RXRα Regulates the Development of Resident Tissue Macrophages

Philpott, Jordan; Kazimierczyk, Simon; Korgaonkar, Parimal; Bordt, Evan A.; Zois, Jaclyn; Vasudevan, Chithirachelvi; Meng, Di; Bhatia, Ishan; Lu, Naifang; Jimena, Brittany; Porter, Caryn; Cherayil, Bobby J.; Jain, Nitya

doi:10.4049/immunohorizons.2200019

Cited by 12 publications

(2 citation statements)

References 31 publications

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“…We compared the nonoverlapping transcription factors between the DE genes in liver macrophages from Bmp9/10 HSC-KO and Smad4 fl/fl Vav1 Cre mice and found 29 transcription factors only downregulated in liver macrophages from Bmp9/10 HSC-KO mice (Figure 2i and Supplementary Table 1). Among these transcription factors, we focused on Rxra because it has been reported to regulate the development of many embryonic tissue-resident macrophages, including KCs (30), but it is unclear whether RXRa regulates the differentiation of blood monocytes to MoKCs. To test this hypothesis, we prepared Rxra fl/fl Csf1r Cre Clec4f DTR mice, in which DT injection can delete KCs and monocytes recruited into the liver to differentiate into liver macrophages, which can be targeted by the Csf1r Cre strain to eliminate the Rxra gene (Supplementary Figure 3a).…”

Section: Resultsmentioning

confidence: 99%

BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

Zhao,

Huang,

et al. 2024

Preprint

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The liver is the largest solid organ in the body and is primarily composed of HCs, ECs, KCs, and HSCs, which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion ofBmp9/10in different liver cell types and demonstrated that HSCs were the major source of BMP9 and BMP10 in the liver. Using transgenic ALK1 (receptor for BMP9/10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs. KCs fromBmp9/10HSC-KO(conditional deletion ofBmp9/10from HSCs) mice lost their signature gene expression, such as ID1/3, CLEC4F, VSIG4 and CLEC2, and were replaced by monocyte-derived macrophages. ECs fromBmp9/10HSC-KOmice also lost their identity and were transdifferentiated into continuous ECs, ultimately leading to collagen IV deposition and liver fibrosis. Hepatic ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2 and Rspo3, to regulate liver iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs fromBmp9/10HSC-KOmice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of BMP9/10 to maintain liver health.

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Section: Resultsmentioning

confidence: 99%

BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

Zhao,

Huang,

et al. 2024

Preprint

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“…We collected prefrontal cortex (PFC) tissue, based on the relevance of this brain region to social behavior and its disruption in disorders such as ASD, from female and male mice at 24 and at 72 hr following saline or LPS challenge and performed flow cytometry to determine the extent of brain infiltration. We defined microglia in the PFC as CD11b + CD45 lo cells, and infiltrating monocytes as CD11b + CD45 hi cells (Philpott et al, 2022)(Supplemental Fig. 2A).…”

Section: Social Behavior Differences Are Not Caused By Sex-biased Mon...mentioning

confidence: 99%

Gonadal Hormones Impart Male-Biased Behavioral Vulnerabilities to Immune Activation via Microglial Mitochondrial Function

Bordt

Moya

et al. 2022

Preprint

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There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

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Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function

Bordt,

Moya,

et al. 2024

Brain, Behavior, and Immunity

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RXRα Regulates the Development of Resident Tissue Macrophages

Cited by 12 publications

References 31 publications

BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

Gonadal Hormones Impart Male-Biased Behavioral Vulnerabilities to Immune Activation via Microglial Mitochondrial Function

Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function

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