Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Tissue-resident macrophages.

Tissue-resident macrophages are a heterogeneous population of immune cells that fulfill tissue-specific and niche-specific functions. These range from dedicated homeostatic functions, such as clearance of cellular debris and iron processing, to central roles in tissue immune surveillance, response to infection and the resolution of inflammation. Recent studies highlight marked heterogeneity in the origins of tissue macrophages that arise from hematopoietic versus self-renewing embryo-derived populations. We discuss the tissue niche-specific factors that dictate cell phenotype, the definition of which will allow new strategies to promote the restoration of tissue homeostasis. Understanding the mechanisms that dictate tissue macrophage heterogeneity should explain why simplified models of macrophage activation do not explain the extent of heterogeneity seen in vivo.

Helminth induced monocytosis conveys protection from respiratory syncytial virus infection in mice.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infants is a major cause of viral bronchiolitis and hospitalisation. We have previously shown in a murine model that ongoing infection with the gut helminth Heligmosomoides polygyrus protects against RSV infection through type I interferon (IFN-I) dependent reduction of viral load. Yet, the cellular basis for this protection has remained elusive. Given that recruitment of mononuclear phagocytes to the lung is critical for early RSV infection control, we assessed their role in this coinfection model. METHODS: Mice were infected by oral gavage with H. polygyrus. Myeloid immune cell populations were assessed by flow cytometry in lung, blood and bone marrow throughout infection and after secondary infection with RSV. Monocyte numbers were depleted by anti-CCR2 antibody or increased by intravenous transfer of enriched monocytes. RESULTS: H. polygyrus infection induces bone marrow monopoiesis, increasing circulatory monocytes and lung mononuclear phagocytes in a IFN-I signalling dependent manner. This expansion causes enhanced lung mononuclear phagocyte counts early in RSV infection that may contribute to the reduction of RSV load. Depletion or supplementation of circulatory monocytes prior to RSV infection confirms that these are both necessary and sufficient for helminth induced antiviral protection. CONCLUSIONS: H. polygyrus infection induces systemic monocytosis contributing to elevated mononuclear phagocyte numbers in the lung. These cells are central to an anti-viral effect that reduces the peak viral load in RSV infection. Treatments to promote or modulate these cells may provide novel paths to control RSV infection in high risk individuals.

Configuration of ammonia on Cu{311}: Infrared spectroscopy and first-principles theory.

We describe Reflection Absorption Infrared Spectroscopy (RAIRS) and first-principles Density Functional Theory (DFT) studies of ammonia adsorption on the Cu{311} surface. Our experimental results indicate an upright chemisorbed species at low coverages, with at least one additional species accompanying this at higher coverages. Our high-coverage RAIRS data cannot be fully explained by DFT models containing only ammonia or its dissociation products, even allowing for molecular tilt and/or the formation of a bilayer. We therefore also consider urea and formamide as possible products of surface reaction with residual carbon monoxide, but these species are again not fully compatible with our observed spectra. The overlayer composition at high coverages remains mysterious.

Macrophages inhibit and enhance endometriosis depending on their origin.

Macrophages are intimately involved in the pathophysiology of endometriosis, a chronic inflammatory disorder characterized by the growth of endometrial-like tissue (lesions) outside the uterus. By combining genetic and pharmacological monocyte and macrophage depletion strategies we determined the ontogeny and function of macrophages in a mouse model of induced endometriosis. We demonstrate that lesion-resident macrophages are derived from eutopic endometrial tissue, infiltrating large peritoneal macrophages (LpM) and monocytes. Furthermore, we found endometriosis to trigger continuous recruitment of monocytes and expansion of CCR2+ LpM. Depletion of eutopic endometrial macrophages results in smaller endometriosis lesions, whereas constitutive inhibition of monocyte recruitment significantly reduces peritoneal macrophage populations and increases the number of lesions. Reprogramming the ontogeny of peritoneal macrophages such that embryo-derived LpM are replaced by monocyte-derived LpM decreases the number of lesions that develop. We propose a putative model whereby endometrial macrophages are "proendometriosis" while newly recruited monocyte-derived macrophages, possibly in LpM form, are "antiendometriosis." These observations highlight the importance of monocyte-derived macrophages in limiting disease progression.

Mucins Shed from the Laminated Layer in Cystic Echinococcosis Are Captured by Kupffer Cells via the Lectin Receptor Clec4F.

Cystic echinococcosis is caused by the larval stages (hydatids) of cestode parasites belonging to the species cluster Echinococcus granulosus sensu lato, with E. granulosus sensu stricto being the main infecting species. Hydatids are bladderlike structures that attain large sizes within various internal organs of livestock ungulates and humans. Hydatids are protected by the massive acellular laminated layer (LL), composed mainly of mucins. Parasite growth requires LL turnover, and abundant LL-derived particles are found at infection sites in infected humans, raising the question of how LL materials are dealt with by the hosts. In this article, we show that E. granulosus sensu stricto LL mucins injected into mice are taken up by Kupffer cells, the liver macrophages exposed to the vascular space. This uptake is largely dependent on the intact mucin glycans and on Clec4F, a C-type lectin receptor which, in rodents, is selectively expressed in Kupffer cells. This uptake mechanism operates on mucins injected both in soluble form intravenously (i.v.) and in particulate form intraperitoneally (i.p.). In mice harboring intraperitoneal infections by the same species, LL mucins were found essentially only at the infection site and in the liver, where they were taken up by Kupffer cells via Clec4F. Therefore, shed LL materials circulate in the host, and Kupffer cells can act as a sink for these materials, even when the parasite grows in sites other than the liver.

CD11c identifies microbiota and EGR2-dependent MHCII+ serous cavity macrophages with sexually dimorphic fate in mice.

The murine serous cavities contain a rare and enigmatic population of short-lived F4/80lo MHCII+ macrophages but what regulates their development, survival, and fate is unclear. Here, we show that mature F4/80lo MHCII+ peritoneal macrophages arise after birth, but that this occurs largely independently of colonization by microbiota. Rather, microbiota specifically regulate development of a subpopulation of CD11c+ cells that express the immunoregulatory cytokine RELM-α, are reliant on the transcription factor EGR2, and develop independently of the growth factor CSF1. Furthermore, we demonstrate that intrinsic expression of RELM-α, a signature marker shared by CD11c+ and CD11c- F4/80lo MHCII+ cavity macrophages, regulates survival and differentiation of these cells in the peritoneal cavity in a sex-specific manner. Thus, we identify a previously unappreciated diversity in serous cavity F4/80lo MHCII+ macrophages that is regulated by microbiota, and describe a novel sex and site-specific function for RELM-α in regulating macrophage endurance that reveals the unique survival challenge presented to monocyte-derived macrophages by the female peritoneal environment.

Cell origin and niche availability dictate the capacity of peritoneal macrophages to colonize the cavity and omentum.

The relationship between macrophages of the peritoneal cavity and the adjacent omentum remains poorly understood. Here, we describe two populations of omental macrophages distinguished by CD102 expression and use an adoptive cell transfer approach to investigate whether these arise from peritoneal macrophages, and whether this depends upon inflammatory status, the origin of peritoneal macrophages and availability of the omental niches. We show that whereas established resident peritoneal macrophages largely fail to migrate to the omentum, monocyte-derived resident cells readily migrate and form a substantial component of omental CD102+ macrophages in the months following resolution of peritoneal inflammation. In contrast, both populations had the capacity to migrate to the omentum in the absence of endogenous peritoneal and omental macrophages. However, inflammatory macrophages expanded more effectively and more efficiently repopulated both CD102+ and CD102- omental populations, whereas established resident macrophages partially reconstituted the omental niche via recruitment of monocytes. Hence, cell origin determines the migration of peritoneal macrophages to the omentum and predisposes established resident macrophages to drive infiltration of monocyte-derived cells.

The expanding world of tissue-resident macrophages.

The term 'macrophage' encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and growth factors (e.g. CSF1/IL-34). They share a core set of functions that largely arise from a uniquely high phagocytic capacity manifest in their ability to clear dying cells, pathogens and scavenge damaged, toxic or modified host molecules. However, macrophages demonstrate a remarkable degree of tissue-specific functionality and have diverse origins that vary by tissue site and inflammation status. With our understanding of this diversity has come an appreciation of the longevity and replicative capacity of tissue-resident macrophages and thus the realisation that macrophages may persist through tissue perturbations and inflammatory events with important consequences for cell function. Here, we discuss our current understanding of the parameters that regulate macrophage survival and function, focusing on the relative importance of the tissue environment versus cell-intrinsic factors, such as origin, how long a cell has been resident within a tissue and prior history of activation. Thus, we reconsider the view of macrophages as wholly plastic cells and raise many unanswered questions about the relative importance of cell life-history versus environment in macrophage programming and function.

First-Principles Dynamics of Fluorine Adsorption on Clean and Monohydrogenated Si{001}.

The interaction of highly reactive species with solid surfaces can result in modes of adsorption quite distinct from the classic molecular and dissociative events that are usually thought to dominate. For instance, compelling experimental evidence suggests that adsorption of F2 at the Si{001} surface is often initiated by abstraction (and binding at the surface) of just one fluorine atom from the molecule; the second fluorine atom subsequently experiences either a separate atomic adsorption event or ejection from the surface altogether. Molecular dynamics simulations using empirical potentials support this concept but massively overestimate the prevalence of atomic ejection. In this work, we report first-principles molecular dynamics calculations that correctly show atomic ejection to be rare while providing insight into the details of abstractive adsorption. In addition, we also examine the case of F2 adsorption onto a monohydrogenated Si{001} surface, finding evidence for a different type of abstractive adsorption, in which a hydrogen atom may be removed from the surface to form a short-lived HFF intermediate. The latter rapidly decomposes to produce either HF or (via reaction with another surface hydrogen atom) H2.

Surface Chirality Influences Molecular Rotation upon Desorption.

Chiral surfaces offer great potential as a medium for enantioselective synthesis or separation, yet their dynamic enantiospecific interactions with adsorbates are not well understood. Here, the influence of chiral surfaces on the molecular rotations of desorbing molecules is investigated. Formic acid desorption from Cu{531} and Cu{110} serve as model systems for desorption processes of an achiral adsorbate from a chiral and an achiral surface. Our first-principles molecular dynamics study reveals a much larger and more directed angular momentum for molecules desorbing from the chiral surface and a clear preference for one sense of rotation. This result provides new insight into desorption and adsorption processes and propensities on chiral surfaces.

Halogen Bonding in Bicomponent Monolayers: Self-Assembly of a Homologous Series of Iodinated Perfluoroalkanes with Bipyridine.

A homologous series of halogen bonding monolayers based on terminally iodinated perfluoroalkanes and 4,4'-bipyridine have been observed on a graphitic surface and noninvasively probed using powder X-ray diffraction. An excellent agreement is observed between the X-ray structures and density functional theory calculations with dispersion force corrections. Theoretical analysis of the binding energies of the structures indicate that these halogen bonds are strong (25 kJ mol-1), indicating that the layers are highly stable. The monolayer structures are found to be distinct from any plane of the corresponding bulk structures, with limited evidence of partitioning of hydrocarbon and perfluoro tectons. The interchain interactions are found to be slightly stronger than those in related aromatic systems, with important implications for 2D crystal engineering.

Comparative study of single-atom gold and iridium on CeO2{111}.

Oxide-supported single-atom catalysts have shown promise for a variety of heterogeneous processes. In addition to their inherent activity and selectivity, these materials come at much lower financial cost, avoiding the use of full-bodied precious-metal catalysts, but at the conceptual expense that more complex structural and electronic considerations need to be understood if we are to exploit their full potential. Here, we focus on the adsorption of single-atom iridium at both stoichiometric and defective CeO2{111} surfaces, by means of first-principles density functional theory. Reference calculations for the adsorption of single-atom gold, on the same set of substrates, provide a valuable set of benchmarks against which to interpret our iridium results.

Interleukin-4 activated macrophages mediate immunity to filarial helminth infection by sustaining CCR3-dependent eosinophilia.

Eosinophils are effectors in immunity to tissue helminths but also induce allergic immunopathology. Mechanisms of eosinophilia in non-mucosal tissues during infection remain unresolved. Here we identify a pivotal function of tissue macrophages (Mϕ) in eosinophil anti-helminth immunity using a BALB/c mouse intra-peritoneal Brugia malayi filarial infection model. Eosinophilia, via C-C motif chemokine receptor (CCR)3, was necessary for immunity as CCR3 and eosinophil impairments rendered mice susceptible to chronic filarial infection. Post-infection, peritoneal Mϕ populations proliferated and became alternatively-activated (AAMϕ). Filarial AAMϕ development required adaptive immunity and interleukin-4 receptor-alpha. Depletion of Mϕ prior to infection suppressed eosinophilia and facilitated worm survival. Add back of filarial AAMϕ in Mϕ-depleted mice recapitulated a vigorous eosinophilia. Transfer of filarial AAMϕ into Severe-Combined Immune Deficient mice mediated immunological resistance in an eosinophil-dependent manner. Exogenous IL-4 delivery recapitulated tissue AAMϕ expansions, sustained eosinophilia and mediated immunological resistance in Mϕ-intact SCID mice. Co-culturing Brugia with filarial AAMϕ and/or filarial-recruited eosinophils confirmed eosinophils as the larvicidal cell type. Our data demonstrates that IL-4/IL-4Rα activated AAMϕ orchestrate eosinophil immunity to filarial tissue helminth infection.

Csf1r-mApple Transgene Expression and Ligand Binding In Vivo Reveal Dynamics of CSF1R Expression within the Mononuclear Phagocyte System.

CSF1 is the primary growth factor controlling macrophage numbers, but whether expression of the CSF1 receptor differs between discrete populations of mononuclear phagocytes remains unclear. We have generated a Csf1r-mApple transgenic fluorescent reporter mouse that, in combination with lineage tracing, Alexa Fluor 647-labeled CSF1-Fc and CSF1, and a modified ΔCsf1-enhanced cyan fluorescent protein (ECFP) transgene that lacks a 150 bp segment of the distal promoter, we have used to dissect the differentiation and CSF1 responsiveness of mononuclear phagocyte populations in situ. Consistent with previous Csf1r-driven reporter lines, Csf1r-mApple was expressed in blood monocytes and at higher levels in tissue macrophages, and was readily detectable in whole mounts or with multiphoton microscopy. In the liver and peritoneal cavity, uptake of labeled CSF1 largely reflected transgene expression, with greater receptor activity in mature macrophages than monocytes and tissue-specific expression in conventional dendritic cells. However, CSF1 uptake also differed between subsets of monocytes and discrete populations of tissue macrophages, which in macrophages correlated with their level of dependence on CSF1 receptor signaling for survival rather than degree of transgene expression. A double ΔCsf1r-ECFP-Csf1r-mApple transgenic mouse distinguished subpopulations of microglia in the brain, and permitted imaging of interstitial macrophages distinct from alveolar macrophages, and pulmonary monocytes and conventional dendritic cells. The Csf1r-mApple mice and fluorescently labeled CSF1 will be valuable resources for the study of macrophage and CSF1 biology, which are compatible with existing EGFP-based reporter lines.

Macrophage origin limits functional plasticity in helminth-bacterial co-infection.

Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.

The biology of serous cavity macrophages.

For decades, it has been known that the serous cavities, which include the peritoneal, pleural and pericardial cavities, harbour large numbers of macrophages. In particular, due to the ease of isolating these cells, the peritoneal cavity has been used as a convenient source of macrophages to examine many facets of macrophage biology over the last 50-60 years. Despite this, it is only recently that the true heterogeneity of serous cavity mononuclear phagocyte compartment, which includes macrophages and dendritic cells, has been revealed. Advances in technologies such as multi-parameter flow cytometry and the 'OMICs' revolution have uncovered the presence of distinct populations of mononuclear phagocytes in the serous cavities. Given that peritoneal macrophages have been implicated in many pathologies, including peritonitis, pancreatitis, endometriosis and acute liver injury, it is imperative to understand the biology of these cells. Here, we review the recent advances in understanding the identity, origin and function of discrete serous cavity mononuclear phagocyte subsets in homeostasis and how these may change when homeostasis is perturbed, focusing on peritoneal and pleural cavities and highlighting differences in the mononuclear phagocytes found in each.

Direct Correlation between Adsorption Energetics and Nuclear Spin Relaxation in a Liquid-saturated Catalyst Material.

The ratio of NMR relaxation time constants T 1 / T 2 provides a non-destructive indication of the relative surface affinities exhibited by adsorbates within liquid-saturated mesoporous catalysts. In the present work we provide supporting evidence for the existence of a quantitative relationship between such measurements and adsorption energetics. As a prototypical example with relevance to green chemical processes we examine and contrast the relaxation characteristics of primary alcohols and cyclohexane within an industrial silica catalyst support. T 1 / T 2 values obtained at intermediate magnetic field strength are in good agreement with DFT adsorption energy calculations performed on single molecules interacting with an idealised silica surface. Our results demonstrate the remarkable ability of this metric to quantify surface affinities within systems of relevance to liquid-phase heterogeneous catalysis, and highlight NMR relaxation as a powerful method for the determination of adsorption phenomena within mesoporous solids.