NIF inhibits the ability of PMNs to produce inflammatory cytokines and reactive oxygen species in response to <i>C. albicans</i>

Invasive fungal infections are associated with high mortality rates. The proliferation of <i>C. albicans</i> is mainly limited by the innate immune system, in which phagocytic cells, especially polymorphonuclear leukocytes (PMNs), play an important role. Several studies have shown that antihypertensive drugs can cause an increased risk of infection, but whether antihypertensive drugs affect the killing activity of PMNs against <i>C. albicans</i> has not been studied. Here, we demonstrated that nifedipine (NIF) inhibits neutrophil killing of <i>C. albicans</i>. NIF reduces the production of reactive oxygen species (ROS) and pro-inflammatory cytokines in PMNs by inhibiting the phosphorylation of NF-κB, thereby inhibiting killing of PMNs against <i>C. albicans</i>. Next, using the <i>C. albicans</i> injection mouse model of fungal sepsis, we observed NIF can exacerbate infection in mice. Finally, our study identified patients with fungal infections from the Medical Information Mart for Intensive Care (MIMIC-IV) database, and analysis of the data showed that NIF led to increased length of stay. In summary, we have found that the antihypertensive drug NIF can negatively regulate antifungal immunity by inhibiting the phosphorylation of the PMNs transcription factor NF-κB.IMPORTANCEIn this study, we demonstrated that NIF inhibited the ability of neutrophils to kill <i>C. albicans</i> by suppressing NF-κB phosphorylation, thereby reducing the production of ROS and pro-inflammatory cytokines in neutrophils. Furthermore, analysis of the MIMIC database revealed that NIF prolonged hospitalization duration in patients with fungal infections. Collectively, our findings suggest that antihypertensive drugs may exert adverse effects on the treatment of fungal infections, which could provide new insights for optimizing therapeutic strategies in clinical practice.