Biology subjects

Sokolowski, K.

Publications and source records attributed to Sokolowski, K..

3 recordsLinked to original sources

bioRxiv2025

Homozygous kinase-dead Csf1r mutation in outbred mice reveals essential and redundant functions of tissue resident macrophages

The proliferation, differentiation and survival of cells of the macrophage lineage depends on signals from the macrophage colony-stimulating factor receptor (CSF1R). On a C57BL/6J background homozygous kinase-dead Csf1r mutation (Csf1rE631K/E631K - E631Km/m) causes perinatal lethality. Here we demonstrate that E631Km/m mice on a mixed genetic background (C57 x BALB/c F2) are osteopetrotic and growth retarded but viable as adults with no other gross developmental deficits. They lack osteoclasts, microglia and most peripheral tissue resident macrophages and exhibit perturbed hematopoiesis. Although CD169+ tissue resident macrophages in bone marrow are considered an essential component of the hematopoietic niche, CD169 is undetectable in E631Km/m marrow and F4/80+ macrophages are depleted. These changes are associated with expansion of mature and immature granulocytes and reduced B cells, whereas monocytes and stem and progenitor populations are unaffected as a proportion of total cells. Erythropoiesis in bone marrow is maintained in E631Km/m mice, associated with a residual population of CSF1R-independent CD169-ve/F4/80+ macrophages. Nevertheless, splenic extramedullary hematopoiesis in E631Km/m mice indicates a degree of bone marrow insufficiency. Red pulp macrophages are retained but CD169+ marginal metallophil macrophages are absent and CD209b+ (SIGNR1) macrophages are present but disorganized. Circulating white blood cell count is unchanged in E631Km/m mice, but the proportion of neutrophils is greatly increased whilst B cells and monocytes are reduced. This novel model reveals the essential roles of CSF1R-dependent macrophages in hematopoiesis and demonstrates that many developmental and homeostatic functions attributed to murine resident tissue macrophages are redundant and/or specific to inbred mouse strains.

immunology↗

bioRxiv2023

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic metabolism to fuel growth.

Background and AimMacrophages 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. Methods and ResultsAcute administration of a CSF1-Fc fusion protein 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 mobilisation of body fat. The impacts of CSF1 on macrophage abundance, liver size and body composition were rapidly reversed to restore homeostasis. CSF1s effects 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. ConclusionThese results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, metabolic regulation and homeostatic control of liver:body weight ratio.

immunology↗

bioRxiv2022

Molecular diversity and connectivity of accessory olfactory system neurons

Olfaction is the primary sensory modality by which most vertebrate species interpret environmental cues for appropriate behavioral outputs. The olfactory system is subdivided into main (MOS) and accessory (AOS) components which process volatile and non-volatile cues. While much is known regarding the molecular diversity of neurons that comprise the MOS, less is known about the AOS. Here, focusing on the AOS which is largely comprised of the peripheral vomeronasal organ (VNO), the accessory olfactory bulb (AOB) and the medial subnucleus of the amygdala (MeA), we studied the molecular diversity and neuronal subtype connectivity of this interconnected circuit. We show that populations of neurons of the AOS can be molecularly subdivided based on their current or prior expression of the transcription factors Foxp2 or Dbx1. We show that the majority of AOB neurons that project directly to the MeA are of the Foxp2-lineage. Using single cell patch clamp electrophysiology, we further reveal that in addition to sex-specific differences across lineage, the relative contributions of excitatory and inhibitory inputs to MeA Foxp2-lineage neurons differ between sexes. Together, this work uncovers a novel molecular diversity of AOS neurons and lineage- and sex-differences in patterns of connectivity.

neuroscience↗