Proton-activated chloride channel 1 is essential for innate host defense against bacterial sepsis.

Abstract

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 <i>de novo Pacc1</i> knockout (^-/-) mice, which presented without major immunologic abnormalities at baseline. Compared to wild-type (WT), <i>Pacc1^-/-</i> myeloid cells showed normal phagocytic uptake of acid-insensitive <i><i>Escherichia coli</i> BioParticles</i>, but impaired development of the acidifying phagolysosome using acid-sensitive <i><i>E. coli</i></i> BioParticles. Transcriptomic profiling of <i>Pacc1</i>^-/- macrophages revealed dysregulated phagolysosomal and cytokine networks (e.g., interferons). Because phagolysosomal bacterial clearance is essential to resolve infection, we challenged <i>Pacc1^-/-</i> mice with intraperitoneal gram-negative <i><i>E. coli</i></i> sepsis. <i>Pacc1^-/-</i> mice displayed increased bacterial burden, immune cell infiltration, inflammation, and lethality. In contrast, phagocytosis-independent <i><i>E. coli</i></i> lipopolysaccharide (LPS)-induced endotoxemia yielded comparable WT and <i>Pacc1^-/-</i> survival, as well as similar inflammatory responses. Finally, we engineered <i>Pacc1</i>-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, <i>LysM-Cre/Pacc1^fl/fl</i> mice exhibited impaired <i><i>E. coli</i></i> sepsis survival but indifferent endotoxemia phenotypes. In conclusion, PACC1 links sterilizing phagolysosomal activity with immune networks in sepsis pathobiology.