Biology subjects

Umstead, T. M.

Publications and source records attributed to Umstead, T. M..

3 recordsLinked to original sources

bioRxiv2025

The aryl hydrocarbon receptor interacting protein suppresses RNA virus-induced type I IFN and IL-6 in mouse macrophages

Aryl hydrocarbon receptor (AhR) interacting protein (AIP) suppresses type I IFN production by interacting with and preventing the nuclear translocation of the transcription factor IRF7. The kinase TBK1 phosphorylates AIP to promote IRF7 binding and the inhibition of the type I interferon (IFN) response. However, it is unknown if AIP expression in innate immune cells is important to suppress type I IFN in the context of RNA virus infection in vitro and in vivo. In this study we generated myeloid cell-specific AIP conditional knockout mice (Aipfl/flxLysM-Cre) to investigate AIP regulation of innate immune signaling in myeloid cells. Bone marrow-derived macrophages (BMDMs) from Aipfl/flxLysM-Cre mice had diminished viral replication and increased production of IFN/b and IL-6 in response to RNA virus infection. AIP-deficient macrophages exhibited increased IRF7 expression and impaired virus-induced IRF7 degradation. AIP interacted with the E3 ubiquitin ligase SOCS1 and enhanced SOCS1 stability and its interaction with IRF7 to promote the proteasomal degradation of IRF7. Aipfl/flxLysM-Cre mice exhibited improved survival upon influenza A virus (IAV) infection compared to control mice. Together, these results indicate that myeloid cell-specific AIP suppresses the innate immune response by targeting IRF7.

immunology↗

bioRxiv2021

Disruption of the surfactant protein A receptor SP-R210L (CD245α/MYO18Aα) alters respiratory function and iron sequestration in alveolar macrophages of aged mice

Previous studies demonstrated that the host defense collectins, surfactant protein A and complement component 1q, modulate tissue-dependent macrophage activation, pathogen clearance, and regulatory macrophage functions through the receptor SP-R210, which consists of two isoforms SP-R210L and SP-R210S. These isoforms are encoded by alternatively spliced mRNAs of the Myo18a MYO18A gene in mice and humans. The present study in conditional transgenic mice revealed novel age-related functions of the SP-R210L isoform in modulating pulmonary mechanics, iron sequestration in alveolar macrophages (AMs), and life-long maintenance of the alveolar macrophage population. Our findings support the novel idea that SP-R210L-deficient AMs undergo bi-directional epigenetic adaptation that results in chronic dysregulation of broncho-alveolar function, immune homeostasis, and maintenance of oncotic balance at the airway-capillary interface. Disruption of SP-R210L increases the risk for development of severe interstitial lung disease during development and aging.

physiology↗

bioRxiv2021

Genomic and epigenomic adaptation in SP-R210 (Myo18A) isoform-deficient macrophages

1Macrophages play fundamental roles in regulation of inflammatory responses to pathogens, resolution of inflammation and tissue repair, and maintenance of tissue homeostasis. The long (L) and short (S) isoforms of SP-R210/MYO18A, a macrophage receptor for surfactant protein A (SP-A) and C1q, regulate basal and inflammatory macrophage phenotype at multiple gene expression, translational, and subcellular levels in addition to their SP-A and C1q-mediated functions; disruption of L renders macrophages hyper-inflammatory, although the underlying mechanism had previously been unexplored. We asked whether disruption of the L isoform led to the hyper-inflammatory state via alteration of global genomic responses. RNA sequencing analysis of SP-R210L(DN) macrophages revealed basal and influenza induced upregulation of genes associated with inflammatory pathways, including TLR, RIG-I, NOD, and cytoplasmic DNA signaling, whereas knockdown of both SP-R210 isoforms (L and S) only resulted in increased RIG-I and NOD signaling. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed increased genome-wide deposition of the pioneer transcription factor PU.1 in SP-R210L(DN) compared to WT cells. ChIP-seq analysis of histone H3 methylation showed alterations in both repressive (H3K9me3 and H3K27me3) and transcriptionally active (H3K9me3) histone marks. Influenza A virus (IAV) infection, which stimulates an array of cytosolic and TLR-mediated antiviral mechanisms, resulted in differential redistribution between proximal promoter and distal sites and decoupling of PU.1 binding from Toll-like receptor regulated gene promoters in SP-R210L(DN) cells. Our findings suggest that SP-R210L-deficient macrophages are poised with an open PU.1-primed chromatin conformation to rapidly respond to inflammatory and metabolic stimuli.

immunology↗