Intermittent Cobalt (II, III) Oxide Exposure Exacerbates Inflammatory Injury through Tumor Necrosis...

Area of Science:

• Environmental Health
• Immunology
• Toxicology

Background:

• Real-world nanoparticle exposure is often intermittent, but its health effects and mechanisms are unclear.
• Bone marrow (BM) immune responses to intermittent environmental stressors are poorly understood.
• Investigating maladaptive trained immunity as a consequence of intermittent nanoparticle exposure.

Purpose of the Study:

• To determine if intermittent cobalt oxide nanoparticle exposure induces maladaptive trained immunity in the bone marrow.
• To elucidate the mechanisms underlying nanoparticle-induced trained immunity.
• To assess the role of tumor necrosis factor-alpha (TNF-α) in this process and its impact on distant organ inflammation.

Main Methods:

• A "prime-rest-rechallenge" mouse model using intermittent cobalt (II, III) oxide (Co₃O₄) nanoparticle inhalation.
• Hematopoietic cell analysis, bioinformatics, and functional validation.
• In vivo TNF-α neutralization experiments.

Main Results:

• Intermittent Co₃O₄ exposure induced a lasting, maladaptive immune memory in the BM (BM-mediated trained immunity).
• This involved hematopoietic reprogramming toward a myeloid-biased phenotype, leading to augmented myelopoiesis upon rechallenge.
• TNF-α was identified as the central mediator, and its neutralization abrogated the trained myelopoietic phenotype.
• Co₃O₄-induced trained immunity exacerbated inflammatory injury in the heart and brain.

Conclusions:

• Intermittent nanoparticle exposure represents a critical risk paradigm.
• Trained immunity in the bone marrow is a key mechanism linking nanoparticles to inflammatory disorders.
• TNF-α is a potential therapeutic target for mitigating risks associated with environmental nanoparticle exposure.