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Microarray data for Bhlhe40-sufficient and -deficient resident macrophages

ABSTRACT: Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance, but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for normal LPM cell cycling. Bhlhe40 repressed the expression of Maf and Mafb and directly promoted expression of cell cycle-related transcripts to enable proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1 and others uniquely bound by Bhlhe40, including Maf and cell cycle-related loci. Our findings demonstrate a tissue-specific control mechanism regulating resident macrophage proliferation in homeostasis and type 2 immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE125727 | GEO | 2019/04/30

REPOSITORIES: GEO

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Chromatin immunoprecipitation sequencing (ChIP-Seq) for Bhlhe40 from naïve and IL-4c-stimulated large peritoneal macrophages (LPMs)

Project description:Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance, but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for normal LPM cell cycling. Bhlhe40 repressed the expression of Maf and Mafb and directly promoted expression of cell cycle-related transcripts to enable proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1 and others uniquely bound by Bhlhe40, including Maf and cell cycle-related loci. Our findings demonstrate a tissue-specific control mechanism regulating resident macrophage proliferation in homeostasis and type 2 immunity.

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HIGHLY PHAGOCYTIC LIPID-ASSOCIATED MACROPHAGES (LAMs) ARE INCREASED 2 IN COLONIC LAMINA PROPRIA IN OBESITY

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Broad-spectrum antibiotics disrupt homeostatic efferocytosis [scRNA-seq]

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Project description:Tissues in multicellular organisms are ‘serviced’ by resident macrophages, which perform both generic and tissue-specific functions. The latter relies on unique tissue-specific molecular programs induced by signals from the microenvironment and executed through a combinatorial action of tissue-specific and broadly expressed transcriptional regulators. Here, we identify the transcription factors Bhlhe40 and Bhlhe41 as novel regulators of alveolar macrophages (AMs) – a population that provides the first line of immune defense and executes homeostatic functions in lung alveoli. In the absence of these factors, AMs exhibited decreased proliferation that resulted in a severe disadvantage of knockout AMs in a competitive setting. Gene expression analyses revealed a broad cell-intrinsic footprint of Bhlhe40/Bhlhe41-deficiency manifested by a downregulation of AM signature genes and induction of signature genes of other macrophage lineages. Genome-wide characterization of Bhlhe40 DNA binding suggested that these transcription factors directly repress the expression of lineage-inappropriate genes in AMs. Taken together, these results identify Bhlhe40 and Bhlhe41 as key regulators of AM self-renewal and guardians of their identity.

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Self-maintenance of Cardiac Resident Reparative Macrophages Attenuates Doxorubicin-induced Cardiomyopathy through the SR-A1-c-Myc Axis

Project description:Rationale: Doxorubicin-induced cardiomyopathy (DiCM) is a significant cause of heart failure and mortality in cancer patients, in which macrophage-orchestrated inflammation serves as an essential pathogenic mechanism. However, the specific roles of tissue-resident and monocyte-derived macrophages in DiCM remain poorly understood. Objective: Uncovering the origins, phenotypes, and functions of proliferative cardiac resident macrophages and mechanistic insights into the self-maintenance of cardiac macrophage during DiCM progression. Methods and Results: Mice were administrated with doxorubicin to induce cardiomyopathy. Dynamic changes of resident and monocyte-derived macrophages were examined by lineage tracing, parabiosis, and bone marrow transplantation. We found that the monocyte-derived macrophages primarily exhibited a pro-inflammatory phenotype that dominated the whole DiCM pathological process and impaired cardiac function. In contrast, cardiac resident macrophages were vulnerable to doxorubicin insult. The survived resident macrophages exhibited enhanced proliferation and conferred a reparative role. Global or myeloid specifically ablation of class A1 scavenger receptor (SR-A1) inhibited proliferation of cardiac resident reparative macrophages and therefore exacerbated cardiomyopathy in DiCM mice. Importantly, the detrimental effect of macrophage SR-A1 deficiency was confirmed by transplantation of GFP+ wild type bone marrow. At the mechanistic level, we show that c-Myc, a key transcriptional factor for the SR-A1-P38-SIRT1 pathway, mediated the effect of SR-A1 in reparative macrophage proliferation in DiCM. Conclusions: The SR-A1-c-Myc axis may represent a promising target to treat DiCM through augmentation of cardiac resident reparative macrophage proliferation.

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Project description:Tissue-resident Macrophages have long been appreciated as playing a fundamental role in the ontogeny and function of several organs. For example, osteoclasts are crucial for proper bone remodeling, microglia for synaptic pruning, and lung alveolar macrophages for clearance of surfactant. Perivascular macrophages have been described in many organs. Our analysis of murine perivascular macrophages in several tissues and organs led us to define a macrophage family, whose members share the expression of a number of surface molecules that are not typically considered macrophage markers, such as Lyve1, Folate Receptor 2 (Folr2), Enpep/CD249, and CD38, as well as other more typical macrophage markers such as CD206 and Tim4. This family of perivascular macrophages also occurs in humans. Importantly, this family of perivascular macrophages relies on the transcription factor c-MAF, encoded by the gene Maf, for its full function. Conditional deletion of the Maf gene in the Lyve1+Folr2+CD38+ macrophage family caused their ablation in the brain, without impact on the microglia, while in the adipose tissue the conditional deletion of the Maf gene in perivascular macrophages resulted in a profoundly altered macrophage gene expression, and brought about an increased vascular branching in this tissue. Mice with conditional Maf deletion were protected from metabolic syndrome when submitted to high fat diet (HFD). Our results show that c-MAF is the master regulator of a family of perivascular macrophages.

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