Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2YR-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2YR binding, suggesting that an optimal affinity (IC, nM) in the piperidine series was achieved for triazolyl -linked glucose conjugates having one (, MRS4872, 3.
View Article and Find Full Text PDFThe severity of allergic asthma is driven by the balance between allergen-specific T regulatory (Treg) and T helper (Th)2 cells. However, it is unclear whether specific subsets of conventional dendritic cells (cDCs) promote the differentiation of these two T cell lineaeges. We have identified a subset of lung resident type 2 cDCs (cDC2s) that display high levels of CD301b and have potent Treg-inducing activity .
View Article and Find Full Text PDFImmune cells experience large cell shape changes during environmental patrolling because of the physical constraints that they encounter while migrating through tissues. These cells can adapt to such deformation events using dedicated shape-sensing pathways. However, how shape sensing affects immune cell function is mostly unknown.
View Article and Find Full Text PDFBackground: Allergic asthma is driven largely by allergen-specific T2 cells, which develop in regional lymph nodes on the interaction of naive CD4 T cells with allergen-bearing dendritic cells that migrate from the lung. This migration event is dependent on CCR7 and its chemokine ligand, CCL21. However, is has been unclear whether the other CCR7 ligand, CCL19, has a role in allergic airway disease.
View Article and Find Full Text PDFBackground: Environmental exposure to peanut through non-oral routes is a risk factor for peanut allergy. Early-life exposure to air pollutants, including particulate matter (PM), is associated with sensitization to foods through unknown mechanisms. We investigated whether PM promotes sensitization to environmental peanut and the development of peanut allergy in a mouse model.
View Article and Find Full Text PDFDNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy.
View Article and Find Full Text PDFAsthma is a chronic disease of the airways that impairs normal breathing. The etiology of asthma is complex and involves multiple factors, including the environment and genetics, especially the distinct genetic architecture associated with ancestry. Compared to early-onset asthma, little is known about genetic predisposition to late-onset asthma.
View Article and Find Full Text PDFP2Y receptor (P2YR) is activated by extracellular UDP-glucose, a damage-associated molecular pattern that promotes inflammation in the kidney, lung, fat tissue, and elsewhere. Thus, selective P2YR antagonists are potentially useful for inflammatory and metabolic diseases. The piperidine ring size of potent, competitive P2YR antagonist (4-phenyl-2-naphthoic acid derivative) PPTN was varied from 4- to 8-membered rings, with bridging/functional substitution.
View Article and Find Full Text PDFCOVID-19 disease is associated with progressive accumulation of SARS-CoV-2-specific mRNA, which is recognized by innate immune receptors, such as TLR3. This in turn leads to dysregulated production of multiple cytokines, including IL-6, IFN-γ, CXCL1, and TNF-α. Excessive production of these cytokines leads to acute lung injury (ALI), which consequently compromises alveolar exchange of O and CO.
View Article and Find Full Text PDFAm J Respir Cell Mol Biol
February 2023
The intensity and longevity of inflammatory responses to inhaled allergens is determined largely by the balance between effector and regulatory immune responses, but the mechanisms that determine the relative magnitudes of these opposing forces remain poorly understood. We have found that the type of adjuvant used during allergic sensitization has a profound effect on both the nature and longevity of the pulmonary inflammation triggered by subsequent reexposure to that same provoking allergen. TLR ligand adjuvants and house dust extracts primed immune responses characterized by a mixed neutrophilic and eosinophilic inflammation that was suppressed by multiple daily allergen challenges.
View Article and Find Full Text PDFHigh affinity phenyl-piperidine P2YR antagonist (PPTN) was modified with piperidine bridging moieties to probe receptor affinity and hydrophobicity. Various 2-azanorbornane, nortropane, isonortropane, isoquinuclidine, and ring-opened cyclopentylamino derivatives preserved human P2YR affinity (fluorescence binding assay), and their pharmacophoric overlay was compared. Enantiomeric 2-azabicyclo[2.
View Article and Find Full Text PDFMucosal sites, such as the lung, serve as crucial, yet vulnerable barriers to environmental insults such as pathogens, allergens, and toxins. Often, these exposures induce massive infiltration and death of short-lived immune cells in the lung, and efficient clearance of these cells is important for preventing hyperinflammation and resolving immunopathology. Herein, we review recent advances in our understanding of efferocytosis, a process whereby phagocytes clear dead cells in a noninflammatory manner.
View Article and Find Full Text PDFDendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo.
View Article and Find Full Text PDFObesity is the major driver of the worldwide epidemic in type 2 diabetes (T2D). In the obese state, chronically elevated plasma free fatty acid levels contribute to peripheral insulin resistance, which can ultimately lead to the development of T2D. For this reason, drugs that are able to regulate lipolytic processes in adipocytes are predicted to have considerable therapeutic potential.
View Article and Find Full Text PDFIn this issue of , Gallego et al reveal new complexity in the relationship between the chemokine receptor, CXCR4, and trafficking of dendritic cells (DCs) from the skin to regional lymph nodes (LNs).
View Article and Find Full Text PDFBackground & Aims: The immune compartment is critical for maintaining tissue homeostasis. A weak immune response increases susceptibility to infection, but immune hyperactivation causes tissue damage, and chronic inflammation may lead to cancer development. In the stomach, inflammation damages the gastric glands and drives the development of potentially preneoplastic metaplasia.
View Article and Find Full Text PDFAirway eosinophilia is a hallmark of allergic asthma and is associated with mucus production, airway hyperresponsiveness, and shortness of breath. Although glucocorticoids are widely used to treat asthma, their prolonged use is associated with several side effects. Furthermore, many individuals with eosinophilic asthma are resistant to glucocorticoid treatment, and they have an unmet need for novel therapies.
View Article and Find Full Text PDFAsthma is a common respiratory disease currently affecting more than 300 million worldwide and is characterized by airway inflammation, hyperreactivity, and remodeling. It is a heterogeneous disease consisting of corticosteroid-sensitive T-helper cell type 2-driven eosinophilic and corticosteroid-resistant, T-helper cell type 17-driven neutrophilic phenotypes. One pathway recently described to regulate asthma pathogenesis is cholesterol trafficking.
View Article and Find Full Text PDFNonhematopoietic cells are emerging as important contributors to many inflammatory diseases, including allergic asthma. Recent advances have led to a deeper understanding of how these cells interact with traditional immune cells, thereby modulating their activities in both homeostasis and disease. In addition to their well-established roles in gas exchange and barrier function, lung epithelial cells express an armament of innate sensors that can be triggered by various inhaled environmental agents, leading to the production of proinflammatory molecules.
View Article and Find Full Text PDFVarious heteroaryl and bicyclo-aliphatic analogues of zwitterionic biaryl P2Y receptor (P2YR) antagonists were synthesized, and affinity was measured in P2YR-expressing Chinese hamster ovary cells by flow cytometry. Given this series' low water solubility, various polyethylene glycol derivatives of the distally binding piperidin-4-yl moiety of moderate affinity were synthesized. Rotation of previously identified 1,2,3-triazole attached to the central -benzoic acid core () provided moderate affinity but not indole and benzimidazole substitution of the aryl-triazole.
View Article and Find Full Text PDFPurpose Of Review: This review summarizes recent progress in our understanding how environmental adjuvants promote the development of asthma.
Recent Findings: Asthma is a heterogeneous set of lung pathologies with overlapping features. Human studies and animal models suggest that exposure to different environmental adjuvants activate distinct immune pathways, which in turn give rise to distinct forms, or endotypes, of allergic asthma.
Alveolar macrophages (AM) play a central role in initiation and resolution of lung inflammation, but the integration of these opposing core functions is poorly understood. AM expression of cholesterol 25-hydroxylase (CH25H), the primary biosynthetic enzyme for 25-hydroxycholesterol (25HC), far exceeds the expression of macrophages in other tissues, but no role for CH25H has been defined in lung biology. As 25HC is an agonist for the antiinflammatory nuclear receptor, liver X receptor (LXR), we speculated that CH25H might regulate inflammatory homeostasis in the lung.
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