Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

Abstract

Background: Eosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings.Objectives: To investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI.Methods: Blood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice (ΔdblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests. Results:Blood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0±2.2cm 2 v 21.6±1.6cm 2 ; p=0.02) and reduced ejection fraction (22.0±3.6% v 34.3±4.0% in p=0.04,) in Δ dblGATA v WT following MI (n=8-9/group), an outcome reproduced by pharmacological depletion. Δ dblGATA mice had increased scar size with disrupted collagen deposition and altered expression of the collagen cross-linking genes plod2 and lox. CD206 + pro-repair macrophages were less prevalent in the infarct zone of Δ dblGATA mice (27.0±2.3% v WT: 39.2.4±3.5%; p=0.01, n=9-11/group) but were restored by replenishment with bone marrow-derived eosinophils. Anti-inflammatory cytokine concentrations were reduced in Δ dblGATA mice and IL-4 complex administration 24h after MI rescued adverse remodelling. Conclusions:Eosinophils are recruited to the heart following MI and are required for effective repair and to prevent adverse remodelling. IL-4 therapy has potential to limit detrimental outcomes when eosinophil availability is low. Condensed abstractIn ST-segment elevation myocardial infarction (STEMI) of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory pro-repair macrophage polarization, enhanced myocardial inflammation, increased scar size and deterioration of myocardial structure and function. Adverse cardiac remodelling in the setting of eosinophil deficiency was prevented by IL-4 therapy.

A lesson from the wild: The natural state of eosinophils is Ly6Ghi

“…The prevailing view of the eosinophil as a purely proinflammatory cell type has been challenged in recent years with a growing number of laboratory mouse studies describing non‐redundant roles in tissue development, homeostasis and repair. This includes a variety of tissues and cell types, for example maintenance of mucosal homeostasis [ 4 ], contractility of blood vessels [ 5 ], control of glucose metabolism in adipose tissue [ 6 ], liver regeneration [ 7 ], and wound healing of injured muscle tissue [ 8 ] including following myocardial infarction [ 9 ]. However, whilst advances have been made in understanding eosinophil contribution to health in laboratory animals, eosinophil functions in humans are largely undefined [ 10 ].…”

Injection site vaccinology of a recombinant vaccinia-based vector reveals diverse innate immune signatures

“…Eosinophils have been reported in pruritic papulovesicular eruptions in a case of generalized vaccinia after smallpox vaccination [ 227 ] and are well described as drivers of allergic diseases such as eosinophilic asthma [ 228 , 229 ]. However, recently a role for eosinophils in tissue repair and wound healing has emerged [ 189 , 190 ], particularly for muscle tissues [ 191 – 193 ]. That the eosinophils in these resolving post-vaccination lesions are distinct from inflammatory eosinophils is supported by the absence of IL-5 mRNA expression ( S2G Table ), with anti-IL-5 therapy used for eosinophilic asthma [ 230 ].…”

Eosinophils Confer Protection Following Myocardial Infarction

“…In conclusion, Toor et al. ( 4 ) provided an informative and interesting study that established a protective role for eosinophils in LV remodeling following MI. The investigators defined a potential mechanism of benefit and suggested that modulation of eosinophil cytokine expression favoring IL-4 might be a target for therapeutic intervention.…”

“…In this issue of JACC: Basic to Translational Science , Toor et al. ( 4 ) examined the role of eosinophils following acute MI. Previous observational studies reported conflicting associations between eosinophil abundance and clinical outcomes.…”

“…Nonetheless, the findings by Toor et al. ( 4 ) suggested that IL-4 signaling might represent the key signal by which eosinophils communicate with resident macrophages and/or infiltrating monocyte-derived macrophages.…”