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Macrophages are versatile myeloid leukocytes with flexible cellular states to perform diverse tissue functions beyond immunity. This plasticity is however often hijacked by diseases to promote pathology. Scanning kinetics of macrophage states by single-cell transcriptomics and flow cytometry, we observed atopic dermatitis drastically exhausted a resident subtype S1. Characterized by FRβ/CD163 expression, S1 exhibited strong efferocytosis and chemoattracted monocytes and eosinophils. Here we have delineated mechanisms regulating monocyte decision to acquire S1 identity in skin. During M-CSF driven macrophage differentiation in healthy skin, FRβ was expressed via intrinsic control of STAT6 and ALK5 activities, and did not require heterotypic cellular crosstalk. In contrast, CD163 expression required exposure to fibroblastic secretion. This process depended on SHP1 activity and involved STAT5 inactivation. Suppressed STAT5 activity caused CD163 expression and rendered macrophage insensitive to further induction by fibroblasts. Parsing coculture experiments with in silico ligand expression, we identified laminin-α2 and type-V collagen secreted by hypodermal fibroblasts as CD163-driving factors. S1 identity loss in AD followed a stepwise cascade: reduced laminins availability first dampened CD163 expression, IL4 and TGFβ subsequently acted on CD163lo/− cells to downregulate FRβ. In AD skin, we showed that imitating this fibroblast-macrophage crosstalk with exogenous laminin-211 encouraged monocyte differentiation to S1 macrophages, fostered homeostatic commitment of extravasated eosinophils, and alleviated dermatitis. Hence, we demonstrated that reinforcing a steady-state cue from hypodermal fibroblasts could override maladaptive pressure on macrophage and restored tissue homeostasis. [ABSTRACT FROM AUTHOR]

Multiple embryonic precursors give rise to leukocytes in adults while the lineage‐based functional impacts are underappreciated. Mesodermal precursors expressing PDGFRα appear transiently during E7.5‐8.5 descend to a subset of Lin–Sca1+Kit+ hematopoietic progenitors found in adult BM. By analyzing a PDGFRα‐lineage tracing mouse line, we here report that PDGFRα‐lineage BM F4/80+SSClo monocytes/macrophages are solely Ly6C+LFA‐1hiMac‐1hi monocytes enriched on the abluminal sinusoidal endothelium while Ly6C–LFA‐1loMac‐1lo macrophages are mostly from non‐PDGFRα‐lineage in vivo. Monocytes with stronger integrin profiles outcompete macrophages for adhesion on an endothelial monolayer or surfaces coated with ICAM‐1‐Fc or VCAM‐1‐Fc. Egress of PDGFRα‐lineage‐rich monocytes and subsequent differentiation to peripheral macrophages spatially segregates them from non‐PDGFRα‐lineage BM‐resident macrophages and allows functional specialization since macrophages derived from these egressing monocytes differ in morphology, phenotype, and functionality from BM‐resident macrophages in culture. Extravasation preference for blood PDGFRα‐lineage monocytes varies by tissues and governs the local lineage composition of macrophages. More PDGFRα‐lineage classical monocytes infiltrated into skin and colon but not into peritoneum. Accordingly, transcriptomic analytics indicated augmented inflammatory cascades in dermatitis skin of BM‐chimeric mice harbouring only PDGFRα‐lineage leukocytes. Thus, the PDGFRα‐lineage origin biasedly generates monocytes predestined for BM exit to support peripheral immunity following extravasation and macrophage differentiation. [ABSTRACT FROM AUTHOR]

Chromosomal insertions are rare structural rearrangements, and the molecular mechanisms underlying their origin are unknown. In this study, we used whole genome sequencing to analyze breakpoints and junction sequences in 4 patients with chromosomal insertions. Our analysis revealed that none of the 4 cases involved a simple insertion mediated by a 3-chromosomal breakage and rejoining events. The inserted fragments consisted of multiple pieces derived from a localized genomic region, which were shuffled and rejoined in a disorderly fashion with variable copy number alterations. The junctions were blunt ended or with short microhomologies or short microinsertions, suggesting the involvement of nonhomologous end-joining. In one case, analysis of the parental origin of the chromosomes using nucleotide variations within the insertion revealed that maternal chromosomal segments were inserted into the paternal chromosome. This patient also carried both maternal alleles, suggesting the presence of zygotic trisomy. These data indicate that chromosomal shattering may occur in association with trisomy rescue in the early postzygotic stage. [ABSTRACT FROM AUTHOR]

H2O2 permeation through a cell membrane significantly affects living organisms, and permeation is controlled by the physico-chemical nature of lipids and other membrane components. We investigated the molecular relationship between H2O2 permeation and lipid membrane structure using three oxidized lipids. POVPC and PazePC act as intra- and inter-molecular permeation promoters, respectively; however, their underlying mechanisms were different. The former changed the partition equilibrium, while the latter changed the permeation pathway. PoxnoPC inhibited permeation under our experimental conditions via an intra-molecular configuration change. Thus, both intra- and inter-molecular processes were found to control the role of oxidized lipids as inhibitors and promoters towards H2O2 permeation with different mechanisms depending on structure and composition. Here, we identified two independent H2O2 permeation routes: (i) permeation through lipid membrane with increased partition coefficient by intra-molecular configurational change and (ii) diffusion through pores (water channels) formed by inter-molecular configurational change of oxidized lipids. We provide new insight into how biological cells control permeation of molecules through intra- and inter-molecular configurational changes in the lipid membrane. Thus, by employing a rational design for both oxidized lipids and other components, the permeation behaviour of H2O2 and other ions and molecules through a lipid membrane could be controlled. [ABSTRACT FROM AUTHOR]