No abstract

Extensive evidence points to a role for GABAergic signaling in the amygdala in mediating the effects of alcohol, including presynaptic changes in GABA release, suggesting effects on GABAergic neurons. However, the majority of studies focus solely on the effects of alcohol on principal neurons. Here we demonstrate that δ-GABARs, which have been suggested to confer ethanol sensitivity, are expressed at a high density on parvalbumin (PV) interneurons in the basolateral amygdala (BLA). Thus, we hypothesized that δ-GABARs on PV interneurons may represent both an initial pharmacological target for alcohol and a site for plasticity associated with the expression of various behavioral maladaptations during withdrawal from binge drinking. To investigate this, we used a mouse model of voluntary alcohol intake (Drinking-in-the-Dark-Multiple Scheduled Access) to induce escalating heavy binge drinking and anxiety-like behavior in mice. This pattern of intake was associated with increased δ protein expression on parvalbumin positive interneurons in both the BLA and hippocampus. Loss of δ-GABARs specifically in PV interneurons (PV:δ) increased binge drinking behavior, reduced sensitivity to alcohol-induced motor incoordination, enhanced sensitivity to alcohol-induced hyperlocomotion and blocked the expression of withdrawal from binge drinking. This study is the first to demonstrate a role for δGABARs specifically in PV-expressing interneurons in modulating binge alcohol intake and withdrawal-induced anxiety.

No abstract

Dendritic cell (DC) accumulation in T-cell zones of secondary lymph organs is a critical event in the maximization of the primary immune response. Here, we demonstrate that mast cell (MC) control of elevated DC trafficking during infection enables the primary adaptive humoral immune response to proceed with heightened intensity. Elevated DC accumulation in draining lymph nodes (DLNs) was found to be the product of continual and incremental recruitment of DCs into the infected tissue site prior to their egress to DLNs. MCs contribute to this pattern of DC trafficking by the release of TNF, which was found to coordinately activate local blood vessel endothelium and DLNs to increase their expression of CD62E and CCL21, respectively. Blockade of either protein interfered with DC accumulation in DLNs, as well as the intensity of the humoral response to bacterial challenge. Thus, MCs enable the humoral immune response to proceed with enhanced intensity, which may be an important consideration in rationale vaccine design. Supported by grants DK50814 and AI50021 from the National Institutes of Health.

Bubonic plague, caused by the gram-negative bacteria Yersinia pestis, is characterized by pathologically swollen lymph nodes (LNs) or buboes. The mechanism by which these buboes form and the adaptive function they provide for the pathogen, if any, remains unknown. We hypothesize that bubo formation is a strategy for flea-borne Y. pestis to establish a foothold in the host for subsequent systemic infection. Our studies indicate that colonization of the draining lymph node (DLN) from the site of infection occurs through the trafficking of infected dendritic cells and monocytes in temporally distinct waves. This is effected by redundant chemotactic signals, including through the receptors CCR7 and CCR2, as evidenced by the upregulation of multiple chemoattractants in the DLN during Y. pestis infection and the improved survival of infected CCR7KO and CCR2KO mice compared to wild-type.

No abstract

Mast cells (MCs) promote immunosurveillance for pathogens in peripheral tissues and line the host vasculature. We observe that MC are activated by dengue virus (DENV), a flavivirus that is spread by mosquito vectors. MC activation by DENV during viremia elevates systemic levels of their vasoactive products, including the MC-specific protease, chymase, and promotes vascular leakage. Symptoms of DENV infection in humans include widespread vascular leakage, pooling of fluid within internal organs and, occasionally, severe hemorrhaging; however, the processes that underlie the immune-mediated vascular pathology during dengue infection are largely unknown. A component of dengue-induced vascular leakage is MC-dependent since mice that lack MCs have greatly reduced vascular permeability during infection. We show that treatment of infected animals with MC-stabilizing drugs restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity based on the measurement of chymase as a serum biomarker. Our findings reveal that MCs mediate DENV-induced vascular pathology, and suggest MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers.