Tumor suppressor p53 regulates intestinal type 2 immunity.

The role of p53 in tumor suppression has been extensively studied and well-established. However, the role of p53 in parasitic infections and the intestinal type 2 immunity is unclear. Here, we report that p53 is crucial for intestinal type 2 immunity in response to the infection of parasites, such as Tritrichomonas muris and Nippostrongylus brasiliensis. Mechanistically, p53 plays a critical role in the activation of the tuft cell-IL-25-type 2 innate lymphoid cell circuit, partly via transcriptional regulation of Lrmp in tuft cells. Lrmp modulates Ca2+ influx and IL-25 release, which are critical triggers of type 2 innate lymphoid cell response. Our results thus reveal a previously unrecognized function of p53 in regulating intestinal type 2 immunity to protect against parasitic infections, highlighting the role of p53 as a guardian of immune integrity.

Assembly of a spatial circuit of T-bet-expressing T and B lymphocytes is required for antiviral humoral immunity.

Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at the T-B boundary enables IFN-γ produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sublineage required for GC growth but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.

Cannabinoid Receptor Subtype-1 Regulates Allergic Airway Eosinophilia During Lung Helminth Infection.

Introduction: Over 1 billion humans carry infectious helminth parasites that can lead to chronic comorbidities such as anemia and growth retardation in children. Helminths induce a T-helper type 2 (Th2) immune response in the host and can cause severe tissue damage and fibrosis if chronic. We recently reported that mice infected with the soil-transmitted helminth, Nippostrongylus brasiliensis, displayed elevated levels of endocannabinoids (eCBs) in the lung and intestine. eCBs are lipid-signaling molecules that control inflammation; however, their function in infection is not well defined. Materials and Methods: A combination of pharmacological approaches and genetic mouse models was used to investigate roles for the eCB system in inflammatory responses and lung injury in mice during parasitic infection with N. brasiliensis. Results: Hemorrhaging of lung tissue in mice infected with N. brasiliensis was exacerbated by inhibiting peripheral cannabinoid receptor subtype-1 (CB1Rs) with the peripherally restricted CB1R antagonist, AM6545. In addition, these mice exhibited an increase in nonfunctional alveolar space and prolonged airway eosinophilia compared to vehicle-treated infected mice. In contrast to mice treated with AM6545, infected cannabinoid receptor subtype-2-null mice (Cnr2-/-) did not display any changes in these parameters compared to wild-type mice. Conclusions: Roles for the eCB system in Th2 immune responses are not well understood; however, increases in its activity in response to infection suggest an immunomodulatory role. Moreover, these findings suggest a role for eCB signaling at CB1Rs but not cannabinoid receptor subtypes-2 in the resolution of Th2 inflammatory responses, which become host destructive over time.

Mapping Rora expression in resting and activated CD4+ T cells.

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment.

Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation.

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

Gut CD4+ T cell phenotypes are a continuum molded by microbes, not by TH archetypes.

CD4+ effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff cells actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analyses to colonic Teff cells in germ-free or conventional mice or in mice after challenge with a range of phenotypically biasing microbes. Unexpected subsets were marked by the expression of the interferon (IFN) signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic helper T cell (TH) subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as TH markers were distributed in a polarized continuum, which was functionally validated. Clones derived from single progenitors gave rise to both IFN-γ- and interleukin (IL)-17-producing cells. Most of the transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activities of activator protein (AP)-1 and IFN-regulatory factor (IRF) transcription factor (TF) families, not the canonical subset master regulators T-bet, GATA3 or RORγ.

The deubiquitinase CYLD controls protective immunity against helminth infection by regulation of Treg cell plasticity.

BACKGROUND: Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent. OBJECTIVE: We sought to investigate the role of CYLD in Treg cell function and TH2 cell immune responses under steady-state conditions and during helminth infection. METHODS: Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays. RESULTS: Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation. CONCLUSIONS: Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into TH2 cell-like effector cells, which potentiates parasite resistance.

Cellular context of IL-33 expression dictates impact on anti-helminth immunity.

Interleukin-33 (IL-33) is a pleiotropic cytokine that can promote type 2 inflammation but also drives immunoregulation through Foxp3+Treg expansion. How IL-33 is exported from cells to serve this dual role in immunosuppression and inflammation remains unclear. Here, we demonstrate that the biological consequences of IL-33 activity are dictated by its cellular source. Whereas IL-33 derived from epithelial cells stimulates group 2 innate lymphoid cell (ILC2)-driven type 2 immunity and parasite clearance, we report that IL-33 derived from myeloid antigen-presenting cells (APCs) suppresses host-protective inflammatory responses. Conditional deletion of IL-33 in CD11c-expressing cells resulted in lowered numbers of intestinal Foxp3+Treg cells that express the transcription factor GATA3 and the IL-33 receptor ST2, causing elevated IL-5 and IL-13 production and accelerated anti-helminth immunity. We demonstrate that cell-intrinsic IL-33 promoted mouse dendritic cells (DCs) to express the pore-forming protein perforin-2, which may function as a conduit on the plasma membrane facilitating IL-33 export. Lack of perforin-2 in DCs blocked the proliferative expansion of the ST2+Foxp3+Treg subset. We propose that perforin-2 can provide a plasma membrane conduit in DCs that promotes the export of IL-33, contributing to mucosal immunoregulation under steady-state and infectious conditions.

The Heterogeneity, Origins, and Impact of Migratory iILC2 Cells in Anti-helminth Immunity.

Soil-transmitted helminths represent a major global health burden with infections and infection-related comorbidities causing significant reductions in the quality of life for individuals living in endemic areas. Repeated infections and chronic colonization by these large extracellular worms in mammals led to the evolution of type-2 immunity characterized by the production of the type-2 cytokines interleukin (IL)-4, IL-5, and IL-13. Although a number of adaptive and innate immune cells produce type-2 cytokines, a key cellular source in the context of helminth infection is group 2 innate lymphoid cells (ILC2s). ILC2s promote mucosal barrier homeostasis, integrity, and repair by rapidly responding to epithelial cues in mucosal tissues. Though tissue-resident ILC2s (nILC2s) have been studied in detail over the last decade, considerably less is known with regard to a subset of inflammatory ILC2s (iILC2s) that migrate to the lungs of mice early after Nippostrongylus brasiliensis infection and are potent early producers of type-2 cytokines. This review will discuss the relationship and differences between nILC2s and iILC2s that establish their unique roles in anti-helminth immunity. We have placed particular emphasis on studies investigating iILC2 origin, function, and their potential long-term contribution to tissue-resident ILC2 reservoirs in settings of helminth infection.

Preconception helminth infection alters offspring microbiota and immune subsets in a mouse model.

Both maternal microbiota and helminth infection may alter offspring immunity but the relationship between these is underexplored. We hypothesized that maternal helminth exposure prior to pregnancy has lasting consequences on offspring intestinal microbiota and consequent immunity. Female BALB/c adult mice were infected with 500L3 Nippostrongylus brasiliensis (N brasiliensis). Infection was cleared by ivermectin treatment, and mice were mated 3 weeks post-infection (NbM). Control mice were not infected but were exposed to ivermectin (NvM). We analysed maternal gut microbiota during pregnancy, breastmilk microbiota and offspring faecal microbiota and immunity 2 weeks after delivery. During pregnancy, NbM (Mothers previously infected with Nippostrongylus brasiliensis) displayed significantly altered stool bacterial communities (R2  = .242; P = .001), with increased abundance of Enterococcaceae versus NvM (Naive mothers). Similarly, we observed a profound impact on breastmilk microbiota in NbM vs NvM. Moreover, NbM pups showed significantly altered gut microbial communities at 14 days of age versus those born to NvM with increased relative abundance of Coriobacteriaceae and Micrococcaceae. These changes were associated with alterations in pup immunity including increased frequencies and numbers of activated CD4 T cells (CD4 + CD44hi) in NbM offspring spleens. Taken together, we show that preconception helminth infections impact offspring immunity possibly through alteration of maternal and offspring microbiota.

Tuft-Cell-Derived Leukotrienes Drive Rapid Anti-helminth Immunity in the Small Intestine but Are Dispensable for Anti-protist Immunity.

Helminths, allergens, and certain protists induce type 2 immune responses, but the underlying mechanisms of immune activation remain poorly understood. In the small intestine, chemosensing by epithelial tuft cells results in the activation of group 2 innate lymphoid cells (ILC2s), which subsequently drive increased tuft cell frequency. This feedforward circuit is essential for intestinal remodeling and helminth clearance. ILC2 activation requires tuft-cell-derived interleukin-25 (IL-25), but whether additional signals regulate the circuit is unclear. Here, we show that tuft cells secrete cysteinyl leukotrienes (cysLTs) to rapidly activate type 2 immunity following chemosensing of helminth infection. CysLTs cooperate with IL-25 to activate ILC2s, and tuft-cell-specific ablation of leukotriene synthesis attenuates type 2 immunity and delays helminth clearance. Conversely, cysLTs are dispensable for the tuft cell response induced by intestinal protists. Our findings identify an additional tuft cell effector function and suggest context-specific regulation of tuft-ILC2 circuits within the small intestine.

Interleukin-33 Induces the Enzyme Tryptophan Hydroxylase 1 to Promote Inflammatory Group 2 Innate Lymphoid Cell-Mediated Immunity.

Group 2 innate lymphoid cells (ILC2s) regulate immunity, inflammation, and tissue homeostasis. Two distinct subsets of ILC2s have been described: steady-state natural ILC2s and inflammatory ILC2s, which are elicited following helminth infection. However, how tissue-specific cues regulate these two subsets of ILC2s and their effector functions remains elusive. Here, we report that interleukin-33 (IL-33) promotes the generation of inflammatory ILC2s (ILC2INFLAM) via induction of the enzyme tryptophan hydroxylase 1 (Tph1). Tph1 expression was upregulated in ILC2s upon activation with IL-33 or following helminth infection in an IL-33-dependent manner. Conditional deletion of Tph1 in lymphocytes resulted in selective impairment of ILC2INFLAM responses and increased susceptibility to helminth infection. Further, RNA sequencing analysis revealed altered gene expression in Tph1 deficient ILC2s including inducible T cell co-stimulator (Icos). Collectively, these data reveal a previously unrecognized function for IL-33, Tph1, and ICOS in promoting inflammatory ILC2 responses and type 2 immunity at mucosal barriers.

Hookworms Evade Host Immunity by Secreting a Deoxyribonuclease to Degrade Neutrophil Extracellular Traps.

Hookworms cause a major neglected tropical disease, occurring after larvae penetrate the host skin. Neutrophils are phagocytes that kill large pathogens by releasing neutrophil extracellular traps (NETs), but whether they target hookworms during skin infection is unknown. Using a murine hookworm, Nippostrongylus brasiliensis, we observed neutrophils being rapidly recruited and deploying NETs around skin-penetrating larvae. Neutrophils depletion or NET inhibition altered larvae behavior and enhanced the number of adult worms following murine infection. Nevertheless, larvae were able to mitigate the effect of NETs by secreting a deoxyribonuclease (Nb-DNase II) to degrade the DNA backbone. Critically, neutrophils were able to kill larvae in vitro, which was enhanced by neutralizing Nb-DNase II. Homologs of Nb-DNase II are present in other nematodes, including the human hookworm, Necator americanus, which also evaded NETs in vitro. These findings highlight the importance of neutrophils in hookworm infection and a potential conserved mechanism of immune evasion.

The Prostaglandin D2 Receptor CRTH2 Promotes IL-33-Induced ILC2 Accumulation in the Lung.

Group 2 innate lymphoid cells (ILC2s) are rare innate immune cells that accumulate in tissues during allergy and helminth infection, performing critical effector functions that drive type 2 inflammation. ILC2s express ST2, the receptor for the cytokine IL-33, and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), a receptor for the bioactive lipid prostaglandin D2 (PGD2). The IL-33-ST2 and the PGD2-CRTH2 pathways have both been implicated in promoting ILC2 accumulation during type 2 inflammation. However, whether these two pathways coordinate to regulate ILC2 population size in the tissue in vivo remains undefined. In this study, we show that ILC2 accumulation in the murine lung in response to systemic IL-33 treatment was partially dependent on CRTH2. This effect was not a result of reduced ILC2 proliferation, increased apoptosis or cell death, or differences in expression of the ST2 receptor in the absence of CRTH2. Rather, data from adoptive transfer studies suggested that defective accumulation of CRTH2-deficient ILC2s in response to IL-33 was due to altered ILC2 migration patterns. Whereas donor wild-type ILC2s preferentially accumulated in the lungs compared with CRTH2-deficient ILC2s following transfer into IL-33-treated recipients, wild-type and CRTH2-deficient ILC2s accumulated equally in the recipient mediastinal lymph node. These data suggest that CRTH2-dependent effects lie downstream of IL-33, directly affecting the migration of ILC2s into inflamed lung tissues. A better understanding of the complex interactions between the IL-33 and PGD2-CRTH2 pathways that regulate ILC2 population size will be useful in understanding how these pathways could be targeted to treat diseases associated with type 2 inflammation.

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung.

Alternatively activated macrophages are essential effector cells during type 2 immunity and tissue repair following helminth infections. We previously showed that Ym1, an alternative activation marker, can drive innate IL-1R-dependent neutrophil recruitment during infection with the lung-migrating nematode, Nippostrongylus brasiliensis, suggesting a potential role for the inflammasome in the IL-1-mediated innate response to infection. Although inflammasome proteins such as NLRP3 have important proinflammatory functions in macrophages, their role during type 2 responses and repair are less defined. We therefore infected Nlrp3 -/- mice with N. brasiliensis Unexpectedly, compared with wild-type (WT) mice, infected Nlrp3 -/- mice had increased neutrophilia and eosinophilia, correlating with enhanced worm killing but at the expense of increased tissue damage and delayed lung repair. Transcriptional profiling showed that infected Nlrp3 -/- mice exhibited elevated type 2 gene expression compared with WT mice. Notably, inflammasome activation was not evident early postinfection with N. brasiliensis, and in contrast to Nlrp3 -/- mice, antihelminth responses were unaffected in caspase-1/11-deficient or WT mice treated with the NLRP3-specific inhibitor MCC950. Together these data suggest that NLRP3 has a role in constraining lung neutrophilia, helminth killing, and type 2 immune responses in an inflammasome-independent manner.

Pre-conception maternal helminth infection transfers via nursing long-lasting cellular immunity against helminths to offspring.

Maternal immune transfer is the most significant source of protection from early-life infection, but whether maternal transfer of immunity by nursing permanently alters offspring immunity is poorly understood. Here, we identify maternal immune imprinting of offspring nursed by mothers who had a pre-conception helminth infection. Nursing of pups by helminth-exposed mothers transferred protective cellular immunity to these offspring against helminth infection. Enhanced control of infection was not dependent on maternal antibody. Protection associated with systemic development of protective type 2 immunity in T helper 2 (TH2) impaired IL-4Rα-/- offspring. This maternally acquired immunity was maintained into maturity and required transfer (via nursing) to the offspring of maternally derived TH2-competent CD4 T cells. Our data therefore reveal that maternal exposure to a globally prevalent source of infection before pregnancy provides long-term nursing-acquired immune benefits to offspring mediated by maternally derived pathogen-experienced lymphocytes.

RELMα-expressing macrophages protect against fatal lung damage and reduce parasite burden during helminth infection.

Alternatively activated macrophages (AAMs) can contribute to wound healing, regulation of glucose and fat metabolism, resolution of inflammation, and protective immunity against helminths. Their differentiation, tissue distribution, and effector functions are incompletely understood. Murine AAMs express high levels of resistin-like molecule (RELM) α, an effector protein with potent immunomodulatory functions. To visualize RELMα+ macrophages (MΦs) in vivo and evaluate their role in defense against helminths, we generated RELMα reporter/deleter mice. Infection with the helminth Nippostrongylus brasiliensis induced expansion of RELMα+ lung interstitial but not alveolar MΦs in a STAT6-dependent manner. RELMα+ MΦs were required for prevention of fatal lung damage during primary infection. Furthermore, protective immunity was lost upon specific deletion of RELMα+ MΦs during secondary infection. Thus, RELMα reporter/deleter mice reveal compartmentalization of AAMs in different tissues and demonstrate their critical role in resolution of severe lung inflammation and protection against migrating helminths.

The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.

Macrophages promote epithelial proliferation following infectious and non-infectious lung injury through a Trefoil factor 2-dependent mechanism.

Coordinated efforts between macrophages and epithelia are considered essential for wound healing, but the macrophage-derived molecules responsible for repair are poorly defined. This work demonstrates that lung macrophages rely upon Trefoil factor 2 to promote epithelial proliferation following damage caused by sterile wounding, Nippostrongylus brasiliensis or Bleomycin sulfate. Unexpectedly, the presence of T, B, or ILC populations was not essential for macrophage-driven repair. Instead, conditional deletion of TFF2 in myeloid-restricted CD11cCre TFF2 flox mice exacerbated lung pathology and reduced the proliferative expansion of CD45- EpCAM+ pro-SPC+ alveolar type 2 cells. TFF2 deficient macrophages had reduced expression of the Wnt genes Wnt4 and Wnt16 and reconstitution of hookworm-infected CD11cCre TFF2flox mice with rWnt4 and rWnt16 restored the proliferative defect in lung epithelia post-injury. These data reveal a previously unrecognized mechanism wherein lung myeloid phagocytes utilize a TFF2/Wnt axis as a mechanism that drives epithelial proliferation following lung injury.

House dust mite drives proinflammatory eicosanoid reprogramming and macrophage effector functions.

BACKGROUND: Eicosanoid lipid mediators play key roles in type 2 immune responses, for example in allergy and asthma. Macrophages represent major producers of eicosanoids and they are key effector cells of type 2 immunity. We aimed to comprehensively track eicosanoid profiles during type 2 immune responses to house dust mite (HDM) or helminth infection and to identify mechanisms and functions of eicosanoid reprogramming in human macrophages. METHODS: We established an LC-MS/MS workflow for the quantification of 52 oxylipins to analyze mediator profiles in human monocyte-derived macrophages (MDM) stimulated with HDM and during allergic airway inflammation (AAI) or nematode infection in mice. Expression of eicosanoid enzymes was studied by qPCR and western blot and cytokine production was assessed by multiplex assays. RESULTS: Short (24 h) exposure of alveolar-like MDM (aMDM) to HDM suppressed 5-LOX expression and product formation, while triggering prostanoid (thromboxane and prostaglandin D2 and E2 ) production. This eicosanoid reprogramming was p38-dependent, but dectin-2-independent. HDM also induced proinflammatory cytokine production, but reduced granulocyte recruitment by aMDM. In contrast, high levels of cysteinyl leukotrienes (cysLTs) and 12-/15-LOX metabolites were produced in the airways during AAI or nematode infection in mice. CONCLUSION: Our findings show that a short exposure to allergens as well as ongoing type 2 immune responses are characterized by a fundamental reprogramming of the lipid mediator metabolism with macrophages representing particularly plastic responder cells. Targeting mediator reprogramming in airway macrophages may represent a viable approach to prevent pathogenic lipid mediator profiles in allergy or asthma.