Search

Interleukin (IL)-17A signaling via Interleukin 17 receptor A (Il17ra) contributes to the inflammatory host response by inducing recruitment of innate immune cells, but also plays a role in homeostatic neutrophilic granulocyte regulation. Monocytes, the other main innate immune cell, have a longer life span and can pursue multiple differentiation pathways towards tissue macrophages. Monocytes are divided into two subpopulations by expression of the Ly6C/Gr1 surface marker in mice. We here investigated the role of Il17ra in monocyte homeostasis and macrophage generation. In Il17ra-/- and in mixed bone marrow chimeric wt/Il17ra-/- mice, the concentrations of circulating Il17ra-/-Gr1low monocytes were significantly decreased compared to wt cells. Pulmonary, splenic and resident peritoneal Il17ra-/- macrophages were significantly fewer than of wt origin. Bone marrow progenitor and monocyte numbers were equal, but the proportion of Il17ra-/-Gr1low monocytes was already decreased at bone marrow level. After monocyte depletion, initial Gr1high and Gr1low monocyte regeneration of Il17ra-/- and wt cells was very similar. However, Il17ra-/-Gr1low counts were not sustained. After labeling with either fluorescent beads or BrdU, Il17ra-/-Gr1high monocyte transition to Gr1low cells was not detectable unlike wt cells. Monocyte recruitment in acute peritonitis, which is known to be largely due to Gr1high cell migration, was unaffected in an identical environment. Unilateral ureteral obstruction induces a less acute inflammatory and fibrotic kidney injury. Compared to wt cells in the same environment, Il17ra-/- macrophage accumulation in the kidney was decreased. In the absence of Il17ra on all myeloid cells, renal fibrosis was significantly attenuated. Our data show that Il17ra modulates Gr1low monocyte counts and suggest defective Gr1high to Gr1low monocyte transition as an underlying mechanism. Lack of Il17ra altered homeostatic tissue macrophage formation and diminished renal inflammation and fibrosis. Il17ra appears to be a novel modulator of monocyte phenotype and possible therapeutic target in renal fibrosis. [ABSTRACT FROM AUTHOR]

The pathogenesis of allergic airway inflammation and disease is complex and still not fully understood. Many cells, factors and mediators are involved in the different aspects of induction, maintenance and persistence of airway inflammation. The heterogeneity and redundancy of this system is one of the main reasons why novel therapeutic targets focusing on the pathogenesis of asthma only hesitantly reach the market and clinical application. Thus, it seems mandatory that we proceed in our efforts to better understand this micro cosmos to succeed in the development of safe and effective drugs for the treatment of more severe and refractory forms of asthma and chronic obstructive pulmonary disease. One of the more recently discovered mediators in the context of airway inflammation are the lipocalins (Lcns). They are a family of proteins that share functional and structural similarities and are involved in the transport of small hydrophobic molecules such as steroids and lipids into the cell. Lcns are found in many different cell types from plants and bacteria through invertebrate cells to cells of vertebrate origin. The purpose of this review is to summarize the role of Lcns in airway diseases, focusing on allergic and infectious inflammation. In particular, we will summarize the present knowledge about Lipocalin 1 and Lipocalin 2, where exciting new discoveries in the recent years have highlighted their role in pulmonary disease and infection. This new class of proteins is another putative candidate for the development of novel drugs against airway inflammation. [ABSTRACT FROM AUTHOR]

Background: The inverse correlation of mycobacterial infection with asthma prevalence and the inhibitory effects of vaccination with Bacille Calmette-Guérin (BCG) on airway hyperreactivity in asthma models suggest modulation of dendritic cell (DC) and T cell functions by mycobacterial compounds. Methods: To delineate these immunological effects, the immunogenicity of BCG Copenhagen, BCG Chicago and BCG Pasteur was compared in a mouse model. Bone marrow-derived dendritic cells (BMDCs) from BALB/c mice were stimulated with ovalbumin (OVA) with or without BCG. BMDCs were phenotypically characterized by flow cytometry, and we used ELISA to measure the cytokine production of BMDCs as well as of co-cultivated allergen-specific T cells in response to OVA-pulsed. Immunomodulatory effects of BCG were studied in a model of allergic airway inflammation by adoptive transfer of allergen-pulsed BMDCs. Results: Immunomodulation with BCG induced production of IL-10 and IL-12 by BMDCs. Co-cultured allergen-specific T cells produced less IL-5, IL-13 and IFN-γ but more IL-10. Also the number of FoxP3+ regulatory T cells was enhanced. Strongest effects were seen with BCG Chicago and BCG Pasteur. In vivo, administration of BCG modulated OVA-pulsed BMDCs then reduced eosinophilic airway inflammation but enhanced infiltration with granulocytes. Airway hyperreactivity and mucus production were reduced and more FoxP3+ T cells were observed. Conclusion: BCG-induced suppression of Th2-type allergic airway inflammation was associated with enhancement of regulatory T cell function but also of Th1-associated neutrophilic airway inflammation. These findings raise concerns regarding the safety profile of BCG as a potential tool for prevention and therapy of allergic airway disease. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]