Eosinophils in health and disease: the LIAR hypothesis

Abstract

Discussions of eosinophils are often descriptions of end-stage effector cells with destructive capabilities mediated predominantly by released cytotoxic cationic granule proteins. Moreover, eosinophils in the medical literature are invariably associated with the pathologies linked with helminth infections or allergic diseases such as asthma. This has led to an almost fatalist view of eosinophil effector functions and associated therapeutic strategies targeting these cells that would make even William of Ockham proud - eosinophil effector functions have physiological consequences that increase patient morbidity/mortality and 'the only good eosinophils are dead eosinophils'. Unfortunately, the strengths of dogmas are also their greatest weaknesses. Namely, while the repetitive proclamation of dogmatic concepts by authoritative sources (i.e. reviews, meeting proceedings, textbooks, etc.) builds consensus within the medical community and lower the entropies surrounding difficult issues, they often ignore not easily explained details and place diminished importance on alternative hypotheses. The goal of this perspective is twofold: (i) we will review recent observations regarding eosinophils and their activities as well as reinterpret earlier data as part of the synthesis of a new paradigm. In this paradigm, we hypothesize that eosinophils accumulate at unique sites in response to cell turnover or in response to local stem cell activity(ies). We further suggest that this accumulation is part of one or more mechanisms regulating tissue homeostasis. Specifically, instead of immune cells exclusively mediating innate host defence, we suggest that accumulating tissue eosinophils are actually regulators of Local Immunity And/or Remodeling/Repair in both health and disease - the LIAR hypothesis; (ii) we want to be inflammatory (pun intended!) and challenge the currently common perspective of eosinophils as destructive end-stage effector cells. Our hope is to create more questions than we answer and provoke everyone to spend countless hours simply to prove us wrong!

Figure 1. Photomicrographic images of “eosinophil-like” cells from invertebrates representative of three major phyla demonstrates the evolutionary conservation of this granulocyte

Ameboid leukocytes with the distinct granulation and, in many cases, the concomitant eosin-binding characteristics (arrowheads) are found in a wide array of invertebrate species, including Arthropoda (Limulus polyphemus (horseshoe crab - Class: Crustacea, H&E) and Blaberus giganteus (giant cockroach - Class: Insecta, phase contrast microscopy)), Mollusca (Atrina rigida (clam - Class: Bivalvia, H&E), and Echinodermata (Stichopus badionotus (sea cucumber - Class: Holothuroidea, H&E). All photomicrographs were reprinted from Comparative Hematology by Warren Andrew (©1965), with permission from Elsevier)

Figure 2. Hematoxylin-eosin (H&E) and Romanowsky-dye (R&D) stained preparations of hematopoietic tissues from representative animals of the five (5) classes of Vertebrata reveal the ubiquitous presence of a uniquely eosinophilic lineage in this sub-phylum

Leukocytes displaying the unique polymorphonucleus and the eosin-binding cytoplasmic granules characteristic of eosinophils are identifiable (arrowheads) in Mammalia (Homo sapiens (human, H&E) and Mus musculus (mouse, R&D)), Aves (Columba livia (rock pigeon, H&E)), Reptilia (Pogona vitticeps (Bearded Dragon, R&D)), Amphibia (Rana pipens (leopard frog, H&E)), and Osteichthyes (Tilapia aurea (Tilapia, H&E)). Scale bar = 20μm.

Figure 3. Schematic representation outlining the LIAR hypothesis and the outcomes-based consequences of eosinophil-mediated activities in health and disease

Peripheral eosinophil () recruitment occurs in response to the release of one or more small molecule mediators of inflammation (e.g., DAMPs) released from localized bursts of cell death (). In the presence of additional eosinophil agonist growth (e.g., IL-5) and survival (e.g., GM-CSF) factors derived from concomitant cell proliferation and/or stem cell activation (), these granulocytes accumulate and establish a local steady-state population. The tissue immune microenvironment subsequently dictates the downstream immune consequences mediated by eosinophil effector functions, leading either to exacerbations of local immune responses (Th2-Polarized Microenvironment), suppression of these site-specific immune responses (Th1/Th17-Polarized Microenvironment), or essentially little to no modulations of local immune responses (Immune-Neutral Microenvironment). In turn, these immune responses modulate the levels of tissue remodeling and/or tissue repair that is also characteristic of eosinophil-mediated effector functions. Thus, the immune microenvironment present upon eosinophil recruitment is a significant situational cue which drives the predominance of specific eosinophil activities. More importantly, this eosinophil-mediated Local Immunity And/or Remodeling/Repair defines the functional roles of eosinophils in unique tissue compartments at homeostatic baseline (i.e., health) as well as within tissues associated with specific diseases.

Figure 4. Histopathological assessments of biopsies from human cancers and tumors from mouse models of cancer show that eosinophil infiltration of tumors is often significant and, more importantly, a widely occurring phenomenon

Immunohistochemistry with a unique and specific monoclonal antibody against the abundant eosinophil secondary granule protein, eosinophil peroxidase (EPX-mAb [73]) demonstrated evidence for eosinophil infiltration in multiple human cancers (darkly staining navy/black cells in each photomicrograph with representative examples noted with arrowheads), including colon tubular adenoma, bladder cancer, mammary ductal carcinoma, pancreatic cancer, and glioblastoma. In addition, staining with a monoclonal antibody specific for another abundant eosinophil secondary granule protein, major basic protein (rat anti-mouse MBP-mAb-14.7.4 [17]) demonstrated the presence of a robust eosinophil tumor infiltrate occurring in a mouse model of pancreatic cancer (Pdx1-Cre (x) KRAS^G12D/+ mice [82]). Scale bar = 100μm.