Matthew J Delano

Matthew J Delano

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Obesity promotes type 2 diabetes (T2D) the 3rd leading cause of death in the United States and accounts for $237 billion healthcare cost. T2D and obesity promote infections that cause sepsis, the leading cause of mortality in the intensive care unit following traumatic injury. Despite advances in supportive care, sepsis mortality remains 25% and escalates over time. Survival from sepsis depends on emergency myelopoiesis of macrophages (MΦ) to clear bacteria and deescalate inflammation. Resolving inflammation requires MΦ polarization from pro-inflammatory M1 to anti-inflammatory MΦ states. The MΦ ability to polarize depends on the intrinsic plasticity inherited from hematopoietic stem and progenitor cells (HSPCs) during emergency myelopoiesis. Our published data in trauma and sepsis in mice and humans demonstrates that obesity and T2D alter HSPC myelopoiesis, inhibit MΦ plasticity and prevent M1Φ polarization to other functional MΦ states. However, the impact of altered MΦ myelopoiesis and restricted M1Φ polarity on sepsis pathogenesis is unknown. A critical need exists to understand the mechanisms by which obesity and T2D alter myelopoiesis, inhibit MΦ plasticity and prevent MΦ polarity to promote bacterial sepsis mortality. We hypothesize that obesity and T2D prime HSPC myelopoiesis to produce dysfunctional M1Φs incapable of bacterial clearance, and effective polarization which hinder inflammation resolution during sepsis and cause mortality. We will test the hypothesis with the following aims that, when completed, will fill the current knowledge void and improve sepsis survival. In Aim 1 we will determine the mechanisms in T2D and obesity that alter myelopoiesis in bacterial sepsis. The findings will reveal how obesity and T2D prime HSPCs and alter myelopoiesis to prevent MΦ polarity in mice and humans with sepsis. In Aim 2 we will identify the functional consequences of obese, T2D M1Φs unable to polarize to other activation states during bacterial sepsis. We will explore how restricted MΦ polarity effects immune cell responses and cytokine production to define how T2D and obesity impede inflammation resolution. The data generated will identify new pathways that promote aberrant myeloid production, restricted MΦ plasticity and prevent inflammation resolution during bacterial sepsis. Novel targeted therapies can then be developed for clinical implementation for bacterial eradication, wound healing and survival from sepsis in obesity and T2D.