Broad-spectrum antibiotics disrupt homeostatic efferocytosis
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ABSTRACT:
PROVIDER: PRJNA1128117 | ENA |
REPOSITORIES: ENA
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Project description:The phagocytic clearance of apoptotic cells, termed efferocytosis, is essential for both tissue homeostasis and tissue health during cell death-inducing treatments. Failure to efficiently clear apoptotic cells augment the risk of pathological inflammation and has been linked to a myriad of autoimmune and inflammatory diseases. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Interestingly, clinical evidence suggests that prolonged use of broad-spectrum antibiotics is associated with an increased risk of autoimmune and inflammatory disease development. We therefore hypothesized that intestinal microbes produce molecular signals that regulate efferocytotic ability in tissue phagocytes beyond the intestines. Here, we find that macrophages, the body’s professional phagocyte, display impaired efferocytosis in the peritoneum of broad-spectrum antibiotics (ABX)-treated, vancomycin-treated, and germ-free mice in vivo, the latter of which could be rescued by fecal microbiota transplantation. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency and capacity in mouse and human macrophages, with both intestinal and local delivery of butyrate capable of rescuing ABX-induced large peritoneal macrophage (LPM) efferocytosis defects. Bulk mRNA sequencing of butyrate-treated primary macrophages in vitro and single cell mRNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice revealed specific regulation of efferocytosis-supportive transcriptional programs. Specifically, we found that the efferocytosis receptor T-cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) was downregulated in LPMs of ABX-treated mice which was rescued by oral butyrate and that TIM-4 was required for the butyrate-induced enhancement of LPM efferocytosis capacity in vivo. Strikingly, LPM efferocytosis was impaired well-beyond withdrawal of ABX and, importantly, ABX-treated mice exhibited significantly worse disease in a mouse model of system lupus erythematosus. Collectively, our results demonstrate that homeostatic efferocytosis relies on distal molecular signals and suggest that a defect in homeostatic efferocytosis may contribute to the clinically observed link between broad-spectrum antibiotics use and inflammatory disease.
2025-06-24 | GSE270751 | GEO
Project description:Broad-spectrum antibiotics disrupt homeostatic efferocytosis [scRNA-seq]
| PRJNA1127434 | ENA
Project description:The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis1 in a tissue, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we find that large peritoneal macrophages (LPMs) display impaired efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated, and germ-free mice in vivo. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency/capacity in mouse and human macrophages, and rescued ABX-induced LPM efferocytosis defects in vivo. Bulk mRNA sequencing of butyrate-treated macrophages in vitro and single cell mRNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice revealed regulation of efferocytosis-supportive transcriptional programs. Specifically, we found that the efferocytosis receptor T-cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) was downregulated in LPMs of ABX-treated mice but rescued by oral butyrate and TIM-4 was required for the butyrate-induced enhancement of LPM efferocytosis capacity. LPM efferocytosis was impaired beyond withdrawal of ABX and ABX-treated mice exhibited significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain link between ABX use and inflammatory disease.
2024-07-16 | GSE270512 | GEO
Project description:Broad-spectrum antibiotics disrupt homeostatic efferocytosis [bulk RNA-seq]
| PRJNA1127440 | ENA
Project description:The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis1 in a tissue, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we find that large peritoneal macrophages (LPMs) display impaired efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated, and germ-free mice in vivo. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosted efferocytosis efficiency/capacity in mouse and human macrophages, and rescued ABX-induced LPM efferocytosis defects in vivo. Bulk mRNA sequencing of butyrate-treated macrophages in vitro and single cell mRNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice revealed regulation of efferocytosis-supportive transcriptional programs. Specifically, we found that the efferocytosis receptor T-cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) was downregulated in LPMs of ABX-treated mice but rescued by oral butyrate and TIM-4 was required for the butyrate-induced enhancement of LPM efferocytosis capacity. LPM efferocytosis was impaired beyond withdrawal of ABX and ABX-treated mice exhibited significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain link between ABX use and inflammatory disease.
2024-07-16 | GSE270514 | GEO
Project description: Not available
| S-EPMC7616532 | biostudies-literature
Project description:RNA N-glycosylation enables innate immune evasion and homeostatic efferocytosis
| PRJNA1235213 | ENA
Project description: Not available
| S-EPMC7739875 | biostudies-literature
Project description:Inflammation is a physiopathological process triggered by infection or tissue damage. Immune system initiates coordinated sequential steps in response to these danger signals. Once the threat has been contained inflammation has to be subsequently shut down. Inflammation resolution is initiated by the reprogramming of pro-inflammatory macrophages toward a pro-resolving profile. This reprogramming is induced in particular by the non-phlogistic engulfment of apoptotic cells, mostly apoptotic neutrophils, a process called efferocytosis. As a matter of fact, macrophages are an essential linchpin regulating both inflammation triggering and sustaining and inflammation resolution. This duality can be achieved through the tremendous plasticity of these innate immune cells. Indeed, depending on microenvironmental signals (cytokines, efferocytosis, growth factors…) macrophages can adopt numerous diverse and sometimes antagonistic phenotypes. The mechanisms governing these transitions remain relatively scattered especially in human. With this project we propose to explore the mechanisms involved in human macrophage reprogramming toward a pro-resolving profile after efferocytosis. The stakes are high due to the estimated prevalence of chronic inflammatory diseases in Western society is 5 to 7%. Chronic inflammation is a burden to patient due to life-long debilitating illness and increased mortality and is also a burden to society due to high costs for therapy and care. Finding new therapies to limit chronic inflammation establishment and persistence is thus a highly valuable goal.
2021-12-01 | E-MTAB-8885 | biostudies-arrayexpress