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Lechner, A. ; Henkel, F. ; Hartung, F. ; Bohnacker, S. ; Alessandrini, F. ; Gubernatorova, E.O.* ; Drutskaya, M.S.* ; Angioni, C.* ; Schreiber, Y.* ; Haimerl, P. ; Ge, Y.* ; Thomas, D.* ; Kabat, A.M.* ; Pearce, E.J.* ; Ohnmacht, C. ; Nedospasov, S.A.* ; Murray, P.J.* ; Chaker, A. ; Schmidt-Weber, C.B. ; Esser-von Bieren, J.

Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.

J. Allergy Clin. Immunol. 149, 2078-2090 (2022)

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BACKGROUND: 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 was not known. OBJECTIVE: To decipher macrophage trained immunity in allergic asthma. METHODS: We used a combination of clinical sampling of house dust mite (HDM)-allergic patients, HDM-induced allergic airway inflammation (AAI) in mice and an in vitro training set-up to analyze persistent changes in macrophage eicosanoid-, cytokine- and chemokine production as well as underlying metabolic and epigenetic mechanisms. Transcriptional and metabolic profiles of patient-derived and in vitro trained macrophages were assessed by RNA sequencing or Seahorse and LC-MS/MS analysis, respectively. RESULTS: We found that macrophages differentiated from bone marrow- or blood monocyte- progenitors of HDM-allergic mice or asthma patients show inflammatory transcriptional reprogramming and excessive mediator (TNF-α, CCL17, leukotriene, PGE₂, 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. HDM-induced AAI elicited a metabolically activated macrophage phenotype, producing high amounts of 2-hydroxyglutarate (2-HG). HDM-induced macrophage training in vitro was mediated by a formyl-peptide receptor 2 (FPR2)-TNF-2-HG-PGE₂/EP2-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. CONCLUSION: Allergen-triggered inflammation drives a TNF-dependent innate memory, which may perpetuate and exacerbate chronic type-2 airway inflammation and thus represents a target for asthma therapy.

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