MicroRNAs (miRNAs) are emerging as central regulators of inflammation, but their role in asthma and airway epithelial cells is not well studied. Glucocorticoids are the cornerstone of therapy in asthma and other inflammatory disease, yet their mechanisms of action are not completely elucidated, and it is not clear whether miRNAs modulate their effects. We aimed to identify miRNAs that regulate cytokine and chemokine expression in airway epithelial cells and whether these miRNAs are subject to the effects of glucocorticoids. MicroRNAomic analyses of immortalized, normal human bronchial epithelial cells identified 7 miRNAs that were altered by inflammatory cytokine treatment and 22 that were regulated by glucocorticoids (n = 3 for each treatment condition). MiR-146a emerged as a central candidate, whose expression was induced by TNF-α and repressed by glucocorticoids. Its role as a candidate in asthmatic inflammation was supported by expression profiling in human asthmatics, which showed that plasma miR-146a expression was elevated in asthma and associated with measures related to worse asthma outcomes, including elevated blood eosinophil counts, higher asthma control questionnaire scores, and need for higher doses of inhaled glucocorticoids. However, transfection of miR-146a in A549 cells treated with TNF-α +/- glucocorticoids produced an anti-inflammatory effect and increased efficacy of glucocorticoids. We propose a model whereby miR-146a is induced by inflammatory conditions as a feedback mechanism to limit inflammation. Exogenous administration of miR-146a augmented the effects of glucocorticoids and could be a novel therapeutic strategy to enhance efficacy of these medications.

Significance: The P-element transposon is a mobile DNA that invaded the Drosophila genome approximately 100 y ago. P elements were identified by studying a genetic syndrome called “hybrid dysgenesis.” The elements use their encoded transposase for mobility, but rely on host-cell factors for essential parts of their life cycle. Here we demonstrate biochemically that a Drosophila -encoded bZIP heterodimer binds to the P-element terminal 31-bp sequences. We used genetics to show that these proteins play a role in repairing DNA breaks caused by P-element transposase activity during hybrid dysgenesis and other types of DNA damage. These results provide an example of the mechanisms that the host genome uses to combat genome instability caused by foreign DNA invasion.

The molecular cross-talk between epithelium and immune cells in the airway mucosa is a key regulator of homeostatic immune surveillance and is crucially involved in the development of chronic lung inflammatory diseases. The patterns of gene expression that follow the sensitization process occurring in allergic asthma and chronic rhinosinusitis and those present in the neutrophilic response of other chronic inflammatory lung diseases such as chronic obstructive pulmonary disease (COPD) are tightly regulated in their specificity. Studies exploring the global transcript profiles associated with determinants of post-transcriptional gene regulation (PTR) such as RNA-binding proteins (RBP) and microRNAs identified several of these factors as being crucially involved in controlling the expression of chemokines upon airway epithelial cell stimulation with cytokines prototypic of Th1- or Th2-driven responses. These studies also uncovered the participation of these pathways to glucocorticoids' inhibitory effect on the epithelial chemokine network. Unmasking the molecular mechanisms of chemokine PTR may likely uncover novel therapeutic strategies for the blockade of proinflammatory pathways that are pathogenetic for asthma, COPD, and other lung inflammatory diseases.

Human granulocytic anaplasmosis (HGA) is a tick-borne, infectious disease caused by Anaplasma phagocytophilum that generally presents with nonspecific symptoms such as fever, chills, headache, malaise, and myalgia. If not treated immediately, HGA can cause hemophagocytic lymphohistiocytosis (HLH), a well-documented but underrecognized sequela of severe HGA. In this article, we report a case of severe HGA with hyperferritinemia in a 74-year-old male from Central Pennsylvania who initially presented with recurrent fevers, nausea, and malaise to our emergency department and was subsequently discharged home that same day. Ten days later, the patient returned with acute kidney injury, elevated liver transaminases, and profound hyperferritinemia to 5130 ng/mL. Empiric doxycycline was administered for suspected tick-borne disease and serologies eventually came back positive for anti–Anaplasma phagocytophilum antibodies. The patient returned to baseline status 15 days after discharge. Our case shows the challenges in the timely diagnosis of HGA and highlights the role of serum ferritin in aiding this diagnosis. Although our patient did not fulfill the HLH diagnostic criteria, our report demonstrates the importance of recognizing HGA as a reversible cause of HLH.

Meprins are multimeric proteases that are implicated in inflammatory bowel disease by both genetic association studies and functional studies in knock-out mice. Patients with inflammatory bowel disease show decreased colonic expression of meprin α, although regulation of expression, particularly under inflammatory stimuli, has not been studied. The studies herein demonstrate that the human meprin α transcript is bound and stabilized by Hu antigen R at baseline, and that treatment with the inflammatory stimulus phorbol 12-myristate 13-acetate downregulates meprin α expression by inducing tristetraprolin. The enhanced binding of tristetraprolin to the MEP1A 3′-UTR results in destabilization of the transcript and occurs at a discrete site from Hu antigen R. This is the first report to describe a mechanism for post-transcriptional regulation of meprin α and will help clarify the role of meprins in the inflammatory response and disease.