The extracellular lysophospholipase D autotaxin (ATX) and its product, lysophosphatidic acid, have diverse functions in development and cancer, but little is known about their functions in the immune ...system. Here we found that ATX had high expression in the high endothelial venules of lymphoid organs and was secreted. Chemokine-activated lymphocytes expressed receptors with enhanced affinity for ATX, which provides a mechanism for targeting the secreted ATX to lymphocytes undergoing recruitment. Lysophosphatidic acid induced chemokinesis in T cells. Intravenous injection of enzymatically inactive ATX attenuated the homing of T cells to lymphoid tissues, probably through competition with endogenous ATX and exertion of a dominant negative effect. Our results support the idea of a new and general step in the homing cascade in which the ectoenzyme ATX facilitates the entry of lymphocytes into lymphoid organs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages and dendritic cells (DC) are distributed throughout the body and play important roles in pathogen detection and tissue homeostasis. In tissues, resident macrophages exhibit distinct ...phenotypes and activities, yet the transcriptional pathways that specify tissue-specific macrophages are largely unknown. We investigated the functions and origins of two peritoneal macrophage populations in mice: small and large peritoneal macrophages (SPM and LPM, respectively). SPM and LPM differ in their ability to phagocytose apoptotic cells, as well as in the production of cytokines in response to LPS. In steady-state conditions, SPM are sustained by circulating precursors, whereas LPM are maintained independently of hematopoiesis; however, both populations are replenished by bone marrow precursors following radiation injury. Transcription factor analysis revealed that SPM and LPM express abundant CCAAT/enhancer binding protein (C/EBP)-β. Cebpb(-/-) mice exhibit elevated numbers of SPM-like cells but lack functional LPM. Alveolar macrophages are also missing in Cebpb(-/-) mice, although macrophage populations in the spleen, kidney, skin, mesenteric lymph nodes, and liver are normal. Adoptive transfer of SPM into Cebpb(-/-) mice results in SPM differentiation into LPM, yet donor SPM do not generate LPM after transfer into C/EBPβ-sufficient mice, suggesting that endogenous LPM inhibit differentiation by SPM. We conclude that C/EBPβ plays an intrinsic, tissue-restricted role in the generation of resident macrophages.
Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 ...(CaMKK2) as a driver of ICB resistance. CaMKK2 is highly expressed in pro-tumor cells and is associated with worsened survival in patients with GBM. Host CaMKK2, specifically, reduces survival and promotes ICB resistance. Multimodal profiling of the TME reveals that CaMKK2 is associated with several ICB resistance-associated immune phenotypes. CaMKK2 promotes exhaustion in CD8
T cells and reduces the expansion of effector CD4
T cells, additionally limiting their tumor penetrance. CaMKK2 also maintains myeloid cells in a disease-associated microglia-like phenotype. Lastly, neuronal CaMKK2 is required for maintaining the ICB resistance-associated myeloid phenotype, is deleterious to survival, and promotes ICB resistance. Our findings reveal CaMKK2 as a contributor to ICB resistance and identify neurons as a driver of immunotherapeutic resistance in GBM.
T helper type 1 (T(H)1)-polarized immune responses, which confer protection against intracellular pathogens, are thought to be initiated by dendritic cells (DCs) that enter lymph nodes from ...peripheral tissues. Here we found after viral infection or immunization, inflammatory monocytes were recruited into lymph nodes directly from the blood to become CD11c(+)CD11b(hi)Gr-1(+) inflammatory DCs, which produced abundant interleukin 12p70 and potently stimulated T(H)1 responses. This monocyte extravasation required the chemokine receptor CCR2 but not the chemokine CCL2 or receptor CCR7. Thus, the accumulation of inflammatory DCs and T(H)1 responses were much lower in Ccr2(-/-) mice, were preserved in Ccl2(-/-) mice and were relatively higher in CCL19-CCL21-Ser-deficient plt mutant mice, in which all other lymph node DC types were fewer in number. We conclude that blood-derived inflammatory DCs are important in the development of T(H)1 immune responses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, ...provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.
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•Early-life stress (ELA) augments excitatory synapses on hypothalamic CRH cells•During ELA, the adjacent microglia poorly survey and prune synapses on CRH neurons•Mechanisms involve MerTK and yield aberrant hormonal and behavioral stress response•Chemogenetic microglial activation throughout ELA normalizes adult stress responses
Early-life adversity (ELA) promotes lifelong aberrant stress responses and vulnerability to mental illnesses. Bolton et al. identify poor dynamics and hypothalamic CRH neurons’ excitatory synapse pruning of ELA microglia, implicating microglial MerTK. Chronic chemogenetic activation of ELA microglia normalized process dynamics, synapse density, and adult hormonal and behavioral stress responses.
The surge in firearm sales from the onset of the COVID-19 pandemic have been linked to increases in firearm violence, which is of public concern given that having firearms in one's home is associated ...with increased risk for domestic violence and suicide. Consistent with pre-pandemic trends, individuals tended to purchase firearms for self-protection during COVID-19. Prior work indicates that protective firearm ownership is motivated not only by perceptions that the world (and one's local environment) is dangerous, but also by one's endorsement of masculinity norms found in U.S. cultures of honor (primarily southern and western states). Honor-based masculinity norms emphasis reputation defense, toughness, and an absolute intolerance of disrespect. The present research examined the relative motivating influences of various threat perceptions and masculine honor endorsement in predicting reasons for non-COVID-19 firearm ownership, firearm purchasing during COVID-19, and purchase intentions. Three separate samples (total
= 2483) of mostly White U.S. men completed online surveys during different months of the first year of the COVID-19 pandemic. Participants completed measures of their endorsement of masculine honor norms, factors associated with firearm purchasing (e.g., dangerous world beliefs, intolerance of uncertainty), and firearm purchasing behaviors. Results indicated that masculine honor endorsement was higher among (1) protective firearm owners compared to non-owners and non-protective owners, (2) firearm owners who purchased a firearm during COVID-19 compared to non-owners and non-purchasing owners, and (3) firearm owners with intentions to purchase firearms in the next year compared to those without intentions and undecided owners. Relative to other predictors (e.g., COVID-19 concerns, dangerous world beliefs), masculine honor endorsement was consistently the strongest predictor of these outcomes. Findings add to the literature by highlighting the strength of masculine honor endorsement in motivating (protective) firearm ownership. Implications for interpersonal violence and suicide are discussed.
We present a sample of 221 new quasar pairs with proper transverse separations Rprop < 1 h-1 Mpc over the redshift range 0.5 < z < 3.0, discovered from an extensive follow-up campaign to find ...companions around the Sloan Digital Sky Survey and 2dF QSO Redshift Survey quasars. This sample includes 26 new binary quasars with separations Rprop < 50 h-1 kpc (c < 10''), more than doubling the number of such systems known. We define a statistical sample of binaries selected with homogeneous criteria and compute its selection function, taking into account sources of incompleteness. The first measurement of the quasar correlation function on scales 10 h-1 kpc < Rprop < 400 h-1 kpc is presented. For Rprop 40 h-1 kpc, we detect an order of magnitude excess clustering over the expectation from the large-scale (Rprop 3 h-1 Mpc) quasar correlation function, extrapolated down as a power law (g = 1.53) to the separations probed by our binaries. The excess grows to ~30 at Rprop ~ 10 h-1 kpc and provides compelling evidence that the quasar autocorrelation function gets progressively steeper on submegaparsec scales. This small-scale excess can likely be attributed to dissipative interaction events that trigger quasar activity in rich environments. Recent small-scale measurements of galaxy clustering and quasar-galaxy clustering are reviewed and discussed in relation to our measurement of small-scale quasar clustering.
We recently developed a monocyte-based cellular vaccine platform for cancer treatment. In contrast to the traditional utilization of monocytes as precursors to generate dendritic cells (DC) for ...vaccination purposes, we find that freshly isolated monocytes with no differentiation process can be loaded with tumor antigens (Ag) and trigger robust antitumor cytotoxic T lymphocyte (CTL) responses. In this chapter, we describe methods to prepare, administer, and evaluate murine Ly-6C
monocyte-based cellular vaccines for their therapeutic efficacy. This includes procedures for isolation, purity determination, Ag loading, administration of bone marrow (BM)-derived monocytes, as well as methods to determine vaccine efficacy through the examination of Ag-specific CD8
T cell expansion and antitumor responses in murine melanoma models. As a vaccine platform, undifferentiated monocytes can be easily adapted to different tumor models with a multitude of target antigens. The method described here seeks to facilitate preclinical research of monocyte-based vaccination as a strategy for cancer immunotherapy.
Efficacy of dendritic cell (DC) cancer vaccines is classically thought to depend on their antigen-presenting cell (APC) activity. Studies show, however, that DC vaccine priming of cytotoxic T ...lymphocytes (CTLs) requires the activity of endogenous DCs, suggesting that exogenous DCs stimulate antitumor immunity by transferring antigens (Ags) to endogenous DCs. Such Ag transfer functions are most commonly ascribed to monocytes, implying that undifferentiated monocytes would function equally well as a vaccine modality and need not be differentiated to DCs to be effective. Here, we used several murine cancer models to test the antitumor efficacy of undifferentiated monocytes loaded with protein or peptide Ag. Intravenously injected monocytes displayed antitumor activity superior to DC vaccines in several cancer models, including aggressive intracranial glioblastoma. Ag-loaded monocytes induced robust CTL responses via Ag transfer to splenic CD8+ DCs in a manner independent of monocyte APC activity. Ag transfer required cell-cell contact and the formation of connexin 43-containing gap junctions between monocytes and DCs. These findings demonstrate the existence of an efficient gap junction-mediated Ag transfer pathway between monocytes and CD8+ DCs and suggest that administration of tumor Ag-loaded undifferentiated monocytes may serve as a simple and efficacious immunotherapy for the treatment of human cancers.
The chemokine receptor CXCR3 plays a central role in inflammation by mediating effector/memory T cell migration in various diseases; however, drugs targeting CXCR3 and other chemokine receptors are ...largely ineffective in treating inflammation. Chemokines, the endogenous peptide ligands of chemokine receptors, can exhibit so-called biased agonism by selectively activating either G protein- or β-arrestin-mediated signaling after receptor binding. Biased agonists might be used as more targeted therapeutics to differentially regulate physiological responses, such as immune cell migration. To test whether CXCR3-mediated physiological responses could be segregated by G protein- and β-arrestin-mediated signaling, we identified and characterized small-molecule biased agonists of the receptor. In a mouse model of T cell-mediated allergic contact hypersensitivity (CHS), topical application of a β-arrestin-biased, but not a G protein-biased, agonist potentiated inflammation. T cell recruitment was increased by the β-arrestin-biased agonist, and biopsies of patients with allergic CHS demonstrated coexpression of CXCR3 and β-arrestin in T cells. In mouse and human T cells, the β-arrestin-biased agonist was the most efficient at stimulating chemotaxis. Analysis of phosphorylated proteins in human lymphocytes showed that β-arrestin-biased signaling activated the kinase Akt, which promoted T cell migration. This study demonstrates that biased agonists of CXCR3 produce distinct physiological effects, suggesting discrete roles for different endogenous CXCR3 ligands and providing evidence that biased signaling can affect the clinical utility of drugs targeting CXCR3 and other chemokine receptors.
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