Human intraepithelial mast cell differentiation and effector function are directed by TGF-β signaling.

Mast cells (MCs) expressing a distinctive protease phenotype (MCTs) selectively expand within the epithelium of human mucosal tissues during type 2 (T2) inflammation. While MCTs are phenotypically distinct from subepithelial MCs (MCTCs), signals driving human MCT differentiation and this subset's contribution to inflammation remain unexplored. Here, we have identified TGF-β as a key driver of the MCT transcriptome in nasal polyps.

Determinants of persistence and recovery of chronic coronavirus disease 2019 chemosensory dysfunction.

Background: In 2% to 4% of patients, coronavirus disease 2019 (COVID-19) chemosensory dysfunction (CSD) persists beyond 6 months, accounting for up to 4 million people in the United States. The predictors of persistence and recovery require further exploration.

Objective: We sought to define the predictors of recovery and assess the quality of CSD in registry subjects with self-reported persistent smell and taste dysfunction after COVID-19.

Weep and sweep and the broom: tuft cell acetylcholine limits the worm.

Two studies defined how tuft cell acetylcholine promotes parasite expulsion. Billip et al. demonstrated that acetylcholine increases water secretion, to promote the 'weep' response.

A nasal cell atlas reveals heterogeneity of tuft cells and their role in directing olfactory stem cell proliferation.

The olfactory neuroepithelium serves as a sensory organ for odors and forms part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. Among them, microvillous cells (MVCs) are strategically positioned at the apical surface, but their specific functions are enigmatic, and their relationship to the other specialized epithelial cells is unclear.

Cysteinyl-maresin 3 inhibits IL-13 induced airway hyperresponsiveness through alternative activation of the CysLT receptor.

Background: Cysteinyl-maresins, also known as maresin-conjugates in tissue regeneration (MCTRs), are recently discovered lipid mediators proposed to reduce airway inflammation.

Objective: To investigate the influence of MCTRs on IL-13-induced airway hyperresponsiveness in isolated human and mice airways.

Methods: Before responsiveness to contractile agonists were assessed in myographs, human small bronchi were cultured for 2 days and mouse tracheas were cultured for 1-4 days.

Brush cells fine-tune neurogenic inflammation in the airways.

Airway epithelial cells, once considered a simple barrier layer, are now recognized as providing an active site for antigen sensing and immune response initiation. Most mucosal sites contain chemosensory epithelial cells, rare and specialized cells gaining recognition for their unique functions in sensing and directing the immune response symphony. In this issue of the JCI, Hollenhorst, Nandigama, et al.

Isolation, Ex Vivo Culture, and Stimulation of Tracheal and Nasal Chemosensory Cells.

Brush cells are chemosensory epithelial cells present at most mucosal surfaces.Brush cells are a dominant source of cysteinyl leukotrienes and IL-25 in the airway epithelium and are equipped with the machinery to generate prostaglandins and acetylcholine. Activation of innate type 2 lymphoid cells and dendritic cells triggered by brush cell-derived mediators skew the immune response in the airway to type 2 inflammation that underlies atopic disease such as asthma.

Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation.

Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25 (IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not been clarified.

Isolation of Nasal Brush Cells for Single-cell Preparations.

Solitary chemosensory epithelial cells are scattered in most mucosal surfaces. They are referred to as tuft cells in the intestinal mucosa, brush cells in the trachea, and solitary chemosensory and microvillous cells in the nasal mucosa. They are the primary source of IL-25 in the epithelium and are also engaged in acetylcholine generation.

The CysLTR receptor mediates leukotriene C-driven acute and chronic itch.

Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC, LTD, and LTE, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC and its signaling through the CysLT receptor 2 (CysLTR) in itch.

Lineage-specific regulation of inducible and constitutive mast cells in allergic airway inflammation.

Murine mast cells (MCs) contain two lineages: inducible bone marrow-derived mucosal MCs (MMCs) and constitutive embryonic-derived connective tissue MCs (CTMCs). Here, we use RNA sequencing, flow cytometry, and genetic deletion in two allergic lung inflammation models to define these two lineages. We found that inducible MCs, marked by β7 integrin expression, are highly distinct from airway CTMCs at rest and during inflammation and unaffected by targeted CTMC deletion.

IL-5Rα marks nasal polyp IgG4- and IgE-expressing cells in aspirin-exacerbated respiratory disease.

Background: The cause of severe nasal polyposis in aspirin-exacerbated respiratory disease (AERD) is unknown. Elevated antibody levels have been associated with disease severity in nasal polyps, but upstream drivers of local antibody production in nasal polyps are undetermined.

Objective: We sought to identify upstream drivers and phenotypic properties of local antibody-expressing cells in nasal polyps from subjects with AERD.

Epithelial cell function and remodeling in nasal polyposis.

Objective: To review the latest discoveries on airway epithelial cell diversity and remodeling in type 2 inflammation, including nasal polyposis.

Data Sources: Reviews and primary research manuscripts were identified from PubMed, Google, and Bioarchives, using the search words airway epithelium, nasal polyposis, or chronic rhinosinusitis with nasal polyposis AND basal cell, ciliated cell, secretory cell, goblet cell, neuroendocrine cell, pulmonary neuroendocrine cell, ionocyte, brush cell, solitary chemosensory cell, microvillus cell, or tuft cell.

Study Selections: Studies were selected based on novelty and likely relevance to airway epithelial innate immune functions or the pathobiology of type 2 inflammation.

Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2.

Chemosensory epithelial cells (EpCs) are specialized cells that promote innate type 2 immunity and protective neurally mediated reflexes in the airway. Their effector programs and modes of activation are not fully understood. Here, we define the transcriptional signature of two choline acetyltransferase-expressing nasal EpC populations.

Isolation and Quantitative Evaluation of Brush Cells from Mouse Tracheas.

Tracheal brush cells are cholinergic chemosensory epithelial cells poised to transmit signals from the airway lumen to the immune and nervous systems. They are part of a family of chemosensory epithelial cells which include tuft cells in the intestinal mucosa, brush cells in the trachea, and solitary chemosensory and microvillous cells in the nasal mucosa. Chemosensory cells in different epithelial compartments share key intracellular markers and a core transcriptional signature, but also display significant transcriptional heterogeneity, likely reflective of the local tissue environment.

The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation.

Respiratory epithelial cells (EpCs) orchestrate airway mucosal inflammation in response to diverse environmental stimuli, but how distinct EpC programs are regulated remains poorly understood. Here, we report that inhalation of aeroallergens leads to expansion of airway brush cells (BrCs), specialized chemosensory EpCs and the dominant epithelial source of interleukin-25 (IL-25). BrC expansion was attenuated in mice lacking either LTC synthase, the biosynthetic enzyme required for cysteinyl leukotriene (CysLT) generation, or the EpC receptor for leukotriene E (LTE), CysLTR.

Leukotriene E4 elicits respiratory epithelial cell mucin release through the G-protein-coupled receptor, GPR99.

Cysteinyl leukotrienes (cysLTs), leukotriene C4 (LTC4), LTD4, and LTE4 are proinflammatory lipid mediators with pathobiologic function in asthma. LTE4, the stable cysLT, is a weak agonist for the type 1 and type 2 cysLT receptors (CysLTRs), which constrict airway smooth muscle, but elicits airflow obstruction and pulmonary inflammation in patients with asthma. We recently identified GPR99 as a high-affinity receptor for LTE4 that mediates cutaneous vascular permeability.

Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies.

Background: Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined.

Objective: We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD.

Mouse mast cell protease-6 and MHC are involved in the development of experimental asthma.

Allergic asthma is a complex disease with a strong genetic component where mast cells play a major role by the release of proinflammatory mediators. In the mouse, mast cell protease-6 (mMCP-6) closely resembles the human version of mast cell tryptase, β-tryptase. The gene that encodes mMCP-6, Tpsb2, resides close by the H-2 complex (MHC gene) on chromosome 17.

Mouse mast cell proteases 4 and 5 mediate epidermal injury through disruption of tight junctions.

We previously established a mast cell (MC)-dependent thermal injury model in mice with ulceration and scar formation that depended on nonredundant functions of mouse MC protease (mMCP)4 and mMCP5. We hypothesized that MC activation is an early event and now find by histology that exocytosis of granule contents occurred by 2 min after thermal injury in wild-type (WT) C57BL/6 mice and in the mMCP4- or mMCP5-deficient mice. The degranulation was equivalent for MCs in the dermis and hypodermis of all three strains, but only the WT mice showed an appreciable increase in epidermal thickness.

Mast cells recruited to mesenteric lymph nodes during helminth infection remain hypogranular and produce IL-4 and IL-6.

Mast cells (MC) and basophils share expression of the high-affinity receptor for IgE (FcεRI) but can be distinguished by their divergent expression of KIT and CD49b. In BALB/c mice, MC lineage cells expressing high levels of FcεRI by flow cytometry were seen only in bone marrow whereas those expressing intermediate levels of FcεRI were present in bone marrow and spleen of naive mice and in mesenteric lymph nodes (mLN) of Trichinella spiralis-infected mice. These FcεRI(+)KIT(+)CD49b(-) cells had a membrane phenotype similar to i.

Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies.

Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion.