Proteinases and the innate immune receptor Toll-like receptor 4 (TLR4) are essential for expression of allergic inflammation and diseases such as asthma. A mechanism that links these inflammatory mediators is essential for explaining the fundamental basis of allergic disease but has been elusive. Here, we demonstrate that TLR4 is activated by airway proteinase activity to initiate both allergic airway disease and antifungal immunity. These outcomes were induced by proteinase cleavage of the clotting protein fibrinogen, yielding fibrinogen cleavage products that acted as TLR4 ligands on airway epithelial cells and macrophages. Thus, allergic airway inflammation represents an antifungal defensive strategy that is driven by fibrinogen cleavage and TLR4 activation. These findings clarify the molecular basis of allergic disease and suggest new therapeutic strategies.

MicroRNAs (miRNAs) are short, non-coding RNAs that target and silence protein coding genes through 3-UTR elements. Evidence increasingly assigns an immunosuppressive role for miRNAs in immunity, but relatively few miRNAs have been studied, and an overall understanding of the importance of these regulatory transcripts in complex in vivo systems is lacking.Here we have applied multiple technologies to globally analyze miRNA expression and function in allergic lung disease, an experimental model of asthma. Deep sequencing and microarray analyses of the mouse lung short RNAome revealed numerous extant and novel miRNAs and other transcript classes. Similar to mRNAs, lung miRNA expression changed dynamically during the transition from the naive to the allergic state, suggesting numerous functional relationships. A possible role for miRNA editing in altering the lung mRNA target repertoire was also identified. Multiple members of the highly conserved let-7 miRNA family were the most abundant lung miRNAs, and we confirmed in vitro that interleukin 13 (IL-13), a cytokine essential for expression for allergic lung disease, is regulated by mmulet-7a. However, inhibition of let-7 miRNAs in vivo using a locked nucleic acid profoundly inhibited production of allergic cytokines and the disease phenotype. Our findings thus reveal unexpected complexity in the miRNAome underlying allergic lung disease and demonstrate a proinflammatory role for let-7 miRNAs. MicroRNAs (miRNAs)3 are short regulatory RNAs with the potential to target and suppress multiple genes across diverse signaling pathways comprising biologically meaningful networks. Consequently, miRNAs that are inappropriately expressed in the context of specific diseases are of particular interest as therapeutic targets if they can be shown to coordinate such networks. Initially transcribed as relatively long primary transcripts, pri-miRNAs are subsequently modified by the nuclear RNAses Drosha and Pasha to yield precursor miRNAs (pre-miRNAs) that are further processed by the cytoplasmic RNase III Dicer to form short double-stranded miR-miR* duplexes, one strand of which (miR) is then integrated into the RNA-induced silencing complex that includes the enzymes Dicer and Argonaute (Ago). The mature miRNAs (ϳ17-24 nt) direct the RNA-induced silencing complex to specific target sites located within the 3Ј-UTR of target genes. Once bound to target sites, miRNAs repress translation through mRNA decay, translational inhibition, and/or sequestration into processing bodies (1-3).Recent estimates indicate that over 60% of protein-coding genes carry 3Ј-UTR miRNA target sites, suggesting a role for miRNAs in the control of gene expression in diverse processes (4). Indeed, miRNAs have now been firmly linked to the regulation of early development (5), cell proliferation, and cell death (6); apoptosis and fat metabolism (7); and cell differentiation (8). In addition, studies of miRNA expression in chronic lymphocytic leukemia (9), colonic adenocarcinoma (10), Burkitt lymphoma, and cardiac ...

The DNA binding protein methyl-CpG binding protein 2 (MeCP2) critically influences neuronal and brain function by modulating gene expression, and children with overexpression of the MECP2 gene exhibit postnatal neurological syndromes. We demonstrate that some children with MECP2 duplication also display variable immunological abnormalities that include reductions in memory T and B cells and natural killer cells and immunoglobulin assay responses. Moreover, whereas mice with MeCP2 overexpression were unable to control infection with the intra-macrophage parasite Leishmania major and secrete interferon-γ (IFN-γ) from involved lymph nodes, they were able to control airway fungal infection by Aspergillus niger and mount protective T helper cell type 2 (TH2)–dependent allergic responses. Relative to normal T cells, TH cells from children and mice with MECP2 duplication displayed similar impairments in IFN-γ secretion and TH1 responses that were due to both MeCP2-dependent suppression of IFN-γ transcription and sequestration of the IFN-γ locus as assessed by chromatin immunoprecipitation assay. Thus, overexpressed MeCP2 aberrantly suppresses IFN-γ secretion from TH cells, potentially leading to a partially immunodeficient state. Our findings establish a rational basis for identifying, treating, and preventing infectious complications potentially affecting children with MECP2 duplication.

Th e activity of wildlife viewing rests on an underlying contradiction. Wild animals are generally human-averse; they avoid humans and respond to human encounters by fl eeing and retreating to cover. One would therefore expect human viewing of wild animals to be at best unpredictable, intermittent, and fl eeting. Yet in recent decades, wildlife viewing has become a major recreational activity for millions of people around the world and has emerged as a thriving commercial industry. How can these two things-widespread wildlife intolerance of humans and large-scale human observation of wildlife-be squared? Th e answer is that wild animals are only viewed on this scale because they have been made viewable through human intervention. Th is article examines two kinds of intervention-habituation and attraction-that change wildlife behavior toward humans and render hitherto elusive animals susceptible to regular, proximate, and protracted human viewing.

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