforms, thereby being implicated in severe allergic lung inflammation. Interestingly, a recent study on this issue has suggested that ER stress responses and several associated molecular platforms, including phosphoinositide 3-kinase-δ and mitochondria, may be crucial players in the development of severe allergic inflammation in the SAFS. Defining emerging roles of ER and associated cellular platforms in SAFS may offer promising therapeutic options in the near future.

Keyword

Severe asthma; fungi; SAFS; ER stress; subcellular organelles; innate immunity

MeSH Terms

Aspergillosis, Allergic Bronchopulmonary
Asthma*
Biological Factors
Endoplasmic Reticulum*
Fungi
Immunity, Innate
Inflammation*
Mitochondria
Organelles
Phenotype
Pneumonia
Precipitating Factors
Biological Factors

Figure

• 

  Fig. 1 Fungal exposure leads to the activation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in the lung. Inhaled fungi possess a wide array of ligands that activate pattern recognition receptors (PRRs) expressed on structural cells (e.g. airway epithelial cells) and dendritic cells (DCs). Fungi can also produce large amounts of secreted enzymes, such as proteases, which disrupt tight junctions of airway epithelium. Initial recognition of fungi is followed by allergic sensitization and eosinophilic airway inflammation through close interactions between various facets of host immunity (not presented here). During this process, various cell types, including frontline cells (e.g. airway epithelial cells, DCs, and alveolar macrophages) and adaptive T and B cells, produce large amounts of cytokines/chemokines as well as host defensive molecules. Increased protein folding demand in these cells results in ER stress and triggers UPR. UPR signaling is orchestrated by 3 ER-localized sensors, namely, PERK, IRE1, and ATF6. These adaptive responses together reduce protein folding demand, increase enzymes and chaperones involved in protein folding, and facilitate protein degradation pathway. However, when cells fail to resolve ER stress, UPR mediates ER stress-induced apoptosis.

• 

  Fig. 2 Cytoplasmic interactions involving endoplasmic reticulum (ER), mitochondria, and NLRP3 inflammasome may contribute to fungi-induced severe eosinophilic allergic inflammation in the lung. Initial fungal recognition activates the cell membrane-associated phosphoinositide 3-kinase delta (PI3K-δ) signaling pathway in various structural cells and immune cells. This process is followed by the downstream cascade of protein interactions and phosphorylation, leading to diverse biological consequences in these cells. Particularly, PI3K-δ modulates fungi-induced ER stress and UPR activation, especially in airway epithelial cells. Furthermore, mitochondrial generation of reactive oxygen species (mtROS) and NLRP3 inflammasome activation in response to respiratory fungal exposure are closely related to this process. The net result of these associations may play a key role in the pathogenesis of fungi-induced severe eosinophilic allergic inflammation in the lung.

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