An Allosteric Shift in CD11c Affinity Activates a Proatherogenic State in Arrested Intermediate Monocytes.

Intermediate monocytes (iMo; CD14+CD16+) increase in number in the circulation of patients with unstable coronary artery disease (CAD), and their recruitment to inflamed arteries is implicated in events leading to mortality following MI. Monocyte recruitment to inflamed coronary arteries is initiated by high affinity ß2-integrin (CD11c/CD18) that activates ß1-integrin (VLA-4) to bind endothelial VCAM-1. How integrin binding under shear stress mechanosignals a functional shift in iMo toward an inflammatory phenotype associated with CAD progression is unknown. Whole blood samples from patients treated for symptomatic CAD including non-ST elevation MI, along with healthy age-matched subjects, were collected to assess chemokine and integrin receptor levels on monocytes. Recruitment on inflamed human aortic endothelium or rVCAM-1 under fluid shear stress was assessed using a microfluidic-based artery on a chip (A-Chip). Membrane upregulation of high affinity CD11c correlated with concomitant activation of VLA-4 within focal adhesive contacts was required for arrest and diapedesis across inflamed arterial endothelium to a greater extent in non-ST elevation MI compared with stable CAD patients. The subsequent conversion of CD11c from a high to low affinity state under fluid shear activated phospho-Syk- and ADAM17-mediated proteolytic cleavage of CD16. This marked the conversion of iMo to an inflammatory phenotype associated with nuclear translocation of NF-κB and production of IL-1ß+ We conclude that CD11c functions as a mechanoregulator that activates an inflammatory state preferentially in a majority of iMo from cardiac patients but not healthy patients.

Ethologically relevant repeated acute social stress induces maternal neglect in the lactating female mouse.

Psychosocial stress is a top predictor of peripartum mood disorders in human mothers. In the present study, we developed a novel paradigm testing the effects of direct and vicarious social stress on maternal and mood-related behaviors in B6 mice. Using a novel housing paradigm, we examined the extent to which postpartum dams withdrew from litters following psychosocial stress. Repeated acute direct social stress involved exposing dams to a virgin male mouse for 7 min/day on postpartum days 5-7 during a brief (15-min) mother-pup separation. To remove the effects of direct stress, the vicarious social stress dams were housed in the same vivarium as direct social stressed dams, but without direct exposure to intruders. Control dams were given mock intruder exposure and housed in a separate vivarium room containing breeding mice. All dams experienced pup separation, and maternal care was investigated upon reunion. Direct and vicarious social stress induced significant deficits in maternal care and increased maternal anxiety relative to controls. Although vicarious stress effects were more likely to occur on days when there was acute stress exposure, direct stress sustained maternal deficits 24 h after the final stressor. Together, these data suggest psychosocial stress induces aberrant maternal phenotypes in mice.