Summary Pentraxins are a family of ancient innate immune mediators conserved throughout evolution. The classical pentraxins include serum amyloid P component (SAP) and C-reactive protein (CRP), that are part of acute phase proteins synthesized in response to infection1, 2. Both recognize microbial pathogens and activate the classical complement pathway through C1q3,4. More recently, members of the pentraxin family were found to interact with cell surface Fcγ receptors (FcγR) and activate leukocyte-mediated phagocytosis5-8. We now describe the structural mechanism for pentraxin binding to FcγR and its functional activation of FcγR-mediated phagocytosis and cytokine secretion. The complex structure between human SAP and FcγRIIa reveals a diagonally bound receptor on each SAP pentamer with both D1 and D2 domains of the receptor contacting the ridge helices from two SAP subunits. The 1:1 stoichiometry between SAP and FcγRIIa infers the requirement for multivalent pathogen binding for receptor aggregation. Mutational and binding studies show that pentraxins are diverse in their binding specificity to FcγR isoforms but conserved in their recognition structure. The shared binding site for SAP and IgG results in competition for FcγR binding and the inhibition of immune complex-mediated phagocytosis by soluble pentraxins. These results establish the antibody-like functions for pentraxins in the FcγR pathway, suggest an evolutionary overlap between the innate and adaptive immune systems, and have novel therapeutic implications for autoimmune diseases.

Activation of ␤-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory storage processes and longterm potentiation in downstream targets of BLA efferents, including the hippocampus. Here, we show that this activation also increases hippocampal levels of activity-regulated cytoskeletal protein (Arc), an immediate-early gene (also termed Arg 3.1) implicated in hippocampal synaptic plasticity and memory consolidation processes. Infusions of the ␤-adrenoreceptor agonist, clenbuterol, into the BLA immediately after training on an inhibitory avoidance task enhanced memory tested 48 h later. The same dose of clenbuterol significantly increased Arc protein levels in the dorsal hippocampus. Additionally, posttraining intra-BLA infusions of a memory-impairing dose of lidocaine significantly reduced Arc protein levels in the dorsal hippocampus. Increases in Arc protein levels were not accompanied by increases in Arc mRNA, suggesting that amygdala modulation of Arc protein and synaptic plasticity in efferent brain regions occurs at a posttranscriptional level. Finally, infusions of Arc antisense oligodeoxynucleotides into the dorsal hippocampus impaired performance of an inhibitory avoidance task, indicating that the changes in Arc protein expression are related to the observed changes in memory performance.activity-regulated cytoskeletal-associated gene ͉ emotional memory ͉ immediate-early gene ͉ memory consolidation ͉ memory systems E motionally arousing events are typically well remembered.Extensive evidence indicates that the enhancing effect of emotional arousal on memory consolidation is mediated by release of adrenal stress hormones (i.e., epinephrine and glucocorticoids) that, in turn, affects neurotransmitter systems that converge in the basolateral amygdala (BLA) to alter noradrenergic activity (1). Direct infusions of drugs into the BLA that target noradrenergic receptors affect the consolidation of memory for a variety of behavioral tasks. For example, posttraining intra-BLA infusions of the ␤-adrenoreceptor agonist, clenbuterol, enhance memory of inhibitory avoidance training (2-4), and infusions of norepinephrine enhance retention of contextual fear conditioning (5), conditioned taste aversion (6), and spatial water maze training (7).Amygdala activation influences the consolidation of memories for such an array of behavioral tasks by modulating neuroplasticity in many other brain regions engaged in memory processing (1,8). For example, posttraining infusions of d-amphetamine into the amygdala enhance retention of both spatial and cued versions of a water maze task. Inactivating the hippocampus after training with infusion of lidocaine prevents the amygdalainduced enhancement of memory for the spatial version of the task and posttraining infusions of lidocaine into the caudate nucleus prevent the amygdala-induced enhancement of memory for training on the cued version of the task (9). These findings suggest that the amygdala modulates the consolidation of memory for the spatial training ...

Macrophage-mediated programmed cell removal (PrCR) is a process essential for the clearance of unwanted (damaged, dysfunctional, aged, or harmful) cells. The detection and recognition of appropriate target cells by macrophages is a critical step for successful PrCR, but its molecular mechanisms have not been delineated. Here using the models of tissue turnover, cancer immunosurveillance, and hematopoietic stem cells, we show that unwanted cells such as aging neutrophils and living cancer cells are susceptible to “labeling” by secreted calreticulin (CRT) from macrophages, enabling their clearance through PrCR. Importantly, we identified asialoglycans on the target cells to which CRT binds to regulate PrCR, and the availability of such CRT-binding sites on cancer cells correlated with the prognosis of patients in various malignancies. Our study reveals a general mechanism of target cell recognition by macrophages, which is the key for the removal of unwanted cells by PrCR in physiological and pathophysiological processes.

No abstract