Plasma and tissue levels of High Mobility Group Box Protein 1 (HMGB1), a nuclear non-histone DNA-binding protein, are elevated for prolonged periods in chronic and acute inflammatory conditions, such as those associated with hemorrhage, trauma, or sepsis. Blockade of HMGB1 reduces organ dysfunction and improves survival in these pathophysiologic conditions. While HMGB1 was initially postulated to have potent proinflammatory properties and to contribute to acute lung injury, multiple organ dysfunction, and mortality by directly activating macrophages and other cellular populations, results from our laboratory and others have demonstrated that HMGB1 itself does not induce macrophages to produce cytokines or other proinflammatory mediators. In recent studies, we found that HMGB1 inhibits phagocytosis of apoptotic neutrophils by macrophages in vivo and in vitro. Phagocytosis of apoptotic cells, also called efferocytosis, is an essential feature of immune responses and is critical to resolution of inflammation. Our findings therefore describe a novel mechanism through which HMGB1 may be involved in enhancing inflammatory responses and contributing to the development, perpetuation, and severity of organ dysfunction associated with severe infection, blood loss, or trauma. Our hypothesis is that: HMGB1, by acting as a "don't eat me" signal that directly affects the accumulation and clearance of neutrophils in the lungs and other organs, is centrally involved in determining the development, perpetuation, and severity of hemorrhage and sepsis induced organ dysfunction.
Our specific aims are: 1) To determine the mechanisms through which HMGB1 modulates phagocytosis and clearance of neutrophils by identifying the receptors on macrophages that are engaged by HMGB1 and that participate in modulating phagocytosis of apoptotic neutrophils, delineating the effects of HMGB1 in modifying the expression of receptors and ligands involved in phagocytosis of neutrophils, examining alterations in intracellular signaling pathways that occur in macrophages exposed to apoptotic neutrophils associated with HMGB1, and measuring the expression of pro- and anti-inflammatory cytokines by macrophages after ingestion of apoptotic neutrophils either associated with or not associated with HMGB1;2) To examine the role of HMGB1 binding co-factors, including IL-12, LPS, TNF-1, and bacterial DNA, in modulating the ability of HMGB1 to affect phagocytosis of apoptotic neutrophils and activation of macrophages during efferocytosis;and 3) To determine the in vivo mechanisms through which HMGB1 contributes to the development and severity of acute lung injury, by identifying the importance of HMGB1 in modulating phagocytosis of apoptotic neutrophils in the lungs, delineating how interactions between HMGB1 and proinflammatory mediators affect phagocytosis of apoptotic neutrophils in the lungs, and examining the importance of HMGB1 in modulating phagocytosis of apoptotic neutrophils in the lungs during hemorrhage, TLR2, or TLR4 induced acute lung injury. The proposed studies should not only improve understanding of cellular mechanisms leading to ALI and organ system failure after hemorrhage, severe trauma, and sepsis, but also are likely to suggest novel therapeutic interventions aimed at decreasing the incidence and/or severity of organ system dysfunction and improving survival in patients with these life-threatening conditions.

Public Health Relevance

Description Plasma and tissue levels of High Mobility Group Box Protein 1 (HMGB1) are elevated for prolonged periods in chronic and acute inflammatory conditions. Our recent findings, showing that HMGB1 can diminish the uptake and clearance of neutrophils by macrophages, suggest a novel mechanism through which HMGB1 participates in the development of organ failure after hemorrhage, trauma, and life-threatening infection. The studies proposed in this application should not only improve understanding of cellular mechanisms leading to organ dysfunction and death after trauma, hemorrhage, or sepsis, but also are likely to suggest novel therapeutic interventions aimed at improving outcome for patients suffering from these clinical problems.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM087748-04
Application #
8307955
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$297,939
Indirect Cost
$94,568
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Jiang, Shaoning; Park, Dae Won; Tadie, Jean-Marc et al. (2014) Human resistin promotes neutrophil proinflammatory activation and neutrophil extracellular trap formation and increases severity of acute lung injury. J Immunol 192:4795-803
Tadie, Jean-Marc; Bae, Hong-Beom; Jiang, Shaoning et al. (2013) HMGB1 promotes neutrophil extracellular trap formation through interactions with Toll-like receptor 4. Am J Physiol Lung Cell Mol Physiol 304:L342-9
Jiang, Shaoning; Park, Dae Won; Stigler, William S et al. (2013) Mitochondria and AMP-activated protein kinase-dependent mechanism of efferocytosis. J Biol Chem 288:26013-26
Bae, Hong-Beom; Tadie, Jean-Marc; Jiang, Shaoning et al. (2013) Vitronectin inhibits efferocytosis through interactions with apoptotic cells as well as with macrophages. J Immunol 190:2273-81
Bae, Hong-Beom; Zmijewski, Jaroslaw W; Deshane, Jessy S et al. (2012) Vitronectin inhibits neutrophil apoptosis through activation of integrin-associated signaling pathways. Am J Respir Cell Mol Biol 46:790-6
Lin, Wan-Yu; Tiwari, Hemant K; Gao, Guimin et al. (2012) Similarity-based multimarker association tests for continuous traits. Ann Hum Genet 76:246-60
Tadie, Jean-Marc; Bae, Hong-Beom; Deshane, Jessy S et al. (2012) Toll-like receptor 4 engagement inhibits adenosine 5'-monophosphate-activated protein kinase activation through a high mobility group box 1 protein-dependent mechanism. Mol Med 18:659-68
Tadie, Jean-Marc; Bae, Hong-Beom; Banerjee, Sami et al. (2012) Differential activation of RAGE by HMGB1 modulates neutrophil-associated NADPH oxidase activity and bacterial killing. Am J Physiol Cell Physiol 302:C249-56
Davis, Kasey; Banerjee, Sami; Friggeri, Arnaud et al. (2012) Poly(ADP-ribosyl)ation of high mobility group box 1 (HMGB1) protein enhances inhibition of efferocytosis. Mol Med 18:359-69
Bae, Hong-Beom; Zmijewski, Jaroslaw W; Deshane, Jessy S et al. (2011) AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. FASEB J 25:4358-68

Showing the most recent 10 out of 24 publications