Search

Lucy Gracen,1 Melanie Aikebuse,2,3 Babak Sarraf,2– 4 Steven M McPhail,5 Anthony W Russell,6 James O’Beirne,7 Katharine M Irvine,8 Suzanne Williams,9 Patricia C Valery,4,* Elizabeth E Powell2– 4,* 1Department of Gastroenterology and Hepatology, Royal Brisbane and Women’s Hospital, Herston, QLD, Australia; 2Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia; 3Centre for Liver Disease Research, Faculty of Medicine, Translational Research Institute, The University of Queensland, Woolloongabba, QLD, Australia; 4QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; 5Australian Centre for Health Services Innovation School of Public Health, Institute of Health and Biomedical Innovation, Queensland University of Technology (QUT), Brisbane, QLD, Australia; 6Endocrinology and Diabetes, the Alfred Hospital, Melbourne, VIC, Australia; 7Department of Gastroenterology and Hepatology, Sunshine Coast University Hospital, Birtinya, QLD, Australia; 8Mater Research, Translational Research Institute, Brisbane, QLD, Australia; 9Inala Primary Care General Practice, Inala, QLD, Australia*These authors contributed equally to this workCorrespondence: Elizabeth E Powell, Centre for Liver Disease Research, Faculty of Medicine, Translational, Research Institute, The University of Queensland, Level 5, West Wing, 37, Kent Street, Woolloongabba, Brisbane, QLD, 4102, Australia, Tel +61 412 014 337, Email e.powell@uq.edu.auBackground: Although clinical guidelines endorse screening for metabolic dysfunction-associated steatotic liver disease (MASLD) with advanced fibrosis in people with type 2 diabetes (T2D), the feasibility of and barriers and considerations relevant to implementing this approach in the community remain unclear.Methods: Sequential adults with T2D attending selected community clinics during 2021– 2023 were invited to receive a “liver health check” (n=543). A further 95 participants were referred directly from their general practitioner (GP) or self-referred to the study. A total of 302 participants underwent a point of care assessment of hepatic steatosis and stiffness (FibroScan) and were advised to see their GP to discuss the results. “Template” letters containing key results, their interpretation and advice about management of cardiometabolic risk, patient follow-up and referral criteria, were sent to participants’ GPs.Results: Referral to a tertiary liver clinic was advised in GP letters for 45 (15%) participants with an increased risk of clinically significant fibrosis (liver stiffness measurement ≥ 8), 15 participants with ‘red flags’ (eg splenomegaly, thrombocytopenia) and 2 with unsuccessful FibroScan examinations. A referral from GPs to the liver clinic was received for 27 (44%) of these 62 participants. Approximately 90% of GPs rated the “template” letters favourably on a Likert rating scale.Conclusion: The low rate of participation in the “liver health check” and liver clinic referral reflects a real-world scenario and may stem from societal under-recognition and engagement with MASLD, competing health priorities or under-appreciation of the link between liver fibrosis severity and mortality risk. Further studies need to address strategies to enhance participation in liver health assessments and determine their impact on liver-related morbidity/mortality and overall survival.Keywords: NAFLD, primary care, chronic liver disease, FibroScan

Macrophage and osteoclast proliferation, differentiation and survival are regulated by colony-stimulating factor 1 receptor (CSF1R) signaling. Osteopetrosis associated with Csf1 and Csf1r mutations has been attributed to the loss of osteoclasts and deficiency in bone resorption. Here, we demonstrate that homozygous Csf1r mutation in rat leads to delayed postnatal skeletal ossification associated with substantial loss of osteal macrophages in addition to osteoclasts. Osteosclerosis and site-specific skeletal abnormalities were reversed by intraperitoneal transfer of wild-type bone marrow cells (bone marrow cell transfer, BMT) at weaning. Following BMT, IBA1+ macrophages were detected before TRAP+ osteoclasts at sites of ossification restoration. These observations extend evidence that osteal macrophages independently contribute to bone anabolism and are required for normal postnatal bone growth and morphogenesis., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

Bacteria adapt to selective pressure in their immediate environment in multiple ways. One mechanism involves the acquisition of independent mutations that disable or modify a key pathway, providing a signature of adaptation via convergent evolution. Extra-intestinal pathogenic Escherichia coli (ExPEC) belonging to sequence type 95 (ST95) represent a global clone frequently associated with severe human infections including acute pyelonephritis, sepsis, and neonatal meningitis. Here, we analysed a publicly available dataset of 613 ST95 genomes and identified a series of loss-of-function mutations that disrupt cellulose production or its modification in 55.3% of strains. We show the inability to produce cellulose significantly enhances ST95 invasive infection in a rat model of neonatal meningitis, leading to the disruption of intestinal barrier integrity in newborn pups and enhanced dissemination to the liver, spleen and brain. Consistent with these observations, disruption of cellulose production in ST95 augmented innate immune signalling and tissue neutrophil infiltration in a mouse model of urinary tract infection. Mutations that disrupt cellulose production were also identified in other virulent ExPEC STs, Shigella and Salmonella, suggesting a correlative association with many Enterobacteriaceae that cause severe human infection. Together, our findings provide an explanation for the emergence of hypervirulent Enterobacteriaceae clones., (© 2024. The Author(s).)

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Acute administration of a CSF1-Fc fusion protein to mice led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilization of body fat. The impacts of CSF1 on macrophage abundance, liver size, and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, and control of liver-to-body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilization, without changes in appetence, which may have novel implications for managing metabolic syndrome. NEW & NOTEWORTHY CSF1 administration expands tissue macrophages, which transforms systemic metabolism. CSF1 drives fat mobilization and glucose uptake to support liver growth. The effects of CSF1 are independent of normal hormonal metabolic regulation. The effects of CSF1 are rapidly reversible, restoring homeostatic body composition. CSF1-dependent macrophages and liver size are coupled in a dynamic equilibrium.

Macrophages contribute to many aspects of development and homeostasis, innate and acquired immunity, immunopathology, and tissue repair. Every tissue contains an abundant resident macrophage population. Inflammatory stimuli promote the recruitment of monocytes from the blood and their adaptation promotes the removal of the stimulus and subsequent restoration of normal tissue architecture. Dysregulation of this response leads to chronic inflammation and tissue injury. In many tissues, their differentiation and survival are dependent on the colony stimulating factor 1 receptor (CSF1R) signalling axis, which is highly conserved across all vertebrates. Complete loss of either CSF1R or its cognate ligands, colony stimulating factor 1 (CSF1), and interleukin 34 (IL-34), results in the loss of many tissue-resident macrophage populations. This provides a useful paradigm to study macrophages.There are many tools used to visualize tissue-resident macrophages and their precursors, monocytes, in mice and humans. Particularly in mice there are genetic tools available to delete, enhance and manipulate monocytes and macrophages and their gene products to gain insight into phenotype and function. The laboratory rat has many advantages as an experimental model for the understanding of human disease, but the analytical resources are currently more limited than in mice. Here, we describe available genetic models, antibodies, and immunohistochemistry (IHC) methods that may be used to visualize tissue-resident macrophages in rats., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)