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Challenges that face the academic research enterprise are numerous. These concerns include, but are not limited to: declines in extramural funding for investigatorinitiated research, an aging faculty workforce (the average age of securing a faculty's first R01 is over 42), insufficient funds to support faculty laboratories, and limited access to cuttingedge, next generation infrastructure and methods to support research. This manuscript describes an institutional approach to providing leading-edge core facilities and enhancing the effectiveness of their operations by implementing process improvements, managing the lifecycle of core facilities, and monitoring key core facilities' metrics. This approach has created a number of standardized, transparent processes to effectively manage central infrastructure that enables enterprise-wide research, including a process for capital equipment planning, a procedure to evaluate new cores, a method for reviewing and managing the lifecycle of existing cores (invest, maintain, or sun-down), an investment in the administration and operational efficiencies of the cores, and support for the development and implementation of new methodologies for our investigators. The execution of these processes has provided faculty with forward-looking technologies to facilitate innovative research and provide a competitive edge for extramural support.

Chemokine receptors transduce signals important for the function and trafficking of leukocytes. Recently, it has been shown that CC chemokine receptor (CCR)8 is selectively expressed by Th2 subsets, but its functional relevance is unclear. To address the biological role of CCR8, we generated CCR8 deficient (-/-) mice. Here we report defective T helper type 2 (Th2) immune responses in vivo in CCR8(-/)- mice in models of Schistosoma mansoni soluble egg antigen (SEA)-induced granuloma formation as well as ovalbumin (OVA)- and cockroach antigen (CRA)-induced allergic airway inflammation. In these mice, the response to SEA, OVA, and CRA showed impaired Th2 cytokine production that was associated with aberrant type 2 inflammation displaying a 50 to 80% reduction in eosinophils. In contrast, a prototypical Th1 immune response, elicited by Mycobacteria bovis purified protein derivative (PPD) was unaffected by CCR8 deficiency. Mechanistic analyses indicated that Th2 cells developed normally and that the reduction in eosinophil recruitment was likely due to systemic reduction in interleukin 5. These results indicate an important role for CCR8 in Th2 functional responses in vivo.

Objective: To determine cell-specific gene expression profiles that contribute to development of abdominal aortic aneurysms (AAAs). Background: AAAs represent the most common pathological aortic dilation leading to the fatal consequence of aortic rupture. Both immune and structural cells contribute to aortic degeneration, however, gene specific alterations in these cellular subsets are poorly understood. Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis of AAAs and control tissues. AAA-related changes were examined by comparing gene expression profiles as well as detailed receptor-ligand interactions. An integrative analysis of scRNA-seq data with large genome-wide association study data was conducted to identify genes critical for AAA development. Results: Using scRNA-seq we provide the first comprehensive characterization of the cellular landscape in human AAA tissues. Unbiased clustering analysis of transcriptional profiles identified seventeen clusters representing 8 cell lineages. For immune cells, clustering analysis identified 4 T-cell and 5 monocyte/macrophage subpopulations, with distinct transcriptional profiles in AAAs compared to controls. Gene enrichment analysis on immune subsets identified multiple pathways only expressed in AAA tissue, including those involved in mitochondrial dysfunction, proliferation, and cytokine secretion. Moreover, receptor-ligand analysis defined robust interactions between vascular smooth muscle cells and myeloid populations in AAA tissues. Lastly, integrated analysis of scRNA-seq data with genome-wide association study studies determined that vascular smooth muscle cell expression of SORT1 is critical for maintaining normal aortic wall function. Conclusions: Here we provide the first comprehensive evaluation of single-cell composition of the abdominal aortic wall and reveal how the gene expression landscape is altered in human AAAs. [ABSTRACT FROM AUTHOR]

Abstract Airway hyper-reactivity is a characteristic feature of many inflammatory lung diseases and is defined as an exaggerated degree of airway narrowing. Chemokines and their receptors are involved in several pathological processes that are believed to contribute to airway hyper-responsiveness, including recruitment and activation of inflammatory cells, collagen deposition and airway wall remodeling. These proteins are therefore thought to represent important therapeutic targets in the treatment of airway hyper-responsiveness. This review highlights the processes thought to be involved in airway hyper-responsiveness in allergic asthma, and the role of chemokines in these processes. Overall, the application of chemokines to the prevention or treatment of airway hyper-reactivity has tremendous potential.

TLRs are a family of receptors that mediate immune system pathogen recognition. In the respiratory system, TLR activation has both beneficial and deleterious effects in asthma. For example, clinical data [...]

TLR9 activation is important for the maintenance of mycobacteria-elicited pulmonary granulomatous responses, hallmarks of protective immune responses following mycobacterial infection. However, the mechanism or mechanisms underlying this effect of TLR9 are not clear. Here, we show that Tlr9-deficient mice challenged with a Mycobacterium antigen display an altered Th17 cytokine profile, decreased accumulation of granuloma-associated myeloid DCs, and profoundly impaired delta-like 4 (dll4) Notch ligand expression. Mechanistic analysis revealed that WT bone marrow--derived DCs but not macrophages promoted the differentiation of Th17 cells from bacillus Calmette-Guerin--challenged (BCG-challenged) lung [CD4.sup.+] T cells. Both lung and bone marrow DCs isolated from Tlr9-deficient mice inoculated with Mycobacterium antigen expressed lower levels of dll4 Notch ligand than the same cells isolated from WT mice. Passively immunizing WT mice with neutralizing antibodies specific for dll4 during granuloma formation resulted in larger granulomas and lower levels of Th17-related cytokines. In addition, dll4 specifically regulated Th17 activation in vitro. Together, these results suggest dll4 plays an important role in promoting Th17 effector activity during a mycobacterial challenge. Furthermore, TLR9 seems to be required for optimal dll4 expression and the regulation of Mycobacterium antigen--elicited granuloma formation in mice., Introduction Granulomas represent a spectrum of inflammatory sequestration responses that may be initiated by a variety of agents, including noninfectious environmental factors and infectious microbial pathogens (1), (2). One of [...]

Eotaxin/CCL11 is involved in acute, but not chronic, allergic airway responses to Aspergillus fumigatus. Am J Physiol Lung Cell Mol Physiol 283: L198-L204, 2002. First published February 8, 2002; 10.1152/ ajplung.00341.2001.--Eotaxin/CCL11 is a major chemoattractant for eosinophils and Th2 cells. As such, it represents an attractive target in the treatment of allergic disease. The present study addresses the role of eotaxin/CCL11 during acute and chronic allergic airway responses to the fungus Aspergillus fumigatus. Mice lacking the eotaxin gene (Eo-/-) and wild-type mice (Eo+/+) were sensitized to A. fumigatus and received either an intratracheal challenge with soluble A. fumigatus antigens (acute model) or an intratracheal challenge with live A. fumigatus spores or conidia (chronic model). Airway hyperresponsiveness and eosinophil, but not T cell, recruitment were significantly decreased at 24 h after the soluble allergen in A. fumigatus-sensitized Eo-/- mice compared with similarly sensitized Eo+/+ mice. In contrast, the development of chronic allergic airway disease due to A. fumigatus conidia was not altered by the lack of eotaxin. Together, these data suggest that eotaxin initiates allergic airway disease due to A. fumigatus, but this chemokine did not appear to contribute to the maintenance of A. fumigatus-induced allergic airway disease. eosinophil; allergy; airway hyperreactivity

Research was conducted to examine the hypothesis that interleukin (IL)-10 regulates quartz-induced pulmonary inflammation in rats. Inflammation and chemokine expression in rats treated with either anti-IL-10 antibody or rmIL-10 were characterized. Results demonstrate that IL-10 serves as a constitutive anti-inflammatory factor in the rat lung and that its effect on quartz-induced inflammation is mediated, in part, by attenuation of MIP-2 gene expression.

A study was conducted to examine C-X-C chemokines generated by endotoxin-stimulated human alveolar macrophages. The macrophages were stimulated with or without Escherichia coli endotoxin before being determined from volunteers by bronchoalveolar lavage. Total cellular RNA was then obtained from the adherent macrophage layers. Results indicated strategies for controlling alveolar macrophage-based inflammatory signals in the lungs.