Eosinophil-mediated inflammation in the absence of eosinophilia

Abstract

The increase of eosinophil levels is a hallmark of type-2 inflammation. Blood eosinophil counts act as a convenient biomarker for asthma phenotyping and the selection of biologics, and they are even used as a prognostic factor for severe coronavirus disease 2019. However, the circulating eosinophil count does not always reflect tissue eosinophilia and vice versa. The mismatch of blood and tissue eosinophilia can be seen in various clinical settings. For example, blood eosinophil levels in patients with acute eosinophilic pneumonia are often within normal range despite the marked symptoms and increased number of eosinophils in bronchoalveolar lavage fluid. Histological studies using immunostaining for eosinophil granule proteins have revealed the extracellular deposition of granule proteins coincident with pathological conditions, even in the absence of a significant eosinophil infiltrate. The marked deposition of eosinophil granule proteins in tissue is often associated with cytolytic degranulation. Recent studies have indicated that extracellular trap cell death (ETosis) is a major mechanism of cytolysis. Cytolytic ETosis is a total cell degranulation in which cytoplasmic and nuclear contents, including DNA and histones that act as alarmins, are also released. In the present review, eosinophil-mediated inflammation in such mismatch conditions is discussed.

Keywords: Eosinophil granule proteins; Eosinophils; Extracellular traps.

Fig. 1. Clinical course of a case with AEP.

(A) Dynamics of blood eosinophil counts. Values indicate the peripheral white blood cell (WBC) counts (green line) and eosinophil (Eo) counts (blue line). On day 2, the patient was treated with an intravenous administration of methylprednisolone (mPSL). (B) Chest x-ray on day 2 (before performing a bronchoalveolar lavage and mPSL administration) and day 9 (6 days after treatment). (C) Response of eosinophils to cigarette smoke extract (CSE). CSE was prepared as described by a previous report [161]. Peripheral whole blood cells stimulated with CSE for 10 minutes and red blood cells were lysed using BD FACS Lysing Solution (BD Biosciences, San Jose, CA, USA). The eosinophil shape change induced by CSE was evaluated using a FACScan flow cytometer (BD Biosciences). Values shown are the % of control buffer. HV, healthy volunteer.

Fig. 2. Schematic of tissue and blood eosinophilia in acute eosinophilic pneumonia (AEP).

(A) At the onset of AEP, there is a rapid recruitment of blood eosinophils into the lung, resulting in a normal-range blood eosinophil count. (B) After treatment with systemic steroids, the eosinophilic lung inflammation is resolved, mainly through the induction of eosinophil apoptosis in the lungs. The decreased recruitment of blood eosinophils into the lung might result in the retention of eosinophils in circulation, leading to a transient blood eosinophilia.

Fig. 3. Cytolytic eosinophils in a nasal polyp obtained from a case of chronic rhinosinusitis with nasal polyps (eosinophilic chronic rhinosinusitis).

(A) Hematoxylin and eosin (H&E) staining of a nasal polyp, showing a loss of epithelium and inflammatory cell infiltration in submucosal tissue. The boxed area in the left panel is shown magnified in the right panel. Accumulated cells showed cytolysis and a loss of nuclear shape (chromatolysis). Eosinophilic extracellular granules were also noted. (B) A serial section of the tissue shown in panel A was immunostained for major basic protein (MBP) (red) and counterstained for DNA (blue). Image was obtained with a Carl Zeiss LSM780 confocal microscope (×20). The massive deposition of extracellular MBP visible is consistent with the presence of cytolytic eosinophils.

Fig. 4. Eosinophil cell fates and their consequences.

Eosinophils apoptosis can be caused by many factors, including aging, a loss of survival factors, corticosteroids, and anti-interleukin (IL)-5/anti-IL-5 receptor antibodies. Apoptotic eosinophils, typically with nuclear and cytoplasmic condensation, are phagocytosed without the induction of inflammation. Alternately, eosinophils can undergo ETosis upon activation, such as by an immunoglobulin-coated surface, pathogens, or platelet-activating factor with IL-5. Rapid cytolysis without the expression of a “find-me” signal results in the tissue deposition of the cell's total intracellular contents and prolonged inflammation.