Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.

Changes in glycerophosphocholine metabolism are observed in Alzheimer's disease; however, it is not known whether these metabolic disruptions are linked to cognitive decline. Here, using unbiased lipidomic approaches and direct biochemical assessments, we profiled Land's cycle lipid remodeling in the hippocampus, frontal cortex, and temporal-parietal-entorhinal cortices of human amyloid beta precursor protein (ΑβPP) over-expressing mice. We identified a cortex-specific hypo-metabolic signature at symptomatic onset and a cortex-specific hyper-metabolic signature of Land's cycle glycerophosphocholine remodeling over the course of progressive behavioral decline. When N5 TgCRND8 and ΑβPP /PSI mice first exhibited deficits in the Morris Water Maze, levels of lyso-phosphatidylcholines, LPC(18:0/0:0), LPC(16:0/0:0), LPC(24:6/0:0), LPC(25:6/0:0), the lyso-platelet-activating factor (PAF), LPC(O-18:0/0:0), and the PAF, PC(O-22:6/2:0), declined as a result of reduced calcium-dependent cytosolic phospholipase A α (cPLA α) activity in all cortices but not hippocampus. Chronic intermittent hypoxia, an environmental risk factor that triggers earlier learning memory impairment in ΑβPP /PSI mice, elicited these same metabolic changes in younger animals. Thus, this lipidomic signature of phenoconversion appears age-independent. By contrast, in symptomatic N5 TgCRND8 mice, cPLA α activity progressively increased; overall Lyso-phosphatidylcholines (LPC) and LPC(O) and PC(O-18:1/2:0) levels progressively rose. Enhanced cPLA α activity was only detected in transgenic mice; however, age-dependent increases in the PAF acetylhydrolase 1b α to α expression ratio, evident in both transgenic and non-transgenic mice, reduced PAF hydrolysis thereby contributing to PAF accumulation. Taken together, these data identify distinct age-independent and age-dependent disruptions in Land's cycle metabolism linked to symptomatic onset and progressive behavioral decline in animals with pre-existing Αβ pathology. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: https://cos.io/our-services/open-science-badges/.

ovarian tumor (OTU) domain-containing ubiquitin aldehyde-binding protein 1; Otub1 +/− , heterozygous Otub1 deletion; Otub1 fl /fl , mice with floxed Otub1 exons 2 and 3; pcOtub1 Wt/del , potential of conditional Otub1 deletion; PEI, polyethylenimine; scRNA, single-cell RNA (sequencing); SSC-A, side scatter-area; SSC-H, side scatter-height; TEM, transmission electron microscopy; Tx, tamoxifen; Ub, ubiquitin proteins; UBC-Cre ERT2 , Cre ERT2 transgene under the control of the ubiquitin C promoter; wbOtub1 del/del , induced whole-body Otub1 deletion; Wt, wild-type.

Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and non-immune cells, and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular crosstalk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the non-redundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.

No abstract