Cells react to microorganisms by activating inflammatory mechanisms that attract neutrophils, dependent in part on ELR+ CXC chemokines, whose localization within specific compartments (plasma, erythrocyte, airspace, endothelium among others) influences their activity. We hypothesize that the availability of chemokine binding sites on the non-receptor molecules Duffy antigen receptor for chemokines (DARC) and heparan sulfate proteoglycans (HSPG) for CXCL1 is determined, in part, by specific molecular forms of the chemokines CXCL5 and 7. We further propose that binding site availability regulates neutrophil accumulation in the lung. Preliminary findings indicate that targeted deletion of CXCL5 in mouse exerts dichotomous effects on inflammation. CXCL5-/- mice respond to inhaled LPS with decreased neutrophil accumulation, but respond to E coli with increased neutrophil accumulation and improved bacterial clearance. Using both human (primary alveolar type II cells in culture) and murine systems (newly- generated targeted deletions of CXCL5 and CXCL7), we pursue 3 specific aims focused on the potential role of CXCL5 in modulating neutrophil accumulation and host defense.
In Aim 1, We define the effect of CXCL5 and CXCL7 on chemokine scavenging and lung inflammation.
In Aim 2, we propose to determine the extent to which CXCL5 and CXCL7 binding to DARC and HSPG modifies transalveolar movement of chemokines and hence, inflammatory responses.
In Aim 3 we will determine the sites and molecular forms of chemokines bound in the lung endovascular compartment. Understanding the disposition of chemokines, and how they interact will define fundamental mechanisms of kinetics and localization of chemokines, offer promise in diagnostic and predictive algorithms, and permit therapeutic alteration of disease due to sepsis and pneumonia.
Targeted deletion of CXCL5 in mouse increases the neutrophil response to E coli pneumonia and improves bacterial clearance CXCL5, and the closely related chemokine CXCL7 are uniquely suited to influence the binding of many other chemokines to their non-receptor binding molecules DARC and HSPG. By highlighting mechanisms by which chemokines are sequestered and presented by binding molecules these studies present a novel model of the inflammatory response in the lung.
|Gibbs, Julie; Ince, Louise; Matthews, Laura et al. (2014) An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat Med 20:919-26|
|Jaeckle Santos, Lane J; Li, Changhong; Doulias, Paschalis-Thomas et al. (2014) Neutralizing Th2 inflammation in neonatal islets prevents ?-cell failure in adult IUGR rats. Diabetes 63:1672-84|
|Deshmukh, Hitesh S; Liu, Yuhong; Menkiti, Ogechukwu R et al. (2014) The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nat Med 20:524-30|
|Ramon, Hilda E; Beal, Allison M; Liu, Yuhong et al. (2012) The E3 ubiquitin ligase adaptor Ndfip1 regulates Th17 differentiation by limiting the production of proinflammatory cytokines. J Immunol 188:4023-31|
|Balamayooran, Gayathriy; Batra, Sanjay; Cai, Shanshan et al. (2012) Role of CXCL5 in leukocyte recruitment to the lungs during secondhand smoke exposure. Am J Respir Cell Mol Biol 47:104-11|
|Fridlender, Zvi G; Sun, Jing; Mishalian, Inbal et al. (2012) Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One 7:e31524|
|Mei, Junjie; Liu, Yuhong; Dai, Ning et al. (2012) Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice. J Clin Invest 122:974-86|
|Liu, Yuhong; Mei, Junjie; Gonzales, Linda et al. (2011) IL-17A and TNF-? exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J Immunol 186:3197-205|
|Fuentes, Rudy; Wang, Yuhuan; Hirsch, Jessica et al. (2010) Infusion of mature megakaryocytes into mice yields functional platelets. J Clin Invest 120:3917-22|
|Mei, Junjie; Liu, Yuhong; Dai, Ning et al. (2010) CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection. Immunity 33:106-17|
Showing the most recent 10 out of 13 publications