Secreted phospholipase PLA2G5 acts as a hemolytic factor in sepsis
Sepsis is a systemic response to infection with life-threatening consequences such as hemolysis, a predictor of mortality risks for the disease. Here, by measuring organism-wide changes in gene expression, we discovered that the secreted phospholipase PLA2G5 is induced in colon cell types during sepsis. The genetic deletion of Pla2g5 and treatment with a PLA2G5 antibody were both associated with protection from lethal sepsis. Treatment with a PLA2G5 antibody during sepsis was associated with increased splenic red pulp macrophages and improved iron homeostasis, linking PLA2G5 to red blood cell homeostasis during sepsis. Mechanistically, bloodborne PLA2G5 led to intravascular hemolysis through its lipolytic activity on red blood cell membranes. In humans with sepsis due to bacterial, fungal, or viral infections, the serum level of PLA2G5 was elevated and predictive of disease severity and mortality. We conclude that sepsis corrupts PLA2G5 into becoming an intravascular hemolytic factor which is toxic for host red blood cells.
Authors
- Tatsuya Saitoh
- Michihiro Takahama (ORCID: https://orcid.org/0000-0003-0457-3669)
- K.S. Wolfe (ORCID: https://orcid.org/0000-0001-5565-3496)
- Denis Cipurko
- Anna E. Czapar (ORCID: https://orcid.org/0000-0001-5380-676X)
- Yuki Nagasaki (ORCID: https://orcid.org/0000-0002-4717-6877)
- Nicolas Chevrier (ORCID: https://orcid.org/0000-0002-9667-4506)
- Steven M. Dudek
- Yoshimi Miki (ORCID: https://orcid.org/0000-0002-8587-0333)
- Tadafumi Kawamoto (ORCID: https://orcid.org/0000-0002-1450-2381)
- Gabriella Richey
- Makoto Murakami (ORCID: https://orcid.org/0000-0002-4565-6017)
- Yoshitaka Taketomi (ORCID: https://orcid.org/0000-0003-4094-9846)
- Tatsuki Ueda (ORCID: https://orcid.org/0000-0002-6705-5626)
- Fabian Hernandez
- Madison Plaster
Institutions
- Tsurumi University (JP)
- Japan Agency for Medical Research and Development (JP)
- University of Illinois Chicago (US)
- University of Chicago (US)
- University of Chicago Medical Center (US)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Osaka University Hospital (JP)
- Pulmonary and Critical Care Associates (US)
- The University of Tokyo (JP)
- Osaka University of Pharmaceutical Sciences (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-04-30
- DOI
- https://doi.org/10.1172/jci195001
- Primary Topic
- Neurological diseases and metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Silicon Valley Community Foundation
- University of Chicago
- University of Michigan
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Chan Zuckerberg Initiative
- Astellas Foundation for Research on Metabolic Disorders
- Senri Life Science Foundation
- National Institutes of Health
- Japan Society for the Promotion of Science