The Role of Trained Immunity in Brain-Body Communication and Secondary Organ Dysfunction

Objective

Trained immunity (TRIM) is a novel concept in immunology. Maladaptive TRIM offers a framework to understand how innate immune memory drives systemic inflammatory changes and inter-organ communication, leading to secondary tissue dysfunction. Initially identified in infection, TRIM has now been linked to sterile injuries like myocardial infarction (MI) and ischemic stroke. These injuries induce persistent inflammatory changes, propagating maladaptive immune responses across organ systems. Despite its significance, the exact mechanisms of maladaptive TRIM, its role in inter-organ communication, and its relevance to human health remain insufficiently explored. My research has shown that sterile injuries induce epigenetic reprogramming in bone marrow hematopoietic stem and progenitor cells (HSPC), leading to systemic immune activation that exacerbates secondary organ dysfunction. Leveraging my expertise across established research fields (immunology, neuroscience, cardiology, clinical medicine), access to cutting-edge technologies including spatial multi-omics, and new translational models, I am uniquely positioned to address these challenges. The project has four specific aims: Aim 1: Characterize the epigenetic landscape of bone marrow niches in response to sterile tissue injury. Aim 2: Identify disease- and compartment-specific characteristics of bone marrow alterations. Aim 3: Investigate the causal role of maladaptive TRIM in secondary organ dysfunctions. Aim 4: Assess the translational relevance of TRIM. TRAINED will establish TRIM as a key pathomechanism in sterile tissue injuries, identifying key molecular and cellular targets that drive multimorbidity. By defining a detailed mechanistic framework, this project will lay the foundation for the development of novel therapies preventing maladaptive inter-organ communication in sterile injury.