Chemotaxis allows polymorphonuclear neutrophils (PMN) to rapidly reach infected and inflamed sites. However excessive influx of PMN damages host tissues. Better knowledge of the mechanisms that control PMN chemotaxis may lead to improved treatments of inflammatory diseases. Based on our recent findings that ATP and adenosine are involved in PMN chemotaxis, we propose to study here how to regulate this purinergic signaling process in order to prevent tissue damage. Purinergic signaling has three essential components: i) sources of the extracellular ATP and adenosine;ii) purinergic receptors that response to ATP and adenosine and, iii) ecto-nucleotidases that modulate cellular responses by hydrolyzing ATP to adenosine. This proposal is based on the following working hypothesis: Chemotactic agents release ATP from PMN. ATP activates nearby P2Y2 receptors, amplifying gradient sensing. A3 adenosine receptors are recruited to the leading edge where adenosine is generated by CD39/E- NTPDase1 and alkaline phosphatase (ALP). Adenosine and positive feedback through A3 receptors drives cell migration, while negative feedback through A2a receptors facilitates membrane retraction at the back of cells. Interfering with these purinergic signaling processes inhibits chemotaxis, which ameliorates PMN-induced tissue damage and organ failure in sepsis and trauma patients. The following specific aims will be addressed: 1. Mechanism of ATP release from PMN: This section will focus on the mechanisms by which PMN release cellular ATP in response to chemotactic stimulation. Specifically, we will focus on the involvement of hTTYH3 tweety maxi-anion channels, connexin hemi-channels, and degranulation. 2. Mechanism of adenosine formation: Experiments are designed to examine the major ecto-nucleotidases that are responsible for the conversion of released ATP to adenosine. Major emphasis will be placed on the contributions of NTPDase1 and ALP. 3. Purinergic signaling complexes: We will explore the co-localization of chemotactic receptors with ATP release sites, purinergic receptors, and ecto-nucleotidases and investigate if purinergic signaling clusters, comprised of these molecules provide """"""""local excitation and global inhibition"""""""" as proposed in theoretical chemotaxis models. 4. Role of purinergic signaling in vivo: We will study the roles of P2Y2, A3, A2a, and NTPDase1 and ALP in mouse models and test the feasibility of targeting these molecules to prevent host tissue damage. The proposed studies are expected to improve our understanding of the mechanisms that control chemotaxis. This could lead to novel therapeutic approaches to ameliorate host tissue damage caused by excessive influx of activated PMN, for example, in trauma and septic shock patients.

Public Health Relevance

Chemotaxis, a key functional response of neutrophils in health and disease is still poorly understood. In this project we propose to determine how release of cellular ATP and purinergic receptors control chemotaxis and whether this control mechanism can be pharmacologically targeted to prevent inflammation and host tissue damage in trauma patients.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Minnicozzi, Michael
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Beth Israel Deaconess Medical Center
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Sumi, Yuka; Ledderose, Carola; Li, Linglin et al. (2018) Plasma Adenylate Levels are Elevated in Cardiopulmonary Arrest Patients and May Predict Mortality. Shock :
Lee, Albert H; Ledderose, Carola; Li, Xiaoou et al. (2018) Adenosine Triphosphate Release is Required for Toll-Like Receptor-Induced Monocyte/Macrophage Activation, Inflammasome Signaling, Interleukin-1? Production, and the Host Immune Response to Infection. Crit Care Med 46:e1183-e1189
Ledderose, Carola; Liu, Kaifeng; Kondo, Yutaka et al. (2018) Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration. J Clin Invest 128:3583-3594
Li, Xiaoou; Kondo, Yutaka; Bao, Yi et al. (2017) Systemic Adenosine Triphosphate Impairs Neutrophil Chemotaxis and Host Defense in Sepsis. Crit Care Med 45:e97-e104
Ledderose, Carola; Bao, Yi; Kondo, Yutaka et al. (2016) Purinergic Signaling and the Immune Response in Sepsis: A Review. Clin Ther 38:1054-65
Ledderose, Carola; Bao, Yi; Ledderose, Stephan et al. (2016) Mitochondrial Dysfunction, Depleted Purinergic Signaling, and Defective T Cell Vigilance and Immune Defense. J Infect Dis 213:456-64
Ledderose, Carola; Woehrle, Tobias; Ledderose, Stephan et al. (2016) Cutting off the power: inhibition of leukemia cell growth by pausing basal ATP release and P2X receptor signaling? Purinergic Signal 12:439-51
Qi, Baochang; Yu, Tiecheng; Wang, Chengxue et al. (2016) Shock wave-induced ATP release from osteosarcoma U2OS cells promotes cellular uptake and cytotoxicity of methotrexate. J Exp Clin Cancer Res 35:161
Ledderose, Carola; Hefti, Marco M; Chen, Yu et al. (2016) Adenosine arrests breast cancer cell motility by A3 receptor stimulation. Purinergic Signal 12:673-685
Bao, Yi; Ledderose, Carola; Graf, Amelie F et al. (2015) mTOR and differential activation of mitochondria orchestrate neutrophil chemotaxis. J Cell Biol 210:1153-64

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