The leading causes of death following serious burn injury are sepsis and multiple system organ failure secondary to profound innate and adaptive immune dysfunction, though the controlling mechanism for the response is unknown. Major determinants of immune activity are the innate Toll-like receptor (TLR) and nucleotide binding oligomerization domain (NOD)-like receptor (NLR) families. These are expressed by many immune cells and their primary function is to sense microbial molecules leading to cytokine release or cell death. Our overall hypothesis is that impairment of both the innate and adaptive immune systems after burn injury is mediated directly by TLR and NLR signaling. The proposed experiments are designed to test this hypothesis during both immunopathogenic phases after burn injury and investigate innate receptor-blockade as a possible immunotherapeutic approach for clinically relevant issues facing burn patients. First, to determine the mechanism by which TLR and NLR signaling controls the innate immune system after injury: We will determine phenotypic and functional (cytokine and cell death) changes of MF and DC using an animal model of burn injury. We will correlate TLR and NLR expression with changes in their function during early and late after burn injury. We will then use TLR and NLR deficient mice to validate that the altered burn injury-mediated innate immune response is mediated through innate-receptor signaling. Second, to determine the mechanism by which innate signaling controls the adaptive immune response after burn injury: We will examine the effect of burn injury on the expression and activation of TLR and NLR on CD4+ and CD8+ T cells and relevant T cell subsets. We will correlate changes in TLR and NLR expression with the ability of T cells to elicit an adaptive immune response. To determine the relative importance of both direct (expression of innate receptors on T cells) and indirect (expression on MF or DC) innate receptor expression in mediating the adaptive response to burn injury, we will transfer T cells or MF and DC, deficient in innate signaling receptors, into burn or sham recipients and test T cell immune function and survival. Third, to demonstrate that innate receptors are critical for the dysfunctional immunologic response to burn injury in vivo: We will use mice deficient in TLR and NLR innate signaling to examine the role of innate receptors in mediating skin allograft rejection and preventing establishment of effective immune tolerance after burn. We will examine the importance of innate signaling pathways in mediating Pseudomonas aeruginosa susceptibility early and late after burn injury using mice deficient in TLR and NLR signaling.

Public Health Relevance

The leading causes of death following serious burn injury are uncontrolled infection and organ failure. These are due to profound problems with the patient's immune system. We propose to determine the cellular and molecular mechanisms underlying these immune problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076250-05
Application #
8445370
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2009-04-06
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$286,956
Indirect Cost
$93,067
Name
University of North Carolina Chapel Hill
Department
Surgery
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Dunn, Julia L M; Kartchner, Laurel B; Stepp, Wesley H et al. (2018) Blocking CXCL1-dependent neutrophil recruitment prevents immune damage and reduces pulmonary bacterial infection after inhalation injury. Am J Physiol Lung Cell Mol Physiol 314:L822-L834
Linz, Brandon M L; Neely, Crystal J; Kartchner, Laurel B et al. (2017) Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emergency Hematopoiesis. J Immunol 198:2426-2433
Dunn, Julia L M; Hunter, Rebecca A; Gast, Karli et al. (2016) Direct detection of blood nitric oxide reveals a burn-dependent decrease of nitric oxide in response to Pseudomonas aeruginosa infection. Burns 42:1522-1527
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