Allergol Immunopathol (Madr). 2021;49(2):191–207 eISSN:1578-1267, pISSN:0301-0546 Allergologia et immunopathologia Sociedad Española de Inmunología Clínica, Alergología y Asma Pediátrica COP U B L I DO C A T I ON N S www.all-imm.com REVIEW OPEN ACCESS Eosinophil: a central player in modulating pathological complexity in asthma Pulak Pritama, Sanjeet Mannaa, Abhishek Sahub, Shasank Sekhar Swainc, Shankar Ramchandanid, Sachidananda Bissoyib, Manasa Kumar Pandae, Yengkhom Disco Singf, Yugal Kishore Mohantag, Rajendra Kumar Beherab, Bimal Prasad Jitb* aRegional Institute of Biotechnology, Bhubaneswar, Odisha, India bSchool of Life Sciences, Sambalpur University, Sambalpur, Odisha, India cDivision of Microbiology and NCDs, ICMR-Regional Medical Research Centre, Bhubaneswar, Odisha, India dVeer Surendra Sai Institute of Medical Science and Research, Sambalpur, Odisha, India eInstitute of Mineral and Material Technology, CSIR, Bhubaneswar, Odisha, India fCentral Agricultural University, Imphal, India gUniversity of Nizwa, Oman Received 12 September 2020; Accepted 4 November 2020 Available online 1 March 2021 KEYWORDS Abstract eosinophil; Eosinophils are the major inflammatory cells which play a crucial role in the development asthma; of allergic and non-allergic asthma phenotypes. Eosinophilic asthma is the most heteroge- allergy; neous phenotype where activated eosinophils are reported to be significantly associated with inflammation; asthma severity. Activated eosinophils display an array of cell adhesion molecules that not bronchoconstriction only act as an activation marker, suitable for assessing severity, but also secrete several tissue factors, cytokines and chemokines which modulate the clinical severity. Eosinophil activations are also strictly associated with activation of other hetero cellular populations like neutro- phils, macrophages, mast cells, and platelets which culminate in the onset and progression of abnormal phenotypes such as bronchoconstriction, allergic response, fibrosis instigated by tissue inflammation, epithelial injury, and oxidative stress. During the activated state, eosino- phils release several potent toxic signaling molecules such as major basic proteins, eosinophil peroxidase, eosinophil cationic protein (ECP), and lipid mediators, rendering tissue damage and subsequently leading to allergic manifestation. The tissue mediators render a more com- plex manifestation of a severe phenotype by activating prominent signaling cross-talk. Here, in the current review with the help of search engines of PubMed, Medline, etc, we have tried to shed light and explore some of the potent determinants regulating eosinophil activation leading to asthma phenotype. © 2021 Codon Publications. Published by Codon Publications. *Corresponding author: Bimal Prasad Jit. School of Life Sciences, Sambalpur University, Jyoti Vihar, Burla, Sambalpur, Odisha, India. Email address: [email protected] https://doi.org/10.15586/aei.v49i2.50 Copyright: Pulak Pritam, et al. License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/ 192 Pulak Pritam et al. Introduction (IL-5), late differentiation factor which is only active in eosinophil and basophils.15–17 Eosinophilia in patients with Asthma is a globally important non-communicable dis- asthma–especially sputum and blood–are significantly asso- ease of a major public health concern due to its signifi- ciated with basement membrane inflammation of airway cant morbidity, mortality, and clinical severity in both mucosa in comparison to the non-atopic control subjects.18–20 children and adults.1 Although prevalence, severity, and Plenty of evidence indicates variations in eosino- mortality vary with respect to the geographical location, phil count with respect to different corticosteroids thus psychological, and environmental factors, genetic deter- regulating asthma severity.15,21,22 Airway eosinophilia is minants as well as sex also play a prominent role in mod- significantly associated with exacerbation and plays a pre- ulating disease severity.2,3 As per the evidence, low- and dominant role in airway remodeling. Several cell adhesion middle-income countries exhibit higher mortality ratios receptor expressions on activated eosinophils are highly compared to high-income countries, where the disease is crucial in mediating eosinophil arrest in the vascular most prevalent.4 More than 300 million people are affected region, extravasations into the airway wall through bron- by asthma in the world and it is expected that a further chial and epithelial tissue to the airway lumen. It is evident 100 million will be affected by 2025.5 Although the role of that eosinophils in their activated state are characterized key molecular players in the progression of the disease is by an increase in inflammatory mediators and granular pro- yet to be understood, the disease is characterized by the teins in the blood, sputum samples, bronchoalveolar lavage persistence of chronic airway inflammation, respiratory fluid (BAL), and bronchial biopsy specimens in patients with tract infection, airway wall remodeling, edema, and mucus asthma.23–25 Eosinophil infiltration has been observed to hypersecretion, which is significantly associated with pro- cause vasodilatation, microvascular obstruction, and dis- longed cough, chest pain or chest tightness, episodes of ruption of epithelial cells.26 wheezing and shortness of breath.6 Both genetic and environmental factors containing Studies on in vitro and in vivo techniques include diverse allergens activate a variety of immune cells and epithelial experimental approaches in cell culture and human clinical cells finally leading to eosinophil activation, recruitment, models represent the basic molecular network involving and trafficking.27 Activated eosinophils are characterized potent molecular signals and their pathophysiologic scenario by overexpression of several eosinophil surface adhesion instigating cellular activation, oxidative stress stimulating molecules; some receptors also behave as enzymes, recep- inflammatory milieu leading to the pathogenesis, and sever- tors for immunoglobulin G (IgG) immunoglobulin A (IgA), ity of the disease.7–10 Epidemiological evidence indicates sig- cytokines, chemokines and complement proteins which are nificant involvement of multicellular populations and their implicated in cell adhesion, apoptosis, signal transduction, activation leading to disease progression and pathogenesis. eosinophil trafficking, proliferation, activation and promo- The cellular activation and severity are characterized by the tion of survival and death.28,29 The activation state of the release of potential biochemical and inflammatory mediators eosinophils constitutes several activation markers that play such as cytokines, chemokines, eicosanoids, growth factors, a key role in airway remodeling, eosinophil trafficking, and oxidative stress, neural mediators, nitric oxides, and abnor- extravasations.30 Although several cell surface proteins are mal expression of cell adhesion molecules. Accumulation observed to report the eosinophil activation, the role of of these factors promotes smooth muscle cell hyperplasia, integrins is highly crucial. Earlier evidence also indicates goblet cell hyperplasia, epithelial/subepithelial shedding and that integrins play a predominant role in pulmonary func- fibrosis, and blood vessel dysfunction ultimately leading to tion and airway inflammation. General markers of eosino- airway remodeling.11 Exposure to environmental stimuli and phil activation include clusters of differentiation 69 (CD69), allergens causes activation and recruitment of of a variety CD11b, CD4, CD9, CD35, CD44, CD45RO, CD48, CD58, CD63, of cellular populations such as macrophages, dendritic cells, CD66e, CD11a, CD69, CD67, CD81, CD11c, CD18, CD16, CD32, airway epithelial cells, neutrophils, eosinophils, and mast CD64, CD23, CD89, CD54, CD123, CD125, CD62L, CD162, cells inducing cellular damage and inflammatory response in CD108, CD29, CD18, CD32, β2, β1, thymic stromal lymph- patients with asthma.12 opoietin receptor (TSLPR), neuropeptide SR, interleukin 17 receptor A (IL-17RA), IL-13Rα1, human leukocyte antigen DR isotype (HLADR), Galectin 3, platelet-derived growth fac- Eosinophils are in activated state in asthma tor B chain (PDGF-B), and stem cell factor (SCF) (Figure 1). It was reported that eosinophils and T lymphocytes Eosinophils are the major inflammatory cells which play a are increased in the asthmatic airways with respect to crucial role in the development of allergic and non-allergic non-asthmatic controls.31–34 However, the receptors are also asthma phenotypes.13,14 The cell is a bone marrow-derived expressed by other cells such as neutrophils, basophils, and granulocyte with bilobed nucleus having characteristics of mast cells. The only receptor specific to the eosinophils is acidophilic granules and originated from the eosinophil col- the epidermal growth factor-like module containing mucin- ony, forming a unit of myeloid progenitor cells and regulated like hormone-like receptor 1 (EMR1).35 by a variety of signaling molecules like chemokines, cyto- kines, and adhesion molecules. The cells play an important role, particularly in the immune response against allergic Molecular players leading to eosinophil inflammation and parasitic reactions. Eosinophil devel- activation opment in the bone marrow is stimulated by interleukin-3 (IL-3) and granulocyte