SUMMARY MicroRNAs regulated by LPS target genes that contribute to the inflammatory phenotype. Here we show that Akt1, which is activated by LPS, differentially regulates miRNAs including let-7e, miR-155, miR-181c and miR125b. In silico analyses and transfection studies revealed that let-7e represses TLR4 while miR-155 represses SOCS1, two genes critical for LPS-driven TLR signalling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1−/− macrophages exhibited increased responsiveness to LPS in culture and Akt1−/− mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1−/− macrophages restores sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.

Recognition of microbial components is critical for activation of Toll-like receptors (TLRs), subsequent innate immune signaling and directing adaptive immune responses. The DNA sensor TLR9 traffics from the endoplasmic reticulum (ER) to endolysosomal compartments where it is cleaved by resident proteases to generate a competent receptor. Activation of TLR9 by CpG ODN is preceded by agonist endocytosis and delivery into the endolysosomes. The events that dictate this process remain largely unknown, furthermore it is unclear whether the receptors involved in mediating uptake of exogenous DNA are conserved for both naturally-derived pathogenic DNA and synthetic ODNs. Here we report that peritoneal macrophages from a wild-derived inbred mouse strain, MOLF/Ei, are hypo-responsive to CpG-ODN but are fully responsive to bacterial DNA thus implying that microbial recognition is not fully recapitulated by a synthetic analog. To identify the gene responsible for the CpG ODN defect, we have performed genome-wide linkage analysis. Using N2 backcross mice, we mapped the trait with high resolution to a single locus containing Mrc1 as the gene conferring the trait. We show that MRC1 (mannose receptor, CD206) is involved in CpG ODN uptake and trafficking in wild-derived MOLF/Ei peritoneal macrophages. Furthermore, we show that other strains of wild-derived mice also require MRC1 for CpG-induced cytokine responses. These findings reveal novel functions for MRC1 and demonstrate that wild-derived mice are important and indispensable model for understanding naturally occurring regulators of inflammatory responses in innate immune pathways.

Impressive advances in inhalation therapy for patients with asthma and chronic obstructive pulmonary disease (COPD) have occurred in recent years. However, important gaps in care remain, particularly relating to poor adherence to inhaled therapies. Digital inhaler health platforms which incorporate digital inhalers to monitor time and date of dosing are an effective disease and medication management tool, promoting collaborative care between clinicians and patients, and providing more in-depth understanding of actual inhaler use. With advances in technology, nearly all inhalers can be digitalized with add-on or embedded sensors to record and transmit data quantitating inhaler actuations, and some have additional capabilities to evaluate inhaler technique. In addition to providing an objective and readily available measure of adherence, they allow patients to interact with the device directly or through their self-management smartphone application such as via alerts and recording of health status. Clinicians can access these data remotely and

Background: Necroptosis is a regulated signaling pathway leading to necrotic cell death. Results: Genetic mapping identified that down-regulation of the deubiquitinase CYLD confers resistance to necroptosis in a wild-derived mouse strain. Conclusion: Different strains of inbred mice regulate cell death pathways using distinct mechanisms. Significance: Genetic diversity of wild-derived mice underlies phenotypic diversity, which can identify novel mechanisms of regulation in cell death signaling.