Phagosome-mediated anti-bacterial immunity is governed by the proton-activated chloride channel in peritoneal macrophages
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ABSTRACT:
PROVIDER: PRJNA1068182 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR27702617_1.fastq.gz | Fastqsanger.gz | |||
| SRR27702617_2.fastq.gz | Fastqsanger.gz | |||
| SRR27702622_1.fastq.gz | Fastqsanger.gz | |||
| SRR27702622_2.fastq.gz | Fastqsanger.gz |
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Project description:Phagosome-mediated degradation is a well-conserved and highly effective innate immune response against pathogen infections. However, its role in shaping immune responses remains underappreciated. The molecular mechanisms underlying how phagosomes mature are also poorly understood. Here, we identify proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion facilitates phagosomal acidification and protease activation, leading to augmented bactericidal activity in peritoneal macrophages upon Escherichia coli infection. Moreover, enhanced phagosome bacterial degradation in PAC-deficient macrophages promotes downstream STING-IRF3 activation and type 1 interferon (IFN) responses through the release of bacterial ligands. Such ligand release also activates the inflammasome, leading to gasdermin D (GSDMD) cleavage and secretion. The secreted N-terminus GSDMD directly participates in bacterial killing by forming GSDMD pores on bacterial surfaces. Eventually, this macrophage hyperactivation is terminated by pyroptotic cell death. In mice, PAC deletion in macrophages reduced overall peritoneal inflammation and proinflammatory neutrophil and monocyte infiltrations, as well as improved survival after peritoneal infection. Our study thus provides new insights into mechanisms of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation.
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Project description:Bacterial sepsis remains a devastating clinical problem. Here, we describe a protective role for the recently discovered acid-sensitive, proton-activated chloride channel, PACC1 (PAC/ASOR/TMEM206), during sepsis. Initially, we found PACC1 was enriched in healthy human and mouse mononuclear phagocytes, particularly macrophages, and differentially regulated by inflammatory stimuli, suggesting PACC1 involvement in innate immunity. To further investigate, we generated de novo Pacc1 knockout (−/−) mice, which presented without major immunologic abnormalities at baseline. Compared to wild type (WT), Pacc1−/− myeloid cells showed normal phagocytic uptake of acid-insensitive Escherichia coli BioParticles, but impaired development of the acidifying phagolysosome using acid-sensitive E. coli BioParticles. Transcriptomic profiling of Pacc1−/− macrophages revealed dysregulated phagolysosomal and cytokine networks (e.g., interferons). Because phagolysosomal bacterial clearance is essential to resolve infection, we challenged Pacc1−/− mice with intraperitoneal gram-negative E. coli sepsis. Pacc1−/− mice displayed increased bacterial burden, immune cell infiltration, inflammation, and lethality. In contrast, phagocytosis-independent E. coli lipopolysaccharide (LPS)-induced endotoxemia yielded comparable WT and Pacc1−/− survival, as well as similar inflammatory responses. Finally, we engineered Pacc1-floxed (fl/fl) mice crossed with a myeloid lineage Cre-deleter strain to interrogate myeloid cell–intrinsic PACC1 in vivo. Consistent with a predominate role for PACC1 during phagocytosis and bacterial clearance in these cells, LysM-Cre/Pacc1fl/fl mice exhibited impaired E. coli sepsis survival but indifferent endotoxemia phenotypes. In conclusion, PACC1 links sterilizing phagolysosomal activity with immune networks in sepsis pathobiology.
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