Twist mediates suppression of inflammation by type I IFNs and Axl

Type I interferons (IFNs) are pleiotropic cytokines with antiviral and immunomodulatory properties. The immunosuppressive actions of type I IFNs are poorly understood, but IFN-mediated suppression of TNFα production has been implicated in the regulation of inflammation and contributes to the effectiveness of type I IFNs in the treatment of certain autoimmune and inflammatory diseases. In this study, we investigated mechanisms by which type I IFNs suppress induction of TNFα production by immune complexes, Fc receptors, and Toll-like receptors. Suppression of TNFα production was mediated by induction and activation of the Axl receptor tyrosine kinase and downstream induction of Twist transcriptional repressors that bind to E box elements in the TNF promoter and suppress NF-κB–dependent transcription. Twist expression was activated by the Axl ligand Gas6 and by protein S and apoptotic cells. These results implicate Twist proteins in regulation of TNFα production by antiinflammatory factors and pathways, and provide a mechanism by which type I IFNs and Axl receptors suppress inflammatory cytokine production

AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity

The receptor tyrosine kinase (RTK) AXL is induced in response to type I interferons (IFNs) and limits their production through a negative feedback loop. Enhanced production of type I IFNs in Axl(-/-) dendritic cells (DCs) in vitro have led to speculation that inhibition of AXL would promote antiviral responses. Notwithstanding, type I IFNs also exert potent immunosuppressive functions. Here we demonstrate that ablation of AXL enhances the susceptibility to infection by influenza A virus and West Nile virus. The increased type I IFN response in Axl(-/-) mice was associated with diminished DC maturation, reduced production of IL-1β, and defective antiviral T cell immunity. Blockade of type I IFN receptor or administration of IL-1β to Axl(-/-) mice restored the antiviral adaptive response and control of infection. Our results demonstrate that AXL is essential for limiting the immunosuppressive effects of type I IFNs and enabling the induction of protective antiviral adaptive immunity.Fil: Schmid, Edward T.. University of Yale; Estados UnidosFil: Pang, Iris K.. University of Yale; Estados UnidosFil: Carrera Silva, Eugenio Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados UnidosFil: Bosurgi, Lidia. University of Yale; Estados UnidosFil: Miner, Jonathan J. Washington University School of Medicine; Estados UnidosFil: Diamond, Michael S. Washington University School of Medicine; Estados UnidosFil: Iwasaki, Akiko. University of Yale; Estados UnidosFil: Rothlin, Carla. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. University of Yale; Estados Unido

Phagocytosis imprints heterogeneity in tissue-resident macrophages

Tissue-resident macrophages display varying phenotypic and functional properties that are largely specified by their local environment. One of these functions, phagocytosis, mediates the natural disposal of billions of cells, but its mechanisms and consequences within living tissues are poorly defined. Using a parabiosis-based strategy, we identified and isolated macrophages from multiple tissues as they phagocytosed blood-borne cellular material. Phagocytosis was circadianally regulated and mediated by distinct repertoires of receptors, opsonins, and transcription factors in macrophages from each tissue. Although the tissue of residence defined the core signature of macrophages, phagocytosis imprinted a distinct antiinflammatory profile. Phagocytic macrophages expressed CD206, displayed blunted expression of Il1b, and supported tissue homeostasis. Thus, phagocytosis is a source of macrophage heterogeneity that acts together with tissue-derived factors to preserve homeostasis

Lifting the innate immune barriers to antitumor immunity

The immune system evolved for adequate surveillance and killing of pathogens while minimizing host damage, such as due to chronic or exaggerated inflammation and autoimmunity. This is achieved by negative regulators and checkpoints that limit the magnitude and time course of the immune response. Tumor cells often escape immune surveillance and killing. Therefore, disrupting the brakes built into the immune system should effectively boost the anticancer immune response. The success of anti-CTLA4, anti-PD-1 and anti-PD-L1 have firmly established this proof of concept. Since the response rate of anti-CTLA4, anti-PD-1 and anti-PD-L1 is still limited, there is an intense effort for the identification of new targets and development of approaches that can expand the benefits of immunotherapy to a larger patient pool. Additional T cell checkpoints are obvious targets; however, here we focus on the unusual suspects—cells that function to initiate and guide T cell activity. Innate immunity is both an obligate prerequisite for the initiation of adaptive immune responses and a requirement for the recruitment of activated T cells to the site of action. We discuss some of the molecules present in innate immune cells, including natural killer cells, dendritic cells, macrophages, myeloid-derived suppressor cells, endothelial cells and stromal cells, that can activate or enhance innate immune cell functions, and more importantly, the inhibitors or checkpoints present in these cells that restrain their functions. Boosting innate immunity, either by enhancing activator functions or, preferably, by blocking the inhibitors, may represent a new anticancer treatment modality or at least function as adjuvants to T cell checkpoint inhibitors

Management of cell death in parasitic infections

For a long time, host cell death during parasitic infection has been considered a reflection of tissue damage, and often associated with disease pathogenesis. However, during their evolution, protozoan and helminth parasites have developed strategies to interfere with cell death so as to spread and survive in the infected host, thereby ascribing a more intriguing role to infection-associated cell death. In this review, we examine the mechanisms used by intracellular and extracellular parasites to respectively inhibit or trigger programmed cell death. We further dissect the role of the prototypical 'eat-me signal' phosphatidylserine (PtdSer) which, by being exposed on the cell surface of damaged host cells as well as on some viable parasites via a process of apoptotic mimicry, leads to their recognition and up-take by the neighboring phagocytes. Although barely dissected so far, the engagement of different PtdSer receptors on macrophages, by shaping the host immune response, affects the overall infection outcome in models of both protozoan and helminth infections. In this scenario, further understanding of the molecular and cellular regulation of the PtdSer exposing cell-macrophage interaction might allow the identification of new therapeutic targets for the management of parasitic infection

Chronicles of Cell Death Foretold: Specificities in the Mechanism of Disposal

Massive turnover of cells occurs through apoptosis during the constant remodeling of our tissues at homeostasis, from the shedding of cells at exposed barrier surfaces to the elimination of autoreactive lymphocytes. However, a surge of apoptotic cells also accompanies tissue damage, infection, and inflammation. A salient feature of apoptosis in either scenario is the exposure of phosphatidylserine (PtdSer) on the outer leaflet of the plasma membrane. In response to this cue, a range of phagocytes are charged with the sizeable task of engulfing apoptotic bodies and disposing of the billions of cells that perish each day. The presence of apoptotic cells in the remarkably distinct immunological settings described above, therefore, raises the question of how phagocytes are able to coordinate appropriate responses to apoptotic cells—from their silent removal to the production of growth factors or tissue repair molecules—following such a ubiquitous signal as PtdSer exposure. Here, we consider several emergent properties of phagocytes and apoptotic cell clearance that may facilitate specification among this suite of potential responses

The alpha9 nicotinic acetylcholine receptor shares pharmacological properties with type A gammaaminobutyric acid, glycine, and type 3 serotonin receptors

ABSTRACT In the present study, we provide evidence that the ␣9 nicotinic acetylcholine receptor (nAChR) shares pharmacological properties with members of the Cys-loop family of receptors. Thus, the type A ␥-aminobutyric acid receptor antagonist bicuculline, the glycinergic antagonist strychnine, and the type 3 serotonin receptor antagonist ICS-205,930 block ACh-evoked currents in ␣9-injected Xenopus laevis oocytes with the following rank order of potency: strychnine Ͼ ICS-205,930 Ͼ bicuculline. Block by antagonists was reflected in an increase in the acetylcholine (ACh) EC 50 value, with no changes in agonist maximal response or Hill coefficient, which suggests a competitive type of block. Moreover, whereas neither ␥-aminobutyric acid nor glycine modified ACh-evoked currents, serotonin blocked responses to ACh in a concentration-dependent manner. The present results suggest that the ␣9 nAChR must conserve in its primary structure some residues responsible for ligand binding common to other Cys-loop receptors. In addition, it adds further evidence that the ␣9 nAChR and the cholinergic receptor present at the base of cochlear outer hair cells have similar pharmacological properties

IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge

Summary: In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype. : Endocrine IGF1 plays pleiotropic functions and provides signals to macrophages to sustain tissue development and homeostasis. In this work, Spadaro et al. show that M2-like macrophages are an important source of IGF1 itself and that the myeloid-derived IGF1R signaling regulates immune metabolism. Host adaptation to high-fat-diet-induced obesity and helminth clearance requires myeloid IGF1R, but not the response to cold-stress. Keywords: catecholamines, inflammation, tyrosine hydroxylase, immunometabolism, UCP-1, neutrophil