A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis.

The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using (), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E (PGE) as a major immune regulatory mechanism of heGDH.

Pinewood VOC emissions protect from oxazolone-induced inflammation and dysbiosis in a mouse model of atopic dermatitis.

Pinewood, increasingly used in construction and interior fittings, emits high amounts of volatile organic compounds (VOCs), which tend to accumulate in indoor air. Whether indoor VOCs affect the development of atopic dermatitis (AD) is a matter of debate. We aimed to evaluate the effects of pinewood VOCs on the development of AD-like inflammatory phenotype and linked microbiome alterations, both hallmarks of AD.

Extracellular vesicle miRNAs drive aberrant macrophage responses in NSAID-exacerbated respiratory disease.

Background: Extracellular vesicles (EVs) have been implicated in the pathogenesis of asthma, however, how EVs contribute to immune dysfunction and type 2 airway inflammation remains incompletely understood. We aimed to elucidate roles of airway EVs and their miRNA cargo in the pathogenesis of NSAID-exacerbated respiratory disease (N-ERD), a severe type 2 inflammatory condition.

Methods: EVs were isolated from induced sputum or supernatants of cultured nasal polyp or turbinate tissues of N-ERD patients or healthy controls by size-exclusion chromatography and characterized by particle tracking, electron microscopy and miRNA sequencing.

The aryl hydrocarbon receptor regulates lipid mediator production in alveolar macrophages.

Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control.

Trained immunity in type 2 immune responses.

Immunological memory of innate immune cells, also termed "trained immunity", allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice.

Lung Epithelial CYP1 Activity Regulates Aryl Hydrocarbon Receptor Dependent Allergic Airway Inflammation.

The lung epithelial barrier serves as a guardian towards environmental insults and responds to allergen encounter with a cascade of immune reactions that can possibly lead to inflammation. Whether the environmental sensor aryl hydrocarbon receptor (AhR) together with its downstream targets cytochrome P450 (CYP1) family members contribute to the regulation of allergic airway inflammation remains unexplored. By employing knockout mice for AhR and for single CYP1 family members, we found that AhR and CYP1B1 but not CYP1A1 or CYP1A2 animals display enhanced allergic airway inflammation compared to WT.

Phosphatidylinositol 3-Kinase (PI3K) Orchestrates Aspergillus fumigatus-Induced Eosinophil Activation Independently of Canonical Toll-Like Receptor (TLR)/C-Type-Lectin Receptor (CLR) Signaling.

Eosinophilia is associated with various persisting inflammatory diseases and often coincides with chronic fungal infections or fungal allergy as in the case of allergic bronchopulmonary aspergillosis (ABPA). Here, we show that intranasal administration of live Aspergillus fumigatus conidia causes fatal lung damage in eosinophilic interleukin-5 (IL-5)-transgenic mice. To further investigate the activation of eosinophils by A.

Helminthic dehydrogenase drives PGE and IL-10 production in monocytes to potentiate Treg induction.

Immunoregulation of inflammatory, infection-triggered processes in the brain constitutes a central mechanism to control devastating disease manifestations such as epilepsy. Observational studies implicate the viability of Taenia solium cysts as key factor determining severity of neurocysticercosis (NCC), the most common cause of epilepsy, especially in children, in Sub-Saharan Africa. Viable, in contrast to decaying, cysts mostly remain clinically silent by yet unknown mechanisms, potentially involving Tregs in controlling inflammation.

Mild COVID-19 imprints a long-term inflammatory eicosanoid- and chemokine memory in monocyte-derived macrophages.

Monocyte-derived macrophages (MDM) drive the inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and they are a major source of eicosanoids in airway inflammation. Here we report that MDM from SARS-CoV-2-infected individuals with mild disease show an inflammatory transcriptional and metabolic imprint that lasts for at least 5 months after SARS-CoV-2 infection. MDM from convalescent SARS-CoV-2-infected individuals showed a downregulation of pro-resolving factors and an increased production of pro-inflammatory eicosanoids, particularly 5-lipoxygenase-derived leukotrienes.

β-Glucan receptors on IL-4 activated macrophages are required for hookworm larvae recognition and trapping.

Recent advances in the field of host immunity against parasitic nematodes have revealed the importance of macrophages in trapping tissue migratory larvae. Protective immune mechanisms against the rodent hookworm Nippostrongylus brasiliensis (Nb) are mediated, at least in part, by IL-4-activated macrophages that bind and trap larvae in the lung. However, it is still not clear how host macrophages recognize the parasite.

Not just "leuko" after all: Epithelial leukotriene production in type 2 immunity.

New research shows that specialized epithelial cells (tuft cells) are major producers of lipid mediators (leukotrienes) that drive allergic inflammation and host defense against helminth parasites. (See the related Research Article by Ualiyeva .).

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

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: We sought to decipher macrophage-trained immunity in allergic asthma.

Sputum microRNA-screening reveals Prostaglandin EP3 receptor as selective target in allergen-specific immunotherapy.

Background: Several microRNAs (miRs) have been described as potential biomarkers in liquid biopsies and in the context of allergic asthma, while therapeutic effects on the airway expression of miRs remain elusive. In this study, we investigated epigenetic miR-associated mechanisms in the sputum of grass pollen-allergic patients with and without allergen-specific immunotherapy (AIT).

Methods: Induced sputum samples of healthy controls (HC), AIT-treated and -untreated grass pollen-allergic rhinitis patients with (AA) and without asthma (AR) were profiled using miR microarray and whole-transcriptome microarray analysis of the same samples.

Fibroblast growth factor induced Ucp1 expression in preadipocytes requires PGE2 biosynthesis and glycolytic flux.

High uncoupling protein 1 (Ucp1) expression is a characteristic of differentiated brown adipocytes and is linked to adipogenic differentiation. Paracrine fibroblast growth factor 8b (FGF8b) strongly induces Ucp1 transcription in white adipocytes independent of adipogenesis. Here, we report that FGF8b and other paracrine FGFs act on brown and white preadipocytes to upregulate Ucp1 expression via a FGFR1-MEK1/2-ERK1/2 axis, independent of adipogenesis.

What Can Parasites Tell Us About the Pathogenesis and Treatment of Asthma and Allergic Diseases.

The same mechanisms that enable host defense against helminths also drive allergic inflammation. This suggests that pathomechanisms of allergic diseases represent evolutionary old responses against helminth parasites and that studying antihelminth immunity may provide insights into pathomechanisms of asthma. However, helminths have developed an intricate array of immunoregulatory mechanisms to modulate type 2 immune mechanisms.

Influence of glycosylation on IL-12 family cytokine biogenesis and function.

The interleukin 12 (IL-12) family of cytokines regulates T cell functions and is key for the orchestration of immune responses. Each heterodimeric IL-12 family member is a glycoprotein. However, the impact of glycosylation on biogenesis and function of the different family members has remained incompletely defined.

Inflammatory macrophage memory in nonsteroidal anti-inflammatory drug-exacerbated respiratory disease.

Background: Nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) is a chronic inflammatory condition, which is driven by an aberrant arachidonic acid metabolism. Macrophages are major producers of arachidonic acid metabolites and subject to metabolic reprogramming, but they have been neglected in N-ERD.

Objective: This study sought to elucidate a potential metabolic and epigenetic macrophage reprogramming in N-ERD.

Immune serum-activated human macrophages coordinate with eosinophils to immobilize Ascaris suum larvae.

Helminth infection represents a major health problem causing approximately 5 million disability-adjusted life years worldwide. Concerns that repeated anti-helminthic treatment may lead to drug resistance render it important that vaccines are developed but will require increased understanding of the immune-mediated cellular and antibody responses to helminth infection. IL-4 or antibody-activated murine macrophages are known to immobilize parasitic nematode larvae, but few studies have addressed whether this is translatable to human macrophages.