Emerging Evidence for Pleiotropism of Eosinophils

Abstract

Eosinophils are complex granulocytes with the capacity to react upon diverse stimuli due to their numerous and variable surface receptors, which allows them to respond in very different manners. Traditionally believed to be only part of parasitic and allergic/asthmatic immune responses, as scientific studies arise, the paradigm about these cells is continuously changing, adding layers of complexity to their roles in homeostasis and disease. Developing principally in the bone marrow by the action of IL-5 and granulocyte macrophage colony-stimulating factor GM-CSF, eosinophils migrate from the blood to very different organs, performing multiple functions in tissue homeostasis as in the gastrointestinal tract, thymus, uterus, mammary glands, liver, and skeletal muscle. In organs such as the lungs and gastrointestinal tract, eosinophils are able to act as immune regulatory cells and also to perform direct actions against parasites, and bacteria, where novel mechanisms of immune defense as extracellular DNA traps are key factors. Besides, eosinophils, are of importance in an effective response against viral pathogens by their nuclease enzymatic activity and have been lately described as involved in severe acute respiratory syndrome coronavirus SARS-CoV-2 immunity. The pleiotropic role of eosinophils is sustained because eosinophils can be also detrimental to human physiology, for example, in diseases like allergies, asthma, and eosinophilic esophagitis, where exosomes can be significant pathophysiologic units. These eosinophilic pathologies, require specific treatments by eosinophils control, such as new monoclonal antibodies like mepolizumab, reslizumab, and benralizumab. In this review, we describe the roles of eosinophils as effectors and regulatory cells and their involvement in pathological disorders and treatment.

Keywords: biologic treatment; eosinophil; eosinophil extracellular traps; sub-phenotypes.

Figure 1

Eosinophils development and migration. Eosinophils develop mainly in the bone marrow from stem cells turning into eosinophil progenitors (EoP) expressing CD34 by the action of transcription factors (GATA-1, C/EBPα, C/EBPε, IRF8 and PU.1). By IL-5, IL-3 and granulocyte macrophage colony-stimulating factor (GM-CSF) interaction over their specific receptors (IL-5R, IL-3R and GM-CSFR) eosinophils turn into final state through the effect of the transcription factors GATA-1, GATA-2, C/EBPα, Helios, Aiolos and XBP1, and flow into the blood system, being maintained by IL-5 and GM-CSF. From blood, eosinophils transmigrate the vessels, first by performing adhesion by interaction of P-Selectin Ligand (PSGL) with the vascular P-Selectin, and secondly, interacting with the blood vessel molecules vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) using their integrins (α4 and β2 respectively), allowing the rolling and extravasation of eosinophils attracted to the lung epithelium due to the combined action of eotaxin-1 (CCL11), eotaxin-2 (CCL24) and eotaxin-3 (CCL26) towards the eosinophilic CC-chemokine receptors-3 (CCR3) receptor. The migration is also sustained by IL-5 secretion produced in type 2 innate lymphoid cells (ILC2s). Both ILC2s and eosinophils themselves are activated by epithelial alarmins as IL-33, thymic stromal lymphopoietin (TSLP) and IL-25, inducing eosinophil degranulation of eosinophil cationic protein (ECP), major basic proteins (MBP) and eosinophil-derived neurotoxin (EDN), which produce epithelial remodeling.

Figure 2

Eosinophil granules and mechanisms of action. Eosinophils have on their surface diverse receptors including chemokine receptors (CCRs, CXCRs…), lipid mediators’ receptors (CRTH2, LTB4R) or cytokine receptors (IL5Rα, IL-3R and GM-CSFR). These receptors alongside adhesion molecules as integrins α4 and β2 allow eosinophils to migrate and react against very variable stimulus. Eosinophil responses are performed thanks to their granule content. First, enzymatic content as ECP, MBP and EDN are secreted from the specific granules by piecemeal degranulation (mediated by sombrero vesicle transport) allowing viral clearance by their ribonuclease activity and the reaction against secondary parasitic infections. Besides, eosinophils kill bacteria by release of their DNA content, from the nucleus or the mitochondria, forming extracellular DNA traps with bound enzymes. Alongside the DNA traps, sometimes Charcot-Leyden Crystals are released. Finally, eosinophils secrete exosomes from multivesicular bodies fusing to the cell membrane, which are involved in epithelial damage.

Figure 3

Homeostatic and pathophysiological functions of eosinophils. Eosinophils’ versatility makes these cells be able to both regulate homeostasis of diverse organs including, control of mammary duct branching, induction of protection against Chlamydia trachomatis in the uterus, clearance of apoptotic thymocytes in the thymus and tissue repair and regeneration of both skeletal muscle and liver by IL-4. In other organs, eosinophils have been described to perform detrimental roles, such as inducing eosinophilic pancreatitis, being involved in antibody dependent cellular toxicity and self-antigen presentation and immune modulation in the context of autoimmune diseases, while also causing inflammation and epithelial damage in chronic rhinosinusitis. In some organs, eosinophils perform both homeostatic as prejudicial roles, as in the lungs where eosinophils perform pathogen antigen presentation and immune modulation but being also related to asthma pathophysiology. In the adipose tissue, eosinophils participate in beige fat development and glucose tolerance, while inducing also inflammation. In the gastrointestinal tract they regulate mucosal IgA and Th17 cell numbers, inducing eosinophilic esophagitis when over cumulated, and finally, in tumors they both activate tumor rejection by T cells, and induces tissue damage.

Figure 4

Role of eosinophils in the pathophysiology of asthma and biological drugs for its control. Eosinophils are crucial to the development and maintenance of the asthmatic symptoms, being attracted to the airways by two non-exclusive mechanisms. The first one involves activation of the innate immunity, where type 2 innate lymphoid cells (ILC2s) are activated by alarmins (IL-33, IL25 and TSLP) released after damage of airway epithelium and releasing Il-5, the main chemoattractant and inductor of eosinophils activity. Alternatively, or simultaneously, allergens traverse the epithelium and are recognized by dendritic cells and presented to T naïve helper cells (Th0), which are polarized to Th2 cells, secreting Il-4 and Il-13, stimulators of the release of allergen-specific IgE by B cells. IgE recognising the allergen is then able to induce the production of histamine, leukotrienes and prostaglandins by mast cells, being these molecules involved in smooth muscle hypertrophy and contraction. Besides, Th2 cells are also capable of releasing IL-5, which activates eosinophils in an allergen-mediated mechanism. Eosinophils stimulated by IL-5 releasing IL-13 and lipid mediators which activate the epithelium and induce mucus secretion. Also, eosinophils discharge exosomes, toxic proteins (ECP, MBP and EPO) and other mediators as ROS and NO capable of inducing epithelial damage. Exosomes, IL-13 and other lipid mediators released by eosinophils are also inductors of smooth muscle hypertrophy and contraction, highlighting the multiple-pathway pathophysiological role developed by these cells. Hence, biological drugs are indeed treatment options for controlling eosinophils adverse effects in asthma, such as mepolizumab and reslizumab which recognise IL-5 and block its binding over eosinophils, and benralizumab, a monoclonal antibody that binds to IL-5R and induces antibody-dependent cell-mediated cytotoxicity (ADCC) of natural killer (NK) cells over eosinophils.