Tracking of marine predators to protect Southern Ocean ecosystems.

Southern Ocean ecosystems are under pressure from resource exploitation and climate change1,2. Mitigation requires the identification and protection of Areas of Ecological Significance (AESs), which have so far not been determined at the ocean-basin scale. Here, using assemblage-level tracking of marine predators, we identify AESs for this globally important region and assess current threats and protection levels. Integration of more than 4,000 tracks from 17 bird and mammal species reveals AESs around sub-Antarctic islands in the Atlantic and Indian Oceans and over the Antarctic continental shelf. Fishing pressure is disproportionately concentrated inside AESs, and climate change over the next century is predicted to impose pressure on these areas, particularly around the Antarctic continent. At present, 7.1% of the ocean south of 40°S is under formal protection, including 29% of the total AESs. The establishment and regular revision of networks of protection that encompass AESs are needed to provide long-term mitigation of growing pressures on Southern Ocean ecosystems.

Foraging habits of Northwest Atlantic hooded seals over the past 30 years: Future habitat suitability under global warming.

The Arctic is a global warming 'hot-spot' that is experiencing rapid increases in air and ocean temperatures and concomitant decreases in sea ice cover. These environmental changes are having major consequences on Arctic ecosystems. All Arctic endemic marine mammals are highly dependent on ice-associated ecosystems for at least part of their life cycle and thus are sensitive to the changes occurring in their habitats. Understanding the biological consequences of changes in these environments is essential for ecosystem management and conservation. However, our ability to study climate change impacts on Arctic marine mammals is generally limited by the lack of sufficiently long data time series. In this study, we took advantage of a unique dataset on hooded seal (Cystophora cristata) movements (and serum samples) that spans more than 30 years in the Northwest Atlantic to (i) investigate foraging (distribution and habitat use) and dietary (trophic level of prey and location) habits over the last three decades and (ii) predict future locations of suitable habitat given a projected global warming scenario. We found that, despite a change in isotopic signatures that might suggest prey changes over the 30-year period, hooded seals from the Northwest Atlantic appeared to target similar oceanographic characteristics throughout the study period. However, over decades, they have moved northward to find food. Somewhat surprisingly, foraging habits differed between seals breeding in the Gulf of St Lawrence vs those breeding at the "Front" (off Newfoundland). Seals from the Gulf favoured colder waters while Front seals favoured warmer waters. We predict that foraging habitats for hooded seals will continue to shift northwards and that Front seals are likely to have the greatest resilience. This study shows how hooded seals are responding to rapid environmental change and provides an indication of future trends for the species-information essential for effective ecosystem management and conservation.

An evolutionarily distinct ringed seal in the Ilulissat Icefjord.

The Earth's polar regions are low rates of inter- and intraspecific diversification. An extreme mammalian example is the Arctic ringed seal (Pusa hispida hispida), which is assumed to be panmictic across its circumpolar Arctic range. Yet, local Inuit communities in Greenland and Canada recognize several regional variants; a finding supported by scientific studies of body size variation. It is however unclear whether this phenotypic variation reflects plasticity, morphs or distinct ecotypes. Here, we combine genomic, biologging and survey data, to document the existence of a unique ringed seal ecotype in the Ilulissat Icefjord (locally 'Kangia'), Greenland; a UNESCO World Heritage site, which is home to the most productive marine-terminating glacier in the Arctic. Genomic analyses reveal a divergence of Kangia ringed seals from other Arctic ringed seals about 240 kya, followed by secondary contact since the Last Glacial Maximum. Despite ongoing gene flow, multiple genomic regions appear under strong selection in Kangia ringed seals, including candidate genes associated with pelage coloration, growth and osmoregulation, potentially explaining the Kangia seal's phenotypic and behavioural uniqueness. The description of 'hidden' diversity and adaptations in yet another Arctic species merits a reassessment of the evolutionary processes that have shaped Arctic diversity and the traditional view of this region as an evolutionary freezer. Our study highlights the value of indigenous knowledge in guiding science and calls for efforts to identify distinct populations or ecotypes to understand how these might respond differently to environmental change.

Climate change impacts on seabirds and marine mammals: The importance of study duration, thermal tolerance and generation time.

Understanding climate change impacts on top predators is fundamental to marine biodiversity conservation, due to their increasingly threatened populations and their importance in marine ecosystems. We conducted a systematic review of the effects of climate change (prolonged, directional change) and climate variability on seabirds and marine mammals. We extracted data from 484 studies (4808 published studies were reviewed), comprising 2215 observations on demography, phenology, distribution, diet, behaviour, body condition and physiology. The likelihood of concluding that climate change had an impact increased with study duration. However, the temporal thresholds for the effects of climate change to be discernibly varied from 10 to 29 years depending on the species, the biological response and the oceanic study region. Species with narrow thermal ranges and relatively long generation times were more often reported to be affected by climate change. This provides an important framework for future assessments, with guidance on response- and region-specific temporal dimensions that need to be considered when reporting effects of climate change. Finally, we found that tropical regions and non-breeding life stages were poorly covered in the literature, a concern that should be addressed to enable a better understanding of the vulnerability of marine predators to climate change.

KRAS Mutation Variants and Co-occurring PI3K Pathway Alterations Impact Survival for Patients with Pancreatic Ductal Adenocarcinomas.

BACKGROUND: KRAS variant alleles may have differential biological properties which impact prognosis and therapeutic options in pancreatic ductal adenocarcinomas (PDA). MATERIALS AND METHODS: We retrospectively identified patients with advanced PDA who received first-line therapy and underwent blood and/or tumor genomic sequencing at the University of Washington between 2013 and 2020. We examined the incidence of KRAS mutation variants with and without co-occurring PI3K or other genomic alterations and evaluated the association of these mutations with clinicopathological characteristics and survival using a Cox proportional hazards model. RESULTS: One hundred twenty-six patients had genomic sequencing data; KRAS mutations were identified in 111 PDA and included the following variants: G12D (43)/G12V (35)/G12R (23)/other (10). PI3K pathway mutations (26% vs. 8%) and homologous recombination DNA repair (HRR) defects (35% vs. 12.5%) were more common among KRAS G12R vs. non-G12R mutated cancers. Patients with KRAS G12R vs. non-G12R cancers had significantly longer overall survival (OS) (HR 0.55) and progression-free survival (PFS) (HR 0.58), adjusted for HRR pathway co-mutations among other covariates. Within the KRAS G12R group, co-occurring PI3K pathway mutations were associated with numerically shorter OS (HR 1.58), while no effect was observed on PFS. CONCLUSIONS: Patients with PDA harboring KRAS G12R vs. non-G12R mutations have longer survival, but this advantage was offset by co-occurring PI3K alterations. The KRAS/PI3K genomic profile could inform therapeutic vulnerabilities in patients with PDA.

Origin and expansion of the world's most widespread pinniped: Range-wide population genomics of the harbour seal (Phoca vitulina).

The harbour seal (Phoca vitulina) is the most widely distributed pinniped, occupying a wide variety of habitats and climatic zones across the Northern Hemisphere. Intriguingly, the harbour seal is also one of the most philopatric seals, raising questions as to how it colonized its current range. To shed light on the origin, remarkable range expansion, population structure and genetic diversity of this species, we used genotyping-by-sequencing to analyse ~13,500 biallelic single nucleotide polymorphisms from 286 individuals sampled from 22 localities across the species' range. Our results point to a Northeast Pacific origin of the harbour seal, colonization of the North Atlantic via the Canadian Arctic, and subsequent stepping-stone range expansions across the North Atlantic from North America to Europe, accompanied by a successive loss of genetic diversity. Our analyses further revealed a deep divergence between modern North Pacific and North Atlantic harbour seals, with finer-scale genetic structure at regional and local scales consistent with strong philopatry. The study provides new insights into the harbour seal's remarkable ability to colonize and adapt to a wide range of habitats. Furthermore, it has implications for current harbour seal subspecies delineations and highlights the need for international and national red lists and management plans to ensure the protection of genetically and demographically isolated populations.

Strong and lasting impacts of past global warming on baleen whales and their prey.

Global warming is affecting the population dynamics and trophic interactions across a wide range of ecosystems and habitats. Translating these real-time effects into their long-term consequences remains a challenge. The rapid and extreme warming period that occurred after the Last Glacial Maximum (LGM) during the Pleistocene-Holocene transition (7-12 thousand years ago) provides an opportunity to gain insights into the long-term responses of natural populations to periods with global warming. The effects of this post-LGM warming period have been assessed in many terrestrial taxa, whereas insights into the impacts of rapid global warming on marine taxa remain limited, especially for megafauna. In order to understand how large-scale climate fluctuations during the post-LGM affected baleen whales and their prey, we conducted an extensive, large-scale analysis of the long-term effects of the post-LGM warming on abundance and inter-ocean connectivity in eight baleen whale and seven prey (fish and invertebrates) species across the Southern and the North Atlantic Ocean; two ocean basins that differ in key oceanographic features. The analysis was based upon 7032 mitochondrial DNA sequences as well as genome-wide DNA sequence variation in 100 individuals. The estimated temporal changes in genetic diversity during the last 30,000 years indicated that most baleen whale populations underwent post-LGM expansions in both ocean basins. The increase in baleen whale abundance during the Holocene was associated with simultaneous changes in their prey and climate. Highly correlated, synchronized and exponential increases in abundance in both baleen whales and their prey in the Southern Ocean were indicative of a dramatic increase in ocean productivity. In contrast, the demographic fluctuations observed in baleen whales and their prey in the North Atlantic Ocean were subtle, varying across taxa and time. Perhaps most important was the observation that the ocean-wide expansions and decreases in abundance that were initiated by the post-LGM global warming, continued for millennia after global temperatures stabilized, reflecting persistent, long-lasting impacts of global warming on marine fauna.

Factors associated with psychological distress in caregivers of patients with malignant gliomas.

PURPOSE: Caregivers of patients with malignant gliomas are at risk for psychological distress. However, factors associated with distress in this population have not been well described. We conducted a prospective study evaluating psychological distress in patients with malignant gliomas and their caregivers and exploring factors associated with caregiver distress. METHODS: We enrolled patients with newly diagnosed malignant gliomas (N = 77) and their caregivers (N = 61). At baseline and 3, 6, and 9 months after diagnosis, we administered the Hospital Anxiety and Depression Scale to assess psychological distress and the Caregiver Reaction Assessment to evaluate caregiver burden. We performed multivariable regression analyses to investigate caregiver-related, patient-related, and tumor-related factors associated with caregivers' distress. RESULTS: At baseline, 48.3% (29/60) and 26.2% (16/61) of caregivers reported clinically significant anxiety and depression symptoms, respectively. Anxiety and depression symptoms persisted over time. Greater caregiver depression was associated with male gender (B = 1.48, 95% CI 0.16-2.81, p = 0.03), higher caregiver burden (B = 0.08, 95% CI 0.01-0.15, p = 0.02), caregiver anxiety (B = 0.53, 95% CI 0.38-0.68, p < 0.0001), patient depression (B = 0.34, 95% CI 0.13-0.55, p = 0.002), and caring for a younger patient (B = -0.07, 95% CI -0.15 to 0.00, p = 0.049). Factors associated with greater caregiver anxiety symptoms were caregiver depression (B = 0.91, 95% CI 0.71-1.12, p < 0.0001) and younger patient age (B = -0.15, 95% CI -0.24 to -0.05, p = 0.003). CONCLUSION: Male gender, higher caregiver burden, greater patient depression symptoms, and younger patient age are associated with increased distress among caregivers of patients with malignant gliomas, underscoring the need for tailored supportive care interventions targeting caregivers at highest risk for psychological distress.

Circumpolar phylogeography and demographic history of beluga whales reflect past climatic fluctuations.

Several Arctic marine mammal species are predicted to be negatively impacted by rapid sea ice loss associated with ongoing ocean warming. However, consequences for Arctic whales remain uncertain. To investigate how Arctic whales responded to past climatic fluctuations, we analysed 206 mitochondrial genomes from beluga whales (Delphinapterus leucas) sampled across their circumpolar range, and four nuclear genomes, covering both the Atlantic and the Pacific Arctic region. We found four well-differentiated mitochondrial lineages, which were established before the onset of the last glacial expansion ~110 thousand years ago. Our findings suggested these lineages diverged in allopatry, reflecting isolation of populations during glacial periods when the Arctic sea-shelf was covered by multiyear sea ice. Subsequent population expansion and secondary contact between the Atlantic and Pacific Oceans shaped the current geographic distribution of lineages, and may have facilitated mitochondrial introgression. Our demographic reconstructions based on both mitochondrial and nuclear genomes showed markedly lower population sizes during the Last Glacial Maximum (LGM) compared to the preceding Eemian and current Holocene interglacial periods. Habitat modelling similarly revealed less suitable habitat during the LGM (glacial) than at present (interglacial). Together, our findings suggested the association between climate, population size, and available habitat in belugas. Forecasts for year 2100 showed that beluga habitat will decrease and shift northwards as oceans continue to warm, putatively leading to population declines in some beluga populations. Finally, we identified vulnerable populations which, if extirpated as a consequence of ocean warming, will lead to a substantial decline of species-wide haplotype diversity.

[Impact of reslizumab on the course of chronic rhinosinusitis in patients with eosinophilic asthma]. / Vliyanie reslizumaba na techenie khronicheskogo rinosinusita u bol'nykh s eozinofil'noi astmoi.

Chronic rhinosinusitis (CRS) with polyps is associated with eosinophilic inflammation, in which the key mediator is interleukin - 5 (IL-5) and is often combined with asthma. RESEARCH OBJECTIVES: To evaluate the therapeutic potential of reslizumab-humanized anti-IL-5 monoclonal antibody for the treatment of CRS with polyps in patients with severe asthma. PATIENTS AND METHODS: We investigated the cases of 9 patients with severe asthma treated with intravenous reslizumab at a dose of 3 mg per 1 kg of weight with regularity once in 4 weeks. The presence of CRS with polyps was revealed in 7 of 9 patients, SCT scanning of the paranasal sinuses indicated changes in all the patients, 2 patients had symptoms of chronic non-allergic rhinitis (NARES).The treatment effectiveness control was carried out after 6 months from the beginning of the treatment by the dynamics of nasal symptoms (SNOT-22), endoscopic image of the nose, total polyp score (TPS), changes in the SCT of the paranasal sinuses on the Lund-Mackay scale, rhinocytogram, the content of eosinophilic cationic protein in the blood, the level of systemic eosinophilia. The effectiveness of asthma control was assessed by the reduction of the frequency of asthma exacerbations, the need for systemic corticosteroids, spirometry data and Asthma Control Test (ACT) results. Along with a marked improvement in asthma control, 8 out of 9 patients displayed clinical, endoscopic, radiological signs of weakening of nasal symptoms. More significant improvement in asthma control was achieved in patients having CRS with polyps. In the group of patients having CRS with polyps, it was possible to detect anamnestic presence of NARES symptoms in the early stages of the disease. This indicates that NARES can be a precursor to the development of eosinophilic, non-IgE-induced asthma and nasal polyps. CONCLUSION: Treatment with reslizumab in patients with eosinophilic asthma and concomitant CRS with polyps and chronic non-allergic rhinitis (NARES) leads not only to improved control of asthma symptoms, but also to a significant regression of nasal symptoms.

Multi-dimensional predictions of psychotic symptoms via machine learning.

The diagnostic criteria for schizophrenia comprise a diverse range of heterogeneous symptoms. As a result, individuals each present a distinct set of symptoms despite having the same overall diagnosis. Whilst previous machine learning studies have primarily focused on dichotomous patient-control classification, we predict the severity of each individual symptom on a continuum. We applied machine learning regression within a multi-modal fusion framework to fMRI and behavioural data acquired during an auditory oddball task in 80 schizophrenia patients. Brain activity was highly predictive of some, but not all symptoms, namely hallucinations, avolition, anhedonia and attention. Critically, each of these symptoms was associated with specific functional alterations across different brain regions. We also found that modelling symptoms as an ensemble of subscales was more accurate, specific and informative than models which predict compound scores directly. In principle, this approach is transferrable to any psychiatric condition or multi-dimensional diagnosis.

Atypical chemokine receptor ACKR2 controls branching morphogenesis in the developing mammary gland.

Macrophages are important regulators of branching morphogenesis during development and postnatally in the mammary gland. Regulation of macrophage dynamics during these processes can therefore have a profound impact on development. We demonstrate here that the developing mammary gland expresses high levels of inflammatory CC-chemokines, which are essential in vivo regulators of macrophage migration. We further demonstrate that the atypical chemokine receptor ACKR2, which scavenges inflammatory CC-chemokines, is differentially expressed during mammary gland development. We have previously shown that ACKR2 regulates macrophage dynamics during lymphatic vessel development. Here, we extend these observations to reveal a novel role for ACKR2 in regulating the postnatal development of the mammary gland. Specifically, we show that Ackr2-/- mice display precocious mammary gland development. This is associated with increased macrophage recruitment to the developing gland and increased density of the ductal epithelial network. These data demonstrate that ACKR2 is an important regulator of branching morphogenesis in diverse biological contexts and provide the first evidence of a role for chemokines and their receptors in postnatal development processes.

Influence of past climate change on phylogeography and demographic history of narwhals, Monodon monoceros.

The Arctic is warming at an unprecedented rate, with unknown consequences for endemic fauna. However, Earth has experienced severe climatic oscillations in the past, and understanding how species responded to them might provide insight into their resilience to near-future climatic predictions. Little is known about the responses of Arctic marine mammals to past climatic shifts, but narwhals (Monodon monoceros) are considered one of the endemic Arctic species most vulnerable to environmental change. Here, we analyse 121 complete mitochondrial genomes from narwhals sampled across their range and use them in combination with species distribution models to elucidate the influence of past and ongoing climatic shifts on their population structure and demographic history. We find low levels of genetic diversity and limited geographic structuring of genetic clades. We show that narwhals experienced a long-term low effective population size, which increased after the Last Glacial Maximum, when the amount of suitable habitat expanded. Similar post-glacial habitat release has been a key driver of population size expansion of other polar marine predators. Our analyses indicate that habitat availability has been critical to the success of narwhals, raising concerns for their fate in an increasingly warming Arctic.

The endangered Spitsbergen bowhead whales' secrets revealed after hundreds of years in hiding.

Spitsbergen's bowhead whales (Balaena mysticetus) were hunted to near extinction in the world's first commercial whaling enterprise; this population clearly remains threatened, but nothing is known about its distribution, making assessment unfeasible. In this study, we document range, movement patterns and habitat preferences of this population, based on tagging done from an icebreaker-based helicopter. Despite their reduced abundance, Spitsbergen's bowhead whales occupy much of their historical range, stretching across the northern Barents Region from East Greenland eastward to Franz Josef Land. Unlike larger bowhead populations to the west, they do not migrate in a classical sense, but rather disperse from wintering grounds in the northernmost parts of their range during spring, returning northward again in autumn, a pattern opposite in terms of directionality compared to other Arctic bowhead whale populations. The extreme affiliation of this population with cold, ice-filled waters is a concern given ongoing climate warming and concomitant rapid sea ice habitat loss.

Environmental Pollutants Modulate Transcriptional Activity of Nuclear Receptors of Whales In Vitro.

This study reports the transcriptional activity of fin (Balaenoptera physalus) and blue whale (Balaenoptera musculus) peroxisome proliferator-activated receptor γ (PPARG), glucocorticoid receptor (GR), and thyroid hormone receptor ß (THRB), when exposed to 14 persistent organic pollutants (so-called "legacy" persistent organic pollutants (POPs)) and a synthetic mixture of POPs, using GAL4-UAS-based in vitro luciferase reporter gene assays. Polychlorinated biphenyls (PCBs) had both agonistic and antagonistic effects on PPARG and GR, and mainly antagonistic, except for PCB153, effects on THRB. 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) and its metabolites had mainly antagonistic effects on all of the receptors, except for o,p'-DDT. Given that the ligand-binding domain (LBD) of PPARG is the same in killer whales, white whales, polar bears, and humans, and that GR-LBD is identical in killer whales and minke whales and that the LBD of THRB is the same in killer whales, white whales, and humans, it is likely that the results of this study are representative for these other species as well. It is important to note that several environmental pollutants modulated the transcriptional activity of tested nuclear receptors at environmentally relevant concentrations for whales.

Moving forward on all fronts: impact, patterns, and barriers to exercise in cancer survivors and patients living with advanced disease.

INTRODUCTION: Exercise is recommended for all patients with cancer, but there has been limited study of exercise habits in patients across the spectrum of illness. PURPOSE: This pragmatic survey aimed to identify the unmet supportive care needs, self-reported symptoms, and exercise habits among both cancer survivors and patients living with advanced disease to determine adherence to exercise guidelines and to identify barriers and opportunities to improve exercise. METHODS: An anonymous cross-sectional self-administered paper survey was distributed to patients with cancer presenting for oncology clinic visits at an academic cancer center. Survey measures included presence of symptoms and health problems in addition to weekly time spent exercising, change in exercise levels since diagnosis, interest in exercise, and self-reported barriers. Participants reporting at least 150 min of exercise per week were characterized as adherent to guidelines. RESULTS: Among 640 survey respondents, 570 (89%) completed questions about exercise. Only 44% of cancer survivors and 34% of patients living with advanced disease met current guidelines. Survivors who met exercise guidelines had a lower prevalence of fatigue and memory impairments, but this finding was not seen among patients with advanced cancer. Over 70% of patients with advanced disease and 47% of survivors reported decreasing exercise post-diagnosis compared to pre-diagnosis. Prominent barriers to exercise among both groups included burden of illness and time constraints but interest in increasing exercise was high. CONCLUSIONS: There is an opportunity to improve exercise and related outcomes among a large percentage of both cancer survivors and patients living with advanced disease.

Contrasting changes in space use induced by climate change in two Arctic marine mammal species.

Global warming is inducing major environmental changes in the Arctic. These changes will differentially affect species owing to differences in climate sensitivity and behavioural plasticity. Arctic endemic marine mammals are expected to be impacted significantly by ongoing changes in their key habitats owing to their long life cycles and dependence on ice. Herein, unique biotelemetry datasets for ringed seals (RS; Pusa hispida) and white whales (WW; Delphinapterus leucas) from Svalbard, Norway, spanning two decades (1995-2016) are used to investigate how these species have responded to reduced sea-ice cover and increased Atlantic water influxes. Tidal glacier fronts were traditionally important foraging areas for both species. Following a period with dramatic environmental change, RS now spend significantly more time near tidal glaciers, where Arctic prey presumably still concentrate. Conversely, WW spend significantly less time near tidal glacier fronts and display spatial patterns that suggest that they are foraging on Atlantic fishes that are new to the region. Differences in levels of dietary specialization and overall behavioural plasticity are likely reasons for similar environmental pressures affecting these species differently. Climate change adjustments through behavioural plasticity will be vital for species survival in the Arctic, given the rapidity of change and limited dispersal options.

Chinstrap penguin population genetic structure: one or more populations along the Southern Ocean?

BACKGROUND: Historical factors, demography, reproduction and dispersal are crucial in determining the genetic structure of seabirds. In the Antarctic marine environment, penguins are a major component of the avian biomass, dominant predators and important bioindicators of ecological change. Populations of chinstrap penguins have decreased in nearly all their breeding sites, and their range is expanding throughout the Antarctic Peninsula. Population genetic structure of this species has been studied in some colonies, but not between breeding colonies in the Antarctic Peninsula or at the species' easternmost breeding colony (Bouvetøya). RESULTS: Connectivity, sex-biased dispersal, diversity, genetic structure and demographic history were studied using 12 microsatellite loci and a mitochondrial DNA region (HVRI) in 12 breeding colonies in the South Shetland Islands (SSI) and the Western Antarctic Peninsula (WAP), and one previously unstudied sub-Antarctic island, 3600 km away from the WAP (Bouvetøya). High genetic diversity, evidence of female bias-dispersal and a sign of population expansion after the last glacial maximum around 10,000 mya were detected. Limited population genetic structure and lack of isolation by distance throughout the region were found, along with no differentiation between the WAP and Bouvetøya (overall microsatellite F ST = 0.002, p = 0.273; mtDNA F ST  = - 0.004, p = 0.766), indicating long distance dispersal. Therefore, genetic assignment tests could not assign individuals to their population(s) of origin. The most differentiated location was Georges Point, one of the southernmost breeding colonies of this species in the WAP. CONCLUSIONS: The subtle differentiation found may be explained by some combination of low natal philopatric behavior, high rates of dispersal and/or generally high mobility among colonies of chinstrap penguins compared to other Pygoscelis species.

Correction to: Chinstrap penguin population genetic structure: one or more populations along the Southern Ocean?

Correction to: BMC Evolutionary Biology (2018) 18:90 https://doi.org/10.1186/s12862-018-1207-0 .

The chemokine receptors ACKR2 and CCR2 reciprocally regulate lymphatic vessel density.

Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro-lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels.