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Multiple EGF-like domains 10 (Megf10) is a class F scavenger receptor (SR-F3) expressed on astrocytes and myosatellite cells, and recessive mutations in humans result in early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Here we report that Megf10-deficient mice have increased apoptotic cells in the developing cerebellum and have impaired phagocytosis of apoptotic cells by astrocytes ex vivo. We also report that cells transfected with Megf10 gain the ability to phagocytose apoptotic neurons and that Megf10 binds with high affinity to C1q, an eat-me signal for apoptotic cells. In contrast, cells expressing Megf10 with EMARDD mutations have impaired apoptotic cell clearance and impaired binding to C1q. Our studies reveal that Megf10 is a receptor for C1q and identify a novel role for Megf10 in clearance of apoptotic cells in the mammalian developing brain with potential relevance to EMARDD patients and other CNS disorders. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c+ DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c+ cells from CD11c.DTR mice induced the expansion of a variant CD64+ Ly6C+ monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64+ Ly6C+ monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64+ Ly6C+ monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c+ cells induces expansion of a unique CD64+ Ly6C+ monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c+ DCs in immunity. [ABSTRACT FROM AUTHOR]

The molecules and pathways that fine-tune innate inflammatory responses mediated by Toll-like receptor 7 (TLR7) remain to be fully elucidated. Using an unbiased genome-scale screen with short hairpin RNA (shRNA), we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4−/− mice were hyporesponsive to TLR7 agonists and failed to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, which are prone to systemic lupus erythematosus (SLE), and inhibited the antiviral immune response to influenza virus. Our data identify TREML4 as a positive regulator of TLR7 signaling and provide insight into the molecular mechanisms that control antiviral immunity and the development of autoimmunity. [ABSTRACT FROM AUTHOR]

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings using fluorescence dual in situ hybridization, unbiased proteomic analysis and quantitative PCR. We found that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we refer to as the sensome. With aging, sensome transcripts for endogenous ligand recognition were downregulated, whereas those involved in microbe recognition and host defense were upregulated. In addition, aging was associated with an overall increase in the expression of microglial genes involved in neuroprotection. [ABSTRACT FROM AUTHOR]

The clearance of apoptotic cells is critical for the control of tissue homeostasis; however, the full range of receptors on phagocytes responsible for the recognition of apoptotic cells remains to be identified. Here we found that dendritic cells (DCs), macrophages and endothelial cells used the scavenger receptor SCARF1 to recognize and engulf apoptotic cells via the complement component C1q. Loss of SCARF1 impaired the uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulated in tissues, which led to a lupus-like disease, with the spontaneous generation of autoantibodies to DNA-containing antigens, activation of cells of the immune system, dermatitis and nephritis. The discovery of such interactions of SCARF1 with C1q and apoptotic cells provides insight into the molecular mechanisms involved in the maintenance of tolerance and prevention of autoimmune disease. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) are the bridge between the innate and adaptive immune system. DCs are responsible for sensing and patrolling the environment, initiating a host response and instructing the proper adaptive immune response against pathogens. Recent advances in medical treatments have led to increased use of immunosuppressive drugs, leading to the emergence of fungal species that cause life-threatening infections in humans. Three of these opportunistic fungal pathogens: Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans pose the biggest concern for the immune-compromised host. Here we will review the interactions between DCs and these fungal pathogens, the receptors expressed on DCs that mediate these responses and the signaling mechanisms that shape the adaptive host response. [ABSTRACT FROM AUTHOR]

Chemokines and other chemoattractants direct leukocyte migration and are essential for the development and delivery of immune and inflammatory responses. To probe the molecular mechanisms that underlie chemoattractant-guided migration, we did an RNA-mediated interference screen that identified several members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins as mediators of cell migration: SYT7 and SYTL5 were positive regulators of chemotaxis, whereas SYT2 was a negative regulator of chemotaxis. SYT7-deficient leukocytes showed less migration in vitro and in a gout model in vivo. Chemoattractant-induced calcium-dependent lysosomal fusion was impaired in SYT7-deficient neutrophils. In a chemokine gradient, SYT7-deficient lymphocytes accumulated lysosomes in their uropods and had impaired uropod release. Our data identify a molecular pathway required for chemotaxis that links chemoattractant-induced calcium flux to exocytosis and uropod release. [ABSTRACT FROM AUTHOR]

Background. Erythema migrans (EM) is caused primarily by Borrelin afzelii in Europe and solely by Borrelin burgdorferi in the United States. B. burgdorferi infection in the United States has previously been associated with faster expansion of EM lesions and with more associated symptoms, compared with B. afzelii infection in Europe. However, reasons for these differences are not yet known. Methods. We determined the Borrelia species infecting 67 US or Austrian patients with EM. The clinical pictures and chemokine and cytokine mRNA levels in lesional skin were then compared in the 19 B. burgdorferi- infected US patients and the 37 B. afzelii-infected Austrian patients, the 2 largest groups. Results. The 19 B. burgdorferi-infected US patients had faster-expanding EM lesions and a median of 4 associated signs and symptoms, whereas the 37 B. afzelii-infected Austrian patients had slower-expanding lesions and usually did not experience associated symptoms. Compared with the EM lesions of B. afzelii-infected Austrian patients, those of B. burgdorferi-infected US patients had significantly higher mRNA levels of chemokines associated with activation of macrophages, including chernoattractants for neutrophils (CXCL1), macrophages (CCL3 and CCL4), and T helper 1 cells (CXCL9, CXCL10, and CXCL11). In addition, compared with the EM lesions of Austrian patients, the EM lesions of US patients tended to have higher mRNA levels of the macrophage-associated proinflammatory cytokines interleukin 1β and tumor necrosis factor α, and they had significantly higher mRNA expression of the antiinflammatory cytokines interleukin 10 and transforming growth factor β. Conclusions. The EM lesions of B. burgdorferi-infected US patients expanded faster, were associated with more symptoms, and had higher mRNA levels of macrophage-associated chemokines and cytokines than did the EM lesions of B. afzelii-infected Austrian patients. [ABSTRACT FROM AUTHOR]

Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-β (Aβ), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Aβ earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Aβ clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Aβ clearance. [ABSTRACT FROM AUTHOR]

Epithelial cells play an important role in orchestrating mucosal immune responses. In allergic-type inflammation, epithelial cells control the recruitment of eosinophils into the mucosa. Th2-type cytokine-driven release of eosinophil-active chemokines from epithelial cells directs eosinophil migration into the mucosal epithelium. CCR3, the main eosinophil chemokine receptor, regulates this process; however, the respective contribution of individual CCR3 ligands in eosinophil transepithelial migration is less well understood. Using an in vitro transepithelial chemotaxis system, we found that eotaxin-3 produced by IL-4-stimulated airway epithelial cells and CCR3 on eosinophils exclusively mediate eosinophil transepithelial migration. Eotaxin-3 protein levels were also increased in the nasal mucosal epithelium recovered from allergic patients as compared to non-allergic patients. Surprisingly, eotaxin-3 in IL-4-stimulated airway epithelial cells was predominantly cell surface bound, and the cell surface form was critical for eosinophil transepithelial migration. Eotaxin-3 cell surface association was partially glycosaminoglycan (GAG) dependent, but was completely protein dependent, suggesting that eotaxin-3 associates with both GAG and cell surface proteins. We thus provide evidence that cell surface-associated eotaxin-3 is the critical IL-4-dependent chemotactic signal mediating eosinophil transepithelial migration in the setting of allergic inflammation. [ABSTRACT FROM AUTHOR]

Antibody-antigen interactions in the airway initiate inflammation in acute asthma exacerbations. This inflammatory response is characterized by the recruitment of granulocytes into the airways. In murine models of asthma, granulocyte recruitment into the lung contributes to the development of airway hyperresponsiveness (AHR), mucus production, and airway remodeling. Leukotriene B4 is a mediator released following antigen challenge that has chemotactic activity for granulocytes, mediated through its receptor, BLT1. We investigated the role of BLT1 in granulocyte recruitment following antigen challenge. Wild-type mice and BLT1-/- mice were sensitized and challenged with ovalbumin (OVA) to induce acute allergic airway inflammation. In addition, to explore the relevance to antibody-antigen interactions, we injected OVA bound to anti-OVA IgG1 or anti-OVA IgE intratracheally into naïve wild-type and BLT1-/- mice. Cell composition of the lungs, cytokine levels, histology, and AHR were determined. After sensitization and challenge with ovalbumin, there was significantly reduced neutrophil and eosinophil recruitment into the airways of BLT1-/- mice compared with wild-type animals after one or two daily antigen challenges, but this difference was not seen after three or four daily antigen challenges. Mucus production and AHR were not affected, Intratracheal injection of OVA bound to IgG1 or IgE induced neutrophil recruitment into the airways in wild-type mice but not in the BLT1-/- mice. We conclude that BLT1 mediates early recruitment of granulocytes into the airway in response to antigen-antibody interactions in a murine model of acute asthma. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoproteins and DNA. The level of anti-DNA antibodies correlates with disease severity, and the deposition of these immune complexes (ICs) in the kidneys is thought to contribute to disease pathogenesis. Recent evidence suggests that the DNA component of ICs purified from SLE patients (SLE DNA-ICs) contributes to the development of SLE pathology. SLE DNA-ICs induce proliferation of self-reactive B cells and cytokine production by plasmacytoid dendritic cells (PDCs) in a TLR9- dependent manner. One of the cytokines induced by DNA-containing ICs is interferon α (IFN-α). Elevated serum levels of IFN-α and overexpression of interferon-induced genes have been observed in SLE patient blood and shown to correlate with disease severity. We have recently found that the mechanism of IFN-α production by PDCs depends on TLR9 and FcγRIIa (CD32), and CD32 delivers SLE DNA-ICs to intracellular lysosomes containing TLR9. This CD32-TLR9 pathway, which is operative in PDCs, is distinct from the BCR/TLR9 pathway in B cells and may prove to be a novel target for future SLE therapies. In this article, the role of toll-like receptors, cytokines, and Fc receptors expressed by PDCs in the pathogenesis of SLE is summarized. [ABSTRACT FROM AUTHOR]

The organization of cellular niches is known to have a key role in regulating normal stem cell differentiation and regeneration, but relatively little is known about the architecture of microenvironments that support malignant metastasis. Using dynamic in vivo confocal imaging, here we show that murine bone marrow contains unique anatomic regions defined by specialized endothelium. This vasculature expresses the adhesion molecule E-selectin and the chemoattractant stromal-cell-derived factor 1 (SDF-1) in discrete, discontinuous areas that influence the homing of a variety of tumour cell lines. Disruption of the interactions between SDF-1 and its receptor CXCR4 inhibits the homing of Nalm-6 cells (an acute lymphoblastic leukaemia cell line) to these vessels. Further studies revealed that circulating leukaemic cells can engraft around these vessels, suggesting that this molecularly distinct vasculature demarcates a microenvironment for early metastatic tumour spread in bone marrow. Finally, purified haematopoietic stem/progenitor cells and lymphocytes also localize to the same microdomains, indicating that this vasculature might also function in benign states to demarcate specific portals for the entry of cells into the marrow space. Specialized vascular structures therefore appear to delineate a microenvironment with unique physiology that can be exploited by circulating malignant cells. [ABSTRACT FROM AUTHOR]

Stimulation of macrophages by Gram-negative bacterial lipopolysaccharide (LPS) rapidly leads to the activation of several protein kinases and the subsequent phosphorylation of transcription factors that regulate LPS-inducible genes. Several investigators have shown that the MAP kinases (MAPKs) are rapidly activated following LPS stimulation. We previously reported that LPS stimulation also up-regulates the enzymatic activity of protein kinase CK2, a ubiquitous serine/threonine kinase, although the signaling cascade that leads to CK2 activation in macrophages is unknown. Because MAPKs are known to be rapidly activated by LPS, we performed additional studies in order to determine if CK2 activation was a downstream target of MAPKs. Our studies revealed that CK2 activity was rapidly and transiently up-regulated in LPS-stimulated RAW264.7 murine macrophages. We found that PD98059, an inhibitor of ERK kinase activation by the MAP kinase MEK-1, blocked LPS-induced up-regulation of CK2 activity. In contrast, the p38 kinase inhibitor SB203580 did not block CK2 activation by LPS. This finding suggests that CK2 activation was mediated by the ERK kinase signaling cascade, but not by the p38 kinase cascade. We also found that LPS stimulation resulted in the rapid serine phosphorylation of the catalytic α and α′ subunits of CK2. This contrasts with other studies using growth factor-stimulated fibroblasts in which only phosphorylation of the regulatory β subunit of CK2 was observed. Thus, LPS stimulation leads to rapid activation and cell type-specific phosphorylation of CK2 in macrophages. [ABSTRACT FROM PUBLISHER]

The Aegean Conferences' first International Conference on Model Hosts took place on the picturesque Greek island of Crete. This meeting was the first of its kind and gathered together international experts who are using a vast array of hosts as models of infection, including worms, insects, mice, fish, rats, humans, squids, pigs, monkeys, protozoa, amoebae and ticks. [ABSTRACT FROM AUTHOR]

The article focuses on the study of Cao and colleagues regarding the role of cluster of differentiation molecule 11b (CD11b) in the negative regulation of toll-like receptors (TLRs) signaling. It says that CD11b is triggered after the stimulation of TLR. It shows that Escherichia coli infected CD11b-deficient mice have higher concentration of circulating proinflammatory cytokines. It states that signaling pathways of CD11b could be a potential therapeutic for patients with autoimmune diseases.