{"doi":"10.1111/all.15738","title":"Conditional neutrophil depletion challenges their contribution to mouse models of anaphylaxis","abstract":"To the Editor, Anaphylaxis is an acute and potentially lethal systemic allergic reaction. In humans, it is largely accepted that anaphylaxis relies predominately on IgE antibodies.1 However, IgG might also contribute to anaphylaxis induced by infused drugs.1 Several mouse models have been developed to identify key effector cells and mediators of anaphylaxis. Consequently, two main pathways have been identified in mice: a “classical” pathway consisting of IgE, FcεRI, histamine, and mast cells, and an “alternative” pathway involving IgG, FcγRIII, platelet-activating factor (PAF), and—depending on the anaphylaxis model studied—macrophages, basophils, and/or neutrophils.1-3 We and others have reported that neutrophils are potentially important drivers of IgG anaphylaxis in mice, based on experiments using neutrophil-depleting mAbs.1, 4 In contrast, Strait et al.3 showed that injection of anti-Gr-1 mAb 2 days before antigen challenge failed to suppress IgG-mediated anaphylaxis, indicating that the effect of these mAbs likely depends on the dose, timing of injection, and specific model used. We recently described an inducible, antibody-independent, neutrophil depletion mouse model (PMNDTR mice), relying on the selective expression of the diphtheria toxin (DT) receptor on neutrophils.5 Injection of DT in PMNDTR mice leads to a marked depletion of blood, spleen, and bone marrow neutrophils (Figure S1A–D).5 We therefore used PMNDTR mice to reevaluate the contribution of neutrophils to anaphylaxis models. To elicit active systemic anaphylaxis (ASA), mice were immunized with BSA emulsified in Freund's adjuvant, and challenged i.v. with BSA (Figure 1A), a model that mostly relies on IgG.4 As expected, pretreatment of mice with anti-Ly6G or anti-Gr-1 neutrophil-depleting mAbs markedly reduced hypothermia and mortality in this model (Figure 1B,C). Strikingly, however, DT-treated neutrophil-deficient PMNDTR mice exhibited similar anaphylaxis severity to neutrophil-sufficient controls (Figure 1D,E). We obtained similar results in models of IgG2a- or IgG2b-induced passive systemic anaphylaxis (PSA) (Figure 1F–J). Interestingly, while performing the initial treatment to deplete neutrophils, we observed that injection of either anti-Ly6G or anti-Gr-1 mAbs induced a transient hypothermia in WT mice, whereas injection of DT in PMNDTR mice did not induce any apparent side effects (Figure 2A,B). We therefore questioned whether engagement of FcγRs and/or complement by the depleting mAbs might induce an initial anaphylactic-like event that could desensitize mice to subsequent IgG-mediated anaphylaxis. To test this, we administered anti-Ly6G mAb to FcγRNull mice that do not express FcγRs, and to FcγRNull/C1qKO mice that lack both FcγRs and complement component C1q. As expected, neutrophil depletion by mAbs was impaired (Figure S1E–G), which suggests that this depletion occurs at least partly through antibody-dependent cellular cytotoxicity or phagocytosis mediated by FcγRs, and potentially via complement-dependent cytotoxicity. Moreover, transient hypothermia after mAb injection was abolished in FcγR and complement deficient animals (Figure 2C). PAF is a key driver of anaphylaxis.1, 2 We therefore assessed the role of PAF in anti-Ly6G mAb-induced hypothermia using PAF receptor-deficient mice (PtafRKO) which are resistant to PAF-induced shock (Figure S2A). Neutrophil depletion efficacy was unaltered in PtafRKO mice (Figure S2B–D); however, these mice exhibited reduced hypothermia upon injection of anti-Ly6G mAbs (Figure 2D). In agreement with these results, pretreatment of mice with a PAF receptor antagonist (ABT-491) also largely prevented hypothermia upon injection of anti-Ly6G mAbs (Figure 2E,F), without affecting neutrophil depletion efficacy (Figure S2G–I). ABT-491 has a short half-life in vivo (Figure S2E,F). We could then demonstrate that when the PAF-induced hypothermia after anti-Ly6G mAb injection is blocked, then the protective effect of this","journal":"Allergy","year":2023,"id":374543,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1136516,"name":"Caitlin M. Gillis","orcid":"0000-0001-9892-206X","position":1,"is_corresponding":false},{"id":666591,"name":"Ophélie Godon","orcid":"0000-0003-1511-3764","position":2,"is_corresponding":false},{"id":1136517,"name":"Bruno Iannascoli","orcid":"0000-0002-5783-2882","position":3,"is_corresponding":false},{"id":632302,"name":"Eva Conde","orcid":"0000-0002-5545-7054","position":4,"is_corresponding":false},{"id":1040508,"name":"Edouard Leveque","orcid":"0000-0003-0002-729X","position":5,"is_corresponding":false},{"id":1136518,"name":"William P. M. Worrall","orcid":"0000-0003-2507-8173","position":6,"is_corresponding":false},{"id":73046,"name":"Stephen J. Galli","orcid":"0000-0001-5736-5340","position":7,"is_corresponding":false},{"id":632315,"name":"Pierre Bruhns","orcid":"0000-0002-4709-8936","position":8,"is_corresponding":false},{"id":308012,"name":"Laurent L. Reber","orcid":"0000-0003-3384-6769","position":9,"is_corresponding":false},{"id":666593,"name":"Friederike Jönsson","orcid":"0000-0002-1667-8065","position":10,"is_corresponding":false},{"id":632305,"name":"Julien Stackowicz","orcid":"0000-0001-6793-2855","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":null,"created_at":"2026-07-19T01:16:15.380731Z","pmid":"37022292","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}