Intermittent Cobalt (II, III) Oxide Exposure Exacerbates Inflammatory Injury through Tumor Necrosis Factor-Alpha-Dependent Bone Marrow-Mediated Trained Immunity.

Abstract

Environmental nanoparticle exposure in real-world scenarios is often intermittent rather than continuous, yet its associated risks and mechanisms remain poorly understood. This study investigates whether such intermittent exposure induces maladaptive trained immunity within the bone marrow (BM) to drive inflammatory injury. We establish a physiologically relevant "prime-rest-rechallenge" mouse model of intermittent inhalation to cobalt (II, III) oxide (Co₃O₄) nanoparticles, a representative environmental stressor. Using this model, we provide <i>in vivo</i> evidence that intermittent Co₃O₄ exposure establishes a lasting, maladaptive immune memory in the BM─termed BM-mediated trained immunity. Primary Co₃O₄ exposure induces hematopoietic reprogramming toward a myeloid-biased phenotype, a state that is restored following a rest period. Upon secondary challenge, this reprogrammed state drives an augmented myelopoietic response, characterized by a 1.5-fold expansion of myeloid progenitors and a sustained output of mature myeloid cells. Integrated bioinformatics analysis and functional validation identify tumor necrosis factor-alpha (TNF-α), the highest-degree node (degree = 17) in the interaction network, as the central mediator orchestrating this BM-mediated trained immunity. <i>In vivo</i> TNF-α neutralization abrogates this trained myelopoietic phenotype. Furthermore, this Co₃O₄-induced, TNF-α-dependent trained immunity exacerbates inflammatory injury in distant organs, including the heart and brain. Our work establishes intermittent exposure as a critical yet overlooked risk paradigm, reveals trained immunity as a mechanistic link between nanoparticles and inflammatory disorders, and positions TNF-α as a potential therapeutic target to mitigate pollution-related risks.