RNAi Screen and Proteomics Reveal NXF1 as a Novel Regulator of IRF5 Signaling.

Interferon regulatory factor 5 (IRF5) is a key transcription factor of innate immunity, which plays an important role in host restriction to viral infection and inflammation. Genome-wide association studies have implied the association of IRF5 with several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjogren's syndrome, inflammatory bowel disease and multiple sclerosis. However, the regulation of IRF5-mediated immunity is not well understood.

Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation.

Professional phagocytes (such as macrophages) and non-professional phagocytes (such as epithelial cells) clear billions of apoptotic cells and particles on a daily basis. Although professional and non-professional macrophages reside in proximity in most tissues, whether they communicate with each other during cell clearance, and how this might affect inflammation, is not known. Here we show that macrophages, through the release of a soluble growth factor and microvesicles, alter the type of particles engulfed by non-professional phagocytes and influence their inflammatory response.

Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo.

Few apoptotic corpses are seen even in tissues with high cellular turnover, leading to the notion that the capacity for engulfment in vivo is vast. Whether corpse clearance can be enhanced in vivo for potential benefit is not known. In a colonic inflammation model, we noted that the expression of the phagocytic receptor Bai1 was progressively downmodulated.

ShcA regulates late stages of T cell development and peripheral CD4+ T cell numbers.

T cell development in the thymus is a highly regulated process that critically depends upon productive signaling via the preTCR at the β-selection stage, as well as via the TCR for selection from the CD4(+)CD8(+) double-positive stage to the CD4 or CD8 single-positive stage. ShcA is an adapter protein expressed in thymocytes, and it is required for productive signaling through the preTCR, with impaired signaling via ShcA leading to a developmental block at the β-selection checkpoint. However, the role of ShcA in subsequent stages of T cell development has not been addressed.

Apoptosis and engulfment by bronchial epithelial cells. Implications for allergic airway inflammation.

Insult or injury to the lung epithelial cells from pathogens, pollutants, and allergens can initiate the process of apoptotic cell death. Although "Creola bodies," which are clusters of uncleared, apoptotic, epithelial cells, have been seen in the sputum of patients with asthma, the clearance of these dying epithelial cells and the consequence of failed clearance in the airway have not been directly addressed. We have observed that bronchial epithelial cells efficiently engulf their apoptotic neighbors and produce antiinflammatory cytokines when engulfing apoptotic cells.

Unexpected link between an antibiotic, pannexin channels and apoptosis.

Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. Here we show that the quinolone antibiotic trovafloxacin is a novel PANX1 inhibitor, by using a small-molecule screen. Although quinolones are widely used to treat bacterial infections, some quinolones have unexplained side effects, including deaths among children.

Brain angiogenesis inhibitor 1 is expressed by gastric phagocytes during infection with Helicobacter pylori and mediates the recognition and engulfment of human apoptotic gastric epithelial cells.

After Helicobacter pylori infection in humans, gastric epithelial cells (GECs) undergo apoptosis due to stimulation by the bacteria or inflammatory cytokines. In this study, we assessed the expression and function of brain angiogenesis inhibitor 1 (BAI1) in the engulfment of apoptotic GECs using human tissue and cells. After induction of apoptosis by H.

Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation.

Lung epithelial cells can influence immune responses to airway allergens. Airway epithelial cells also undergo apoptosis after encountering environmental allergens; yet, relatively little is known about how these are cleared, and their effect on airway inflammation. Here we show that airway epithelial cells efficiently engulf apoptotic epithelial cells and secrete anti-inflammatory cytokines, dependent upon intracellular signalling by the small GTPase Rac1.

The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis.

Salp15 is a tick saliva protein that inhibits CD4(+) T cell differentiation through its interaction with CD4. The protein inhibits early signaling events during T cell activation and IL-2 production. Because murine Experimental Autoimmune Encephalomyelitis development is mediated by central nervous system-infiltrating CD4(+) T cells that are specific for myelin-associated proteins, we sought to determine whether the treatment of mice with Salp15 during EAE induction would prevent the generation of proinflammatory T cell responses and the development of the disease.

Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo.

Apoptosis and the subsequent clearance of dying cells occurs throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with DOCK1 and the GTPase RAC1, promotes internalization of the dying cells.

The immunosuppresive tick salivary protein, Salp15.

The interaction between Ixodid ticks and their mammalian hosts is a complex relationship. While the mammalian host tries to avoid the completion of the feeding process, the tick has devised strategies to counteract these attempts. Tick saliva contains a vast array of pharmacological activities that presumably aid the tick to evade host responses, including anticomplement, oxidative and innate and adaptive immune responses.

The Ixodes scapularis salivary protein, salp15, prevents the association of HIV-1 gp120 and CD4.

Ixodes scapularis salivary protein, Salp15, inhibits CD4(+) T cell activation by binding to the most-extracellular domains of the CD4 molecule, potentially overlapping with the gp120-binding region. We now show that Salp15 inhibits the interaction of gp120 and CD4. Furthermore, Salp15 prevents syncytia formation between HL2/3 (a stable HeLa cell line expressing the envelope protein) and CD4-expressing cells.

Conformational rearrangement within the soluble domains of the CD4 receptor is ligand-specific.

Ligand binding induces shape changes within the four modular ectodomains (D1-D4) of the CD4 receptor, an important receptor in immune signaling. Small angle x-ray scattering (SAXS) on both a two-domain and a four-domain construct of the soluble CD4 (sCD4) is consistent with known crystal structures demonstrating a bilobal and a semi-extended tetralobal Z conformation in solution, respectively. Detection of conformational changes within sCD4 as a result of ligand binding was followed by SAXS on sCD4 bound to two different glycoprotein ligands: the tick saliva immunosuppressor Salp15 and the HIV-1 envelope protein gp120.

T-cell signaling pathways inhibited by the tick saliva immunosuppressor, Salp15.

The Ixodes scapularis salivary protein Salp15 inhibits the activation of T cells through its interaction with the coreceptor CD4. Salp15 prevents the activation of Lck upon TCR engagement and the formation of lipid rafts. We have now analyzed the signaling pathways that are inhibited by the tick salivary protein in CD4(+) T cells.

Cutting edge: CD4 is the receptor for the tick saliva immunosuppressor, Salp15.

Salp15 is an Ixodes scapularis salivary protein that inhibits CD4+ T cell activation through the repression of TCR ligation-triggered calcium fluxes and IL-2 production. We show in this study that Salp15 binds specifically to the CD4 coreceptor on mammalian host T cells. Salp15 specifically associates through its C-terminal residues with the outermost two extracellular domains of CD4.

Distinct bacterial dissemination and disease outcome in mice subcutaneously infected with Borrelia burgdorferi in the midline of the back and the footpad.

Subcutaneous inoculation of mice with Borrelia burgdorferi, the causative agent of Lyme disease, results in established infection and the development of acute arthritis and carditis, hallmarks of human disease. Because conflicting results may originate from the site of subcutaneous inoculation, we addressed the dissemination capacity of spirochetes injected in the shoulder region versus the footpad. Spirochetes inoculated in the footpad disseminated to a lesser extent to distant organs, such as the ear and the heart.

Delivery of the immunosuppressive antigen Salp15 to antigen-presenting cells by Salmonella enterica serovar Typhimurium aroA mutants.

A Salmonella enterica serovar Typhimurium aroA-deficient delivery system was used to target the immunosuppressive protein Salp15 to antigen-presenting cells. In vitro and in vivo infections with Salp15-containing Salmonella resulted in an impaired CD4(+)-T-cell activation, suggesting that the protein was produced by antigen-presenting cells in a physiologically active form.