Work

Inflammatory injury? NO problem! Depletion of macrophage NOS1 signaling protects host from neutrophil-mediated inflammatory injury while maintaining antimicrobial control during bacterial pneumonia 4274

Year: 2025

Type: article

Abstract: Description Bacterial pneumonia poses challenges due to the risk of lethal inflammatory injury and sepsis. Effective neutrophil (PMN) recruitment is crucial for microbial control, but balancing this with restrained injurious effector functions remains unclear. In an LPS model, we showed that nitric oxide synthase 1, NOS1-/- mice were protected from injury and death, with NOS1-/- macrophages exhibiting reduced pro-inflammatory gene expression. To explore the macrophage-specific role of NOS1, we developed a CX3CR1-driven cre mouse model (NOS1ΔMac) for targeted macrophage depletion. We hypothesize that NOS1-independent inflammatory signals from macrophages program PMNs to limit injury while maintaining antimicrobial activity. In a Klebsiella p. infection model, NOS1ΔMac animals showed improved survival, reduced inflammatory injury, and preserved lung function. Post-infection analysis revealed less histological injury, edema, and improved bacterial containment in the lungs and liver, with no differences in PMN recruitment. To study PMN programming in vitro, we exposed primary PMNs to conditioned media from LPS-treated control or NOS1ΔMac macrophages. PMNs treated with control media showed significantly higher ROS production, NETosis, and inflammatory markers, compared to those treated with NOS1ΔMac media. Our data suggest that antimicrobial control can occur without inflammatory injury, offering therapeutic insights for conditions like sepsis by targeting macrophage NOS1-dependent pathways. Funding Sources This work would not be possible without the generosity from our funding sources: Cullen Award, NHLBI – 1R01HL 163820, AHW, WI Breast Cancer Showhouse, MCW Cancer Center and Research Committee. All animal work is done in accordance with MCW and IACUC standards. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.1974

Authors: Katy M. LaFond, Diego Rodrigues Coelho, Marcelo G. Bonini, Benjamin N. Gantner

Institutions: Medical College of Wisconsin, Northwestern University

Language: English

Topic: Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: bronze

Funder: National Heart, Lung, and Blood Institute