.Importance of Defining Pathways for Recruitment and Turnover of Leukocytes in Inflammation -Inflammation is an immune cell response that leads to the accumulation of white blood cells (leukocytes) at sites of infection, injury or irritation. The extravasation of polymorphonuclear leukocytes (PMNs), primarily neutrophils, through selectin and integrin-mediated pathways, to a site of inflammation is followed by the emigration of monocytes/macrophages (Fig. 1). Released granule proteins from activated neutrophils induce further emigration of inflammatory cells to such sites, involving selectins, P2-integrins and formyl-peptide receptors. Accompanying changes in the chemokine network create a favorable local microenvironment for extravasation of additional inflammatory monocytes. Thus, for this positive feedback loop to end, inflammation must be resolved by the removal of the inflammatory insult (bacteria or wound detritus), along with eventual removal of the emigrated inflammatory cells. While resolution is clearly the key to limiting tissue injury in all types of inflammation, it is remarkable that so little is known about the mechanism of cellular turnover and the factors promoting the resolution of inflammation. It has been thought that resolution occurs through spontaneous apoptosis of neutrophils and their subsequent phagocytosis and engulfment(4). Surprisingly, however, neutrophil apoptosis in vivo is not a major factor in regulating their numbers in inflammation. Unlike T cells, which accumulate following perturbation of pathways involved in leukocyte apoptosis(5,6), inhibition of neutrophil apoptosis does not greatly alter neutrophil turnover in vivo, but the mechanism(s) of targeting viable neutrophils for removal is unknown (5-8). Thus, neutrophil turnover is possibly regulated by nonapoptotic factors.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL085607-08
Application #
8469889
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
8
Fiscal Year
2013
Total Cost
$499,162
Indirect Cost
$56,927
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Liu, Zhenghui; Zhang, Nan; Shao, Bojing et al. (2016) Replacing the Promoter of the Murine Gene Encoding P-selectin with the Human Promoter Confers Human-like Basal and Inducible Expression in Mice. J Biol Chem 291:1441-7
Bergstrom, Kirk; Liu, Xiaowei; Zhao, Yiming et al. (2016) Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. Gastroenterology 151:152-164.e11
Brazil, Jennifer C; Sumagin, Ronen; Cummings, Richard D et al. (2016) Targeting of Neutrophil Lewis X Blocks Transepithelial Migration and Increases Phagocytosis and Degranulation. Am J Pathol 186:297-311
Zhang, Nan; Liu, Zhenghui; Yao, Longbiao et al. (2016) P-Selectin Expressed by a Human SELP Transgene Is Atherogenic in Apolipoprotein E-Deficient Mice. Arterioscler Thromb Vasc Biol 36:1114-21
Crosswhite, Patrick L; Podsiadlowska, Joanna J; Curtis, Carol D et al. (2016) CHD4-regulated plasmin activation impacts lymphovenous hemostasis and hepatic vascular integrity. J Clin Invest 126:2254-66
Shao, Bojing; Yago, Tadayuki; Setiadi, Hendra et al. (2015) O-glycans direct selectin ligands to lipid rafts on leukocytes. Proc Natl Acad Sci U S A 112:8661-6
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2015) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 125:4349-64
Chang, Baojun; Tessneer, Kandice L; McManus, John et al. (2015) Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development. Nat Commun 6:6380
Sweet, Daniel T; Jiménez, Juan M; Chang, Jeremy et al. (2015) Lymph flow regulates collecting lymphatic vessel maturation in vivo. J Clin Invest 125:2995-3007
Astarita, Jillian L; Cremasco, Viviana; Fu, Jianxin et al. (2015) The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture. Nat Immunol 16:75-84

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