In nearly all tissues, there is a continual turnover of cells, usually by the process of apoptosis. In healthy tissues, the dying cells are quickly recognized and cleared by phagocytes. However, failure to promptly clear apoptotic cells leads to their secondary necrosis, release of toxic cytoplasmic contents, and inflammation within tissues. The basis for this project stems from the initial observations by the Ravichandran laboratory that apoptotic cells via soluble factors termed find-me signals attract phagocytes. Our work identified the nucleotides ATP and UTP as one type of find-me signal and critical for clearance of apoptotic cells in vivo (Elliott et al., Nature 2009). Subsequently, in collaboration with two other Project leaders on this P01 (Doug Bayliss and Brant Isakson), we showed that pannexin channels are opened up during early apoptosis, leading to release of nucleotides, setting up a find-me signal gradient to attract phagocytes (Chekeni et al., Nature 2010). PANX1 gene in humans has been linked to heart disease, atherosclerosis, as well as airway inflammation and airway disease. This proposal will directly test the hypothesis that pannexin channels contribute to efficient apoptotic cell clearance, helping limit tissue inflammation, and pathologies associated with atherosclerosis and airway inflammation.
In Aim 1, we will test whether pannexin channel-mediated nucleotide release by dying macrophages (e.g. in atherosclerotic lesions) influences monocyte recruitment to the vascular lesions, and whether this affects atherosclerosis progression, and plaque stability. We will also test specific candidate small molecules that we have identified as potential inhibitors/modifiers of Panx1 channels.
In Aim 2, via global and cell type specific conditional Panx1 knockout mice, we will address the role of Panx1 in airway inflammation, based on our recent observations (Juncadella et al., Nature, 2012). Collectively, these studies should yield new knowledge on communication between dying cells and phagocytes, with direct implications for atherosclerosis and airway inflammation. These studies can also provide a rationale for considering Panx1 channels as a suitable target for therapeutic development and possibly identify new small molecules for such targeting.

Public Health Relevance

Prompt clearance of dying corpses in tissues is essential for preventing induction of inflammation. A key step in apoptotic cell removal is the release of nucleotide find-me signals via the pannexin channels, attracting phagocytes to facilitate clearance. This proposal addresses how the pannexin channels and the cell clearance process influence the onset and progression of atherosclerosis and lung inflammation. The proposed studies will also help identify selective and beneficial pharmacological targeting of pannexins in specific diseases.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
1P01HL120840-01A1
Application #
8787173
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Keller 4th, T C Stevenson; Butcher, Joshua T; Broseghini-Filho, Gilson Brás et al. (2016) Modulating Vascular Hemodynamics With an Alpha Globin Mimetic Peptide (HbαX). Hypertension 68:1494-1503
Penberthy, Kristen K; Ravichandran, Kodi S (2016) Apoptotic cell recognition receptors and scavenger receptors. Immunol Rev 269:44-59
Elliott, Michael R; Ravichandran, Kodi S (2016) The Dynamics of Apoptotic Cell Clearance. Dev Cell 38:147-60
Medina, C B; Ravichandran, K S (2016) Do not let death do us part: 'find-me' signals in communication between dying cells and the phagocytes. Cell Death Differ 23:979-89
Billaud, Marie; Chiu, Yu-Hsin; Lohman, Alexander W et al. (2015) A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells. Sci Signal 8:ra17
Shu, Xiaohong; Keller 4th, T C Stevenson; Begandt, Daniela et al. (2015) Endothelial nitric oxide synthase in the microcirculation. Cell Mol Life Sci 72:4561-75
Arandjelovic, Sanja; Ravichandran, Kodi S (2015) Phagocytosis of apoptotic cells in homeostasis. Nat Immunol 16:907-17
Lohman, Alexander W; Leskov, Igor L; Butcher, Joshua T et al. (2015) Pannexin 1 channels regulate leukocyte emigration through the venous endothelium during acute inflammation. Nat Commun 6:7965
Adamson, Samantha E; Meher, Akshaya K; Chiu, Yu-Hsin et al. (2015) Pannexin 1 is required for full activation of insulin-stimulated glucose uptake in adipocytes. Mol Metab 4:610-8
Good, Miranda E; Begandt, Daniela; DeLalio, Leon J et al. (2015) Emerging concepts regarding pannexin 1 in the vasculature. Biochem Soc Trans 43:495-501

Showing the most recent 10 out of 13 publications