Type I interferon enhances necroptosis of <i>Salmonella</i> Typhimurium–infected macrophages by impairing antioxidative stress responses

Fischer

The Journal of Immunology

et al. 2020

Self Cite

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative bacterium that induces cell death of macrophages as a key virulence strategy. We have previously demonstrated that the induction of macrophage death is dependent on the host's type I IFN (IFN-I) response. IFN-I signaling has been shown to induce tripartite motif (TRIM) 21, an E3 ubiquitin ligase with critical functions in autoimmune disease and antiviral immunity. However, the importance and regulation of TRIM21 during bacterial infection remains poorly understood. In this study, we investigated the role of TRIM21 upon S. Typhimurium infection of murine bone marrow-derived macrophages. Although Trim21 expression was induced in an IFN-I-dependent manner, we found that TRIM21 levels were mainly regulated posttranscriptionally. Following TLR4 activation, TRIM21 was transiently degraded via the lysosomal pathway by chaperone-mediated autophagy (CMA). However, S. Typhimurium-induced mTORC2 signaling led to phosphorylation of Akt at S473, which subsequently impaired TRIM21 degradation by attenuating CMA. Elevated TRIM21 levels promoted macrophage death associated with reduced transcription of NF erythroid 2-related factor 2 (NRF2)-dependent antioxidative genes. Collectively, our results identify IFN-I-inducible TRIM21 as a negative regulator of innate immune responses to S. Typhimurium and a previously unrecognized substrate of CMA. To our knowledge, this is the first study reporting that a member of the TRIM family is degraded by the lysosomal pathway.

“…In accordance with our previous work (25,26), S. Typhimuriuminduced cell death of macrophages after 1 and 6 h of infection ( Fig. 2A).…”

Section: Trim21 Promotes Cell Death Of S Typhimurium-infected Macropsupporting

confidence: 93%

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confidence: 99%

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confidence: 99%

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TRIM21 Is Targeted for Chaperone-Mediated Autophagy during Salmonella Typhimurium Infection

Fischer

The Journal of Immunology

et al. 2020

Self Cite

“…Our findings suggest that IFN-I signaling can modify innate defense in the epithelial as well as the immune compartment and is complementary and compatible with previously proposed mechanisms for IFN-I-enhanced Stm infection in bone-marrow derived immune cells. Such mechanisms include elevated macrophage necroptosis (Hos et al, 2017; Robinson et al, 2012) and transcriptional reprogramming (Perkins et al, 2015), altered dendritic cell homeostasis (Stefan et al, 2017), and increased neutrophil-mediated inflammation (Wilson et al, 2019). The role of IFN-I modulation of lysosome function to Stm infection in non-epithelial cells, such as macrophages, requires further study.…”

Section: Discussionmentioning

confidence: 99%

Functional remodeling of lysosomes by type I interferon modifies host defense

Zhang

Zoued

Liu

et al. 2020

Preprint

SUMMARYOrganelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen Salmonella led us to discover that type I interferon (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I-stimulated genes including Ifitm3, Slc15a3, and Cnp contribute to lysosome acidification. IFN-I-dependent lysosome acidification stimulated intracellular Salmonella virulence gene expression, leading to rupture of the Salmonella-containing vacuole and host cell death. Moreover, IFN-I signaling promoted in vivo Salmonella pathogenesis in the intestinal epithelium, where Salmonella initiates infection. Our findings explain how an intracellular bacterial pathogen co-opts epithelial IFN-I signaling. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.

“…Nrf2 has been recently reported to inhibit STING-dependent IFN-I responses (46)(47)(48), and IFN-I signaling can limit microbial clearance by dysregulating Nrf2 target gene expression (49,50). We therefore utilized IFNAR-deficient cohorts to examine whether hyperactive IFN-I signaling contributes to Nrf2 suppression in mutator macrophages.…”

Section: Ifn-i Signaling Represses Nrf2 Activity and Drives Pro-inflamentioning

confidence: 99%

Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

Lei

Martinez

Torres-Odio

et al. 2020

Preprint

Mitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.