Myeloid cell responsiveness to interferon-gamma is sufficient for initial resistance to Listeria monocytogenes

Eshleman, Emily M.; Bortell, Nikki; McDermott, Daniel S.; Crisler, William J; Lenz, Laurel

doi:10.1016/j.crimmu.2020.01.001

Cited by 4 publications

(5 citation statements)

References 36 publications

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“…7B). This was compatible with the well-studied immune-related responsiveness of myeloid phagocytes via IFNGR1 (Cabral-Marques et al, 2017; Ellis & Beaman, 2004; Eshleman et al, 2020). Also, Aberration in disease genes other than ligands and receptors might also disrupt intercellular communication routes by acting downstream of the receptor.…”

Section: Resultssupporting

confidence: 87%

“…For instance, owing to upregulation of IFNGR1 gene, which encodes an immunodeficiency-associated receptor, we found myeloid phagocytes as affected by this disease. Then, we found three additional disease genes that were upregulated in myeloid phagocytes and were all associated with myeloid-phagocytes–mediated immune response (Banks et al, 2021; Cabral-Marques et al, 2017; Ellis & Beaman, 2004; Eshleman et al, 2020; Stahnke et al, 2021; Suwankitwat et al, 2021; Yang et al, 2020). Thus, exploring disease genes in appropriate cellular context can enhance the mechanistic understanding of disease emergence.…”

Section: Discussionmentioning

confidence: 97%

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Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Hekselman

Vital

Ziv-Agam

et al. 2022

Preprint

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Hereditary diseases manifest clinically in certain tissues, however their affected cell types typically remain elusive. Single-cell expression studies showed that overexpression of disease-associated genes may point to the affected cell types. Here, we developed a method that infers disease-affected cell types from the preferential expression of disease-associated genes in cell types (PrEDiCT). We applied PrEDiCT to single-cell expression data of six human tissues, to infer the cell types affected in 1,113 hereditary diseases. Overall, we identified 110 cell types affected by 714 diseases. We corroborated our findings by literature text-mining and recapitulation in mouse corresponding tissues. Based on these findings, we explored features of disease-affected cell types and cell classes, highlighted cell types affected by mitochondrial diseases and heritable cancers, and identified diseases that perturb intercellular communication. This study expands our understanding of disease mechanisms and cellular vulnerability.

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Section: Resultssupporting

confidence: 87%

Section: Discussionmentioning

confidence: 97%

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Hekselman

Vital

Ziv-Agam

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…In light of this myeloid predominance, we investigated leptomeningeal IFN- γ signaling 11 . We detected elevated levels of IFN- γ in mouse LM, compared to vehicle-injected animals ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Leptomeningeal anti-tumor immunity follows unique signaling principles

Remšík

Tong

Kunes

et al. 2023

Preprint

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Metastasis to the cerebrospinal fluid (CSF)-filled leptomeninges, or leptomeningeal metastasis (LM), represents a fatal complication of cancer. Proteomic and transcriptomic analyses of human CSF reveal a substantial inflammatory infiltrate in LM. We find the solute and immune composition of CSF in the setting of LM changes dramatically, with notable enrichment in IFN-gamma signaling. To investigate the mechanistic relationships between immune cell signaling and cancer cells within the leptomeninges, we developed syngeneic lung, breast, and melanoma LM mouse models. Here we show that transgenic host mice, lacking IFN-gamma or its receptor, fail to control LM growth. Overexpression of Ifn-gamma through a targeted AAV system controls cancer cell growth independent of adaptive immunity. Instead, leptomeningeal IFN-gamma actively recruits and activates peripheral myeloid cells, generating a diverse spectrum of dendritic cell subsets. These migratory, CCR7+ dendritic cells orchestrate the influx, proliferation, and cytotoxic action of natural killer cells to control cancer cell growth in the leptomeninges. This work uncovers leptomeningeal-specific IFN-gamma signaling and suggests a novel immune-therapeutic approach against tumors within this space.

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“…Pretreatment with IFN-γ before infection confirmed the antimicrobial effect of this cytokine by decreasing L. monocytogenes growth at 12 and 24 hours, and blockade of p38 together with IFN-γ resulted in even stronger bacterial clearance (fig. S6B) ( 57 ). To narrow down the beneficial effect of p38 blockade in the context of L. monocytogenes infection, we sought to assess a potential role of p38 in restricting autophagy ( 58 ).…”

Section: Resultsmentioning

confidence: 99%

Stress signaling boosts interferon-induced gene transcription in macrophages

et al. 2022

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Promoters of antimicrobial genes function as logic boards, integrating signals of innate immune responses. One such set of genes is stimulated by interferon (IFN) signaling, and the expression of these genes [IFN-stimulated genes (ISGs)] can be further modulated by cell stress–induced pathways. Here, we investigated the global effect of stress-induced p38 mitogen-activated protein kinase (MAPK) signaling on the response of macrophages to IFN. In response to cell stress that coincided with IFN exposure, the p38 MAPK-activated transcription factors CREB and c-Jun, in addition to the IFN-activated STAT family of transcription factors, bound to ISGs. In addition, p38 MAPK signaling induced activating histone modifications at the loci of ISGs and stimulated nuclear translocation of the CREB coactivator CRTC3. These actions synergistically enhanced ISG expression. Disrupting this synergy with p38 MAPK inhibitors improved the viability of macrophages infected with Listeria monocytogenes . Our findings uncover a mechanism of transcriptional synergism and highlight the biological consequences of coincident stress-induced p38 MAPK and IFN-stimulated signal transduction.

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Myeloid cell responsiveness to interferon-gamma is sufficient for initial resistance to Listeria monocytogenes

Cited by 4 publications

References 36 publications

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Affected cell types for hundreds of Mendelian diseases revealed by analysis of human and mouse single-cell data

Leptomeningeal anti-tumor immunity follows unique signaling principles

Stress signaling boosts interferon-induced gene transcription in macrophages

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