ACE produces an unidentified peptide that dramatically enhances immune cell function against tumors, infections, and Alzheimer's — while ACE inhibitor drugs may inadvertently suppress this immune defense.
Unknown peptideACE produces an as-yet-unidentified peptide (not angiotensin II) that dramatically enhances macrophage and neutrophil immune function
What the researchers found
ACE (angiotensin-converting enzyme) has a second, nonclassical function beyond making angiotensin II: when immune cells like macrophages and neutrophils increase their ACE expression, it dramatically boosts their ability to fight tumors, infections, atherosclerosis, and Alzheimer's disease. Genetically modified 'ACE 10/10' mice with increased macrophage ACE were much more resistant to all these conditions. This immune-boosting effect works through an unknown peptide (not angiotensin II) that shifts macrophage metabolism toward increased mitochondrial fat burning and ATP production. Conversely, ACE inhibitor drugs reduce neutrophil bacteria-killing ability in both mice and humans.
Why it matters
ACE inhibitors are among the most prescribed drugs worldwide for blood pressure. This review reveals that ACE does far more than regulate blood pressure — it produces an unidentified peptide that supercharges immune cell function. This has profound implications: ACE inhibitors may inadvertently weaken immune responses, and identifying the mystery peptide could create new treatments for cancer, infections, atherosclerosis, and Alzheimer's disease.
How the study worked
This is a review article summarizing the authors' extensive research program on nonclassical ACE functions. It draws on data from genetically modified mouse models (ACE 10/10 mice with enhanced macrophage ACE, and NeuACE mice with enhanced neutrophil ACE), metabolic profiling, and studies of ACE inhibitor effects on immune function in mice and humans.
Who was studied
Not applicable (review article covering mouse model research and mechanistic studies)
What this study cannot tell us
Most evidence comes from genetically modified mouse models. The unknown peptide responsible for the immune effects has not been identified or purified. The clinical significance of ACE inhibitor-induced immune suppression in humans needs further study. The review is largely from one research group's body of work.
How to read the evidence
This is a review article summarizing primarily mouse model research from a single research group. The findings are compelling but largely preclinical and the key peptide mediator remains unidentified.
When this study was published
Published in 2024, this is a current review reflecting cutting-edge understanding of ACE's nonclassical immune functions.
The bigger picture
ACE inhibitors are taken by hundreds of millions of people. If these drugs weaken immune function, even modestly, the public health implications are enormous. Conversely, if the mystery peptide produced by ACE can be identified and synthesized, it could become a new class of immune-boosting therapy for cancer, chronic infections, and neurodegenerative diseases. This is a rare example where a well-studied enzyme turns out to have a completely hidden function.
Questions still open
- What is the identity of the unknown peptide that ACE produces to enhance immune function?
- Do patients on long-term ACE inhibitors have measurably weaker immune responses to infections or cancer?
- Could the immune-boosting peptide be administered alongside ACE inhibitors to maintain blood pressure control while preserving immune function?
Common questions
Could ACE inhibitors weaken the immune system?
What is the 'mystery peptide' produced by ACE?
Read the original research
Classical and nonclassical effects of angiotensin-converting enzyme: How increased ACE enhances myeloid immune function.
The Journal of biological chemistry, 300(6), 107388
Citation
Bernstein, Kenneth E; Cao, DuoYao; Shibata, Tomohiro; Saito, Suguru; Bernstein, Ellen A; Nishi, Erika; Yamashita, Michifumi; Tourtellotte, Warren G; Zhao, Tuantuan V; Khan, Zakir. (2024). Classical and nonclassical effects of angiotensin-converting enzyme: How increased ACE enhances myeloid immune function.. The Journal of biological chemistry, 300(6), 107388. https://doi.org/10.1016/j.jbc.2024.107388