Cellular Mechanisms of Immune and Hematopoietic Dysfunction Following Radiation and Burn Injuries

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  • March 20, 2019
Creator
  • Linz, Brandon
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The immune system has evolved to protect the body against damage from infection, disease, or injury. Severe injuries, such as large burns or radiation exposures, induce profound immune dysfunctions at the cellular and humoral levels that heighten the body’s susceptibility to infections. Despite progress made toward reducing the consequences of burn shock, translocation of intestinal bacteria and wound and pulmonary infections leading to sepsis are still major causes of mortality following a traumatic injury. Following a severe burn or radiation injury, the body must respond rapidly to activate or produce new immune cells to challenge the insult and to restore homeostasis also while preventing any bacteria from establishing an infection. Therefore, to improve patient outcomes, it is important to understand not only the immune but also the hematopoietic responses to injury and infection. NLRP12 is a member of the NLR family of proteins that are responsible for coordinating inflammatory responses upon recognition of invading pathogens and damage signals. Mutations in human NLRP12 have been linked to atopic dermatitis and hereditary periodic fevers with skin, however the mechanisms by which NLRP12 affects these conditions remain to be fully elucidated. To better understand these mechanisms, Nlrp12 knockout mice were subjected to a model of radiation-thermal combined injury. Remarkably, Nlrp12 deficient mice failed to repopulate their peripheral immune compartments in addition to a significant reduction in bone marrow cellularity. Prolonged, elevated serum concentrations of TNF in injury Nlrp12-deficient iii animals induced the stem cells responsible for the bulk of myeloid cell production to undergo apoptosis. This defect in repopulation of the peripheral immune system lead all Nlrp12 knockout animals to quickly succumb to an infectious challenge, thus highlighting the importance of Nlrp12 in responding to infection or injury. Following a radiation-thermal combined injury, wild type myeloid progenitor cells underwent apoptosis at a low level. Administration of the glycoprotein granulocyte-monocyte colony stimulating factor was evaluated as a therapeutic to stimulate stem cell maturation and production of myeloid cells following injury. Treatment resulted in increased myeloid cell production: including increases in platelets, red blood cells, immature monocytes, dendritic cells, neutrophils, and macrophages. Notably, platelets and monocytes displayed increased function, in turn decreasing mortality and response to an infectious challenge. The innate immune response was then assessed early after only burn injury. Burn mice were susceptible to an early wound infection with Pseudomonas aeruginosa as shown with increased mortality and systemic bacterial colonization. The defective bacterial clearance was associated with a neutrophil anti- inflammatory polarization phenotype (N2; IL-10+ IL-12-). This work expands on our understanding of NLRP12 function in vivo as well as insights into the cellular mechanisms of immune dysfunction and hematopoiesis following burn and radiation injuries. Furthermore, our results reveal novel treatments for improved hematopoietic and innate immune response to reduce the impact of sepsis and subsequent bacterial infections after injury.
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  • In Copyright
Advisor
  • Cairns, Bruce
  • Miao, Edward
  • Tarrant, Teresa
  • Ting, Jenny P.-Y.
  • Maile, Robert
  • Serody, Jonathan
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2016
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