Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma

Abstract

Infectious agents can reprogram or train macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type-2 inflammatory conditions such as allergic asthma is&nbsp;not known. Therefore, we aim to elucidate the role of trained immunity in allergic airway inflammation (AAI). We used clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced AAI in mice and an <i>in vitro</i> training set-up to analyze persistent changes in macrophage eicosanoid- and chemokine production as well as underlying epigenetic mechanisms. Transcriptional profiles of patient-derived and <i>in vitro</i> trained macrophages were assessed by RNA sequencing and LC-MS/MS analysis, respectively. We found that macrophages differentiated from bone marrow- or blood monocyte- progenitors of HDM-allergic mice or asthma patients showed inflammatory transcriptional reprogramming and excessive mediator (TNF-a, CCL17, leukotriene, IL-6) responses upon stimulation. Macrophages from HDM-allergic mice initially exhibited a type-2 imprint, which shifted towards a classical inflammatory training over time. <i>In vitro</i> HDM-induced macrophage training was mediated by a formyl-peptide receptor 2 (FPR2)-TNF-axis, resulting in an M2-like macrophage phenotype with high CCL17 production. TNF blockade by etanercept or genetic ablation of Tnf in myeloid cells prevented the inflammatory imprinting of bone marrow-derived macrophages from HDM-allergic mice. Our findings suggest that allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type-2 airway inflammation and thus represents a potential target for asthma therapy.