Iron deficiency worsens inflammatory tissue injury: mechanisms and outcomes

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Iron deficiency (ID) and iron deficiency anemia (IDA) are major contributors to the global burden of disease, with ~1.25 billion cases of IDA worldwide. In the United States, ID and IDA are more common in disadvantaged populations, including the low-income groups, Indigenous peoples, and migrants from low-to-middle income countries. The recent realization of the importance of ID as a comorbidity that alters outcomes underscores the need to broaden investigation of the effects of ID in different conditions. We observed in a mouse model an unexpected strong adverse interaction between iron deficiency and inflammation that resulted in increased production of inflammatory mediators and exacerbated apoptosis and tissue injury in the lung, kidney, liver and spleen. This suggests that ID may worsen tissue injury in sepsis, and potentially other inflammatory conditions. Considering the high prevalence of concomitant ID and inflammation around the world, the problem has compelling translational importance. We here propose to define the molecular mechanisms underlying the adverse synergy between ID and inflammatory injury, focusing on macrophage-mediated inflammation, endothelial sensitization to inflammation, and resulting lung and kidney injury. In preliminary work, we uncovered a novel mechanistic link between ID and inflammatory damage whereby ID potentiates inflammation through the NF-κB pathway, and also alters tissue responsiveness to inflammation by modulating the CREB transcription factor and ER stress. We will address the mechanisms in the following aims: Aim 1. Define the mechanism by which iron deficiency potentiates inflammation—In a mouse model of sterile inflammation we will examine the effect of ID on macrophage phenotype, the NF-kB pathway and systemic inflammation. Aim 2. Determine the mechanisms by which iron deficiency potentiates inflammatory lung injury—We will characterize adverse synergy between ID and acute inflammation (LPS) in the lung, and determine how ID modifies the role of CREB transcriptional factor in acute lung injury. Aim 3. Determine the mechanisms by which iron deficiency potentiates inflammatory kidney injury—We will characterize adverse synergy between ID and acute inflammation (LPS) in the kidney, and determine how ID modifies ER stress in acute kidney injury. These concepts and findings will have both fundamental and translational impact and may be relevant to many inflammatory disorders. They may guide future clinical studies to examine the adverse interaction in human conditions, and to ameliorate inflammatory injury through more effective management of iron deficiency.