LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery

Neurotransmitter receptor trafficking during synaptic plasticity requires the concerted action of multiple signaling pathways and the protein transport machinery. However, little is known about the contribution of lipid metabolism during these processes. In this paper, we addressed the question of the role of cholesterol in synaptic changes during long-term potentiation (LTP). We found that N-methyl-d-aspartate-type glutamate receptor (NMDAR) activation during LTP induction leads to a rapid and sustained loss or redistribution of intracellular cholesterol in the neuron. A reduction in cholesterol, in turn, leads to the activation of Cdc42 and the mobilization of GluA1-containing α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) from Rab11-recycling endosomes into the synaptic membrane, leading to synaptic potentiation. This process is accompanied by an increase of NMDAR function and an enhancement of LTP. These results imply that cholesterol acts as a sensor of NMDAR activation and as a trigger of downstream signaling to engage small GTPase (guanosine triphosphatase) activation and AMPAR synaptic delivery during LTP.Peer Reviewe

HLA-DR+ leukocytes acquire CD1 antigens in embryonic and fetal human skin and contain functional antigen-presenting cells

Adequate numbers and functional maturity are needed for leukocytes to exhibit a protective role in host defense. During intrauterine life, the skin immune system has to acquire these prerequisites to protect the newborn from infection in the hostile external environment after birth. We investigated the quantitative, phenotypic, and functional development of skin leukocytes and analyzed the factors controlling their proliferation and trafficking during skin development. We show that CD45+ leukocytes are scattered in embryonic human skin and that their numbers continuously increase as the developing skin generates an environment that promotes proliferation of skin resident leukocytes as well as the influx of leukocytes from the circulation. We also found that CD45+HLA-DRhighCD1c+ dendritic cells (DCs) are already present in the epidermis and dermis at 9 wk estimated gestational age (EGA) and that transforming growth factor β1 production precedes Langerin and CD1a expression on CD45+CD1c+ Langerhans cell (LC) precursors. Functionally, embryonic antigen-presenting cells (APCs) are able to phagocytose antigen, to up-regulate costimulatory molecules upon culture, and to efficiently stimulate T cells in a mixed lymphocyte reaction. Collectively, our data provide insight into skin DC biology and the mechanisms through which skin DCs presumably populate the skin during development

Langerhans cells in Dupuytren's contracture

We have examined biopsies of Dupuytren's contracture palmar fascia, overlying subcutis and skin, and have correlated the distribution of gross macroscopic changes in the hand, mapped pre- and intraoperatively, with light microscopic immunohistochemical findings. We report increased numbers of S100 positive Langerhans cells (an epidermal cell of dendritic lineage) and CD45 positive cells, both in "nodules" and at dermo-epidermal junctions, in the biopsied tissues. This suggests that Langerhans cells migrate from the epidermis into Dupuytren's contracture tissue, possibly in response to local changes in levels of inflammatory cytokines within the tissue. Our findings, together with other reports of increased numbers of dermal dendrocytes and inflammatory cells in Dupuytren's contracture tissue, lend circumstantial support to the "extrinsic theory" of the pathogenesis of Dupuytren's contracture. However, the earliest stages of the disease process have not been defined, and therefore the events which ultimately produce fibrosis in the palmar fascial complex in susceptible individuals could begin in the skin and/or within deeper tissues, especially where there is dysregulation of the immune system