The role of autophagy, a catabolic lysosome-dependent pathway, has recently been recognized in a variety of disorders, including Pompe disease, the genetic deficiency of the glycogen-degrading lysosomal enzyme acid-alpha glucosidase. Accumulation of lysosomal glycogen, presumably transported from the cytoplasm by the autophagic pathway, occurs in multiple tissues, but pathology is most severe in skeletal and cardiac muscle. Skeletal muscle pathology also involves massive autophagic buildup in the core of myofibers. To determine if glycogen reaches the lysosome via autophagy and to ascertain whether autophagic buildup in Pompe disease is a consequence of induction of autophagy and/or reduced turnover due to defective fusion with lysosomes, we generated muscle-specific autophagy-deficient Pompe mice. We have demonstrated that autophagy is not required for glycogen transport to lysosomes in skeletal muscle. We have also found that Pompe disease involves induction of autophagy but manifests as a functional deficiency of autophagy because of impaired autophagosomal-lysosomal fusion. As a result, autophagic substrates, including potentially toxic aggregate-prone ubiquitinated proteins, accumulate in Pompe myofibers and may cause profound muscle damage.

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Perinatal depression (PND) is the most common obstetric complication in the United States. Even when screening results are positive, mothers often do not receive further evaluation, and even when PND is diagnosed, mothers do not receive evidence-based treatments. Studies reveal that postpartum depression (PPD), a subset of PND, leads to increased costs of medical care, inappropriate medical treatment of the infant, discontinuation of breastfeeding, family dysfunction, and an increased risk of abuse and neglect. PPD, specifically, adversely affects this critical early period of infant brain development. PND is an example of an adverse childhood experience that has potential long-term adverse health complications for the mother, her partner, the infant, and the mother-infant dyad. However, PND can be treated effectively, and the stress on the infant can be buffered. Pediatric medical homes should coordinate care more effectively with prenatal providers for women with prenatally diagnosed maternal depression; establish a system to implement PPD screening at the 1-, 2-, 4-, and 6-month well-child visits; use community resources for the treatment and referral of the mother with depression; and provide support for the maternal-child (dyad) relationship, including breastfeeding support. State chapters of the American Academy of Pediatrics, working with state departments of public health, public and private payers, and maternal and child health programs, should advocate for payment and for increased training for PND screening and treatment. American Academy of Pediatrics recommends advocacy for workforce development for mental health professionals who care for young children and mother-infant dyads, and for promotion of evidence-based interventions focused on healthy attachment and parent-child relationships.

Innate immune PRRs sense nucleic acids from microbes and orchestrate cytokine production to resolve infection. Inappropriate recognition of host nucleic acids also results in autoimmune disease. Here we utilize a model of inflammation resulting from accrual of self DNA (DNase II−/− Ifnar−/−) to understand the role of PRR sensing pathways in arthritis and autoantibody production. Using mice deficient in DNase II/Ifnar together with deficiency in either STING or AIM2 (TKO), we reveal central roles for the STING and AIM2 pathway in arthritis. AIM2 TKO mice show limited inflammasome activation and, like STING TKO mice, have reduced inflammation in joints. Surprisingly, autoantibody production is maintained in AIM2 and STING TKO mice, while DNase II−/− Ifnar−/− mice also deficient in Unc93b, a chaperone required for TLR7/9 endosomal localization, fail to produce autoantibodies to nucleic acids. Collectively, these data support distinct roles for cytosolic and endosomal nucleic acid sensing pathways in disease manifestations.

Phagocytic macrophages and dendritic cells are desirable targets for potential RNAi (RNA interference) therapeutics because they often mediate pathogenic inflammation and autoimmune responses. We recently engineered a complex 5 component glucan-based encapsulation system for siRNA (small interfering RNA) delivery to phagocytes. In experiments designed to simplify this original formulation, we discovered that the amphipathic peptide Endo-Porter forms stable nanocomplexes with siRNA that can mediate potent gene silencing in multiple cell types. In order to restrict such gene silencing to phagocytes, a method was developed to entrap siRNA-Endo-Porter complexes in glucan shells of 2-4 μm diameter in the absence of other components. The resulting glucan particles containing fluorescently labelled siRNA were readily internalized by macrophages, but not other cell types, and released the labelled siRNA into the macrophage cytoplasm. Intraperitoneal administration of such glucan particles containing siRNA-Endo-Porter complexes to mice caused gene silencing specifically in macrophages that internalized the particles. These results from the present study indicate that specific targeting to phagocytes is mediated by the glucan, whereas Endo-Porter peptide serves both to anchor siRNA within glucan particles and to catalyse escape of siRNA from phagosomes. Thus we have developed a simplified siRNA delivery system that effectively and specifically targets phagocytes in culture or in intact mice.