Jason J. Xenakis

Eosinophils in innate immunity: an evolving story

Eosinophils are innate immune leukocytes found in relatively low numbers within the blood. Terminal effector functions of eosinophils, deriving from their capacity to release their content of tissue-destructive cationic proteins, have historically been considered primary effector mechanisms against specific parasites, and are likewise implicated in tissue damage accompanying allergic responses such as asthma. However, the past decade has seen dramatic advancements in the field of eosinophil immunobiology, revealing eosinophils to also be key participants in many other facets of innate immunity, from bridging innate and adaptive immune responses to orchestrating tissue remodeling events. Here, we review the multifaceted functions of eosinophils in innate immunity that are currently known, and discuss new avenues in this evolving story.

Eosinophils: Offenders or General Bystanders in Allergic Airway Disease and Pulmonary Immunity?

Eosinophils have long been noted to be present in asthma and other forms of pulmonary inflammation, but whether they act as true offenders or merely as bystanders has been a point of uncertainty. However, in recent years, there has been increasing evidence suggesting that eosinophils are not passive cells in the respiratory system, acting only as markers of allergic inflammation. This review discusses key evidence from animal models and human clinical trials that support the importance of eosinophils as active and necessary, rather than passive and unnecessary, to the pathogenesis of allergic airway disease. Analyses that are supportive of important immunoregulatory roles of eosinophils in allergic pulmonary inflammation are also reviewed. Data indicating that eosinophils contribute to viral, bacterial, and mycobacterial defense and clearance are detailed. Continually increasing evidence has supported a new conception of eosinophils as being multifaceted immune cells with complex interactions with other immune cells and their local environment.

Eosinophil-derived cytokines in health and disease: unraveling novel mechanisms of selective secretion

Over the past two decades, our understanding of eosinophils has evolved from that of categorically destructive effector cells to include active participation in immune modulation, tissue repair processes, and normal organ development, in both health and disease. At the core of their newly appreciated functions is the capacity of eosinophils to synthesize, store within intracellular granules, and very rapidly secrete a highly diverse repertoire of cytokines. Mechanisms governing the selective secretion of preformed cytokines from eosinophils are attractive therapeutic targets and may well be more broadly applicable to other immune cells. Here, we discuss recent advances in deciphering pathways of cytokine secretion, both from intact eosinophils and from tissue‐deposited cell‐free eosinophil granules, extruded from eosinophils undergoing a lytic cell death.

Notch signaling mediates granulocyte-macrophage colony-stimulating factor priming-induced transendothelial migration of human eosinophils.

Priming with cytokines such as granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) enhances eosinophil migration and exacerbates the excessive accumulation of eosinophils within the bronchial mucosa of asthmatics. However, mechanisms that drive GM‐CSF priming are incompletely understood. Notch signaling is an evolutionarily conserved pathway that regulates cellular processes, including migration, by integrating exogenous and cell‐intrinsic cues. This study investigates the hypothesis that the priming‐induced enhanced migration of human eosinophils requires the Notch signaling pathway.

Resident intestinal eosinophils constitutively express antigen presentation markers and include two phenotypically distinct subsets of eosinophils

Intestinal eosinophils are implicated in homeostatic and disease‐associated processes, yet the phenotype of intestinal tissue‐dwelling eosinophils is poorly defined and their roles in intestinal health or disease remain enigmatic. Here we probed the phenotype and localization of eosinophils constitutively homed to the small intestine of naive mice at baseline, and of antigen‐sensitized mice following intestinal challenge. Eosinophils homed to the intestinal lamina propria of naive mice were phenotypically distinguished from autologous blood eosinophils, and constitutively expressed antigen‐presenting cell markers, suggesting that intestinal eosinophils, unlike blood eosinophils, may be primed for antigen presentation. We further identified a previously unrecognized resident population of CD11chi eosinophils that are recovered with intraepithelial leucocytes, and that are phenotypically distinct from both lamina propria and blood eosinophils. To better visualize intestinal eosinophils in situ, we generated eosinophil reporter mice wherein green fluorescent protein expression is targeted to both granule‐delimiting and plasma membranes. Analyses of deconvolved fluorescent z‐section image stacks of intestinal tissue sections from eosinophil reporter mice revealed eosinophils within intestinal villi exhibited dendritic morphologies with cellular extensions that often contacted the basement membrane. Using an in vivo model of antigen acquisition in antigen‐sensitized mice, we demonstrate that both lamina propria‐associated and intraepithelium‐associated eosinophils encounter, and are competent to acquire, lumen‐derived antigen. Taken together these data provide new foundational insights into the organization and functional potential of intestinal tissue‐dwelling eosinophils, including the recognition of different subsets of resident intestinal eosinophils, and constitutive expression of antigen‐presenting cell markers.