Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Phenotypic changes in PMN from production to site of infecction

ABSTRACT: Neutrophils, key cells of the innate immune system, are responsible for preventing bacterial infections. It has recently been established that neutrophils are capable of complex changes in gene expression during inflammation. The concept that neutrophils merely respond to external signals has been replaced by the concept that activated neutrophils can secrete a variety of cytokines and also have an active regulatory role in angiogenesis and tumoural fate. Currently, neutrophil research relies mostly in animal models that reproduce human physiology and pathology. Although, in many respects, there is a conservation of functions in mice and humans, little is known about genomic conservation of neutrophils between mice and humans. We hypothesize that neutrophils are transcriptionally active cells that alters their gene expression profile as they migrate into different compartments. To identify changes in neutrophil gene expression in the circulation and inflamed tissue we used recent advances in neutrophil isolation, RNA amplification and microarray technologies that allowed us to compare the transcriptome of neutrophils. Additionally, using bioinformatics, we investigate the genomic conservation of neutrophils between mice and humans. Total RNA obtained from isolated neutrophils from Bone Marrow, Blood and Peritoneal Exudate from Black 6 mice.

ORGANISM(S): Mus musculus

SUBMITTER: Flavia Lakschevitz

PROVIDER: E-GEOD-43513 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Lipocalin 24p3 (24p3) is a neutrophil secondary granule protein. 24p3 is also a siderocalin, which binds several bacterial siderophores. It was therefore proposed that synthesis and secretion of 24p3 by stimulated macrophages or release of 24p3 upon neutrophil degranulation sequesters iron-laden siderophores to attenuate bacterial growth. Accordingly, 24p3-deficient mice are susceptible to bacterial pathogens whose siderophores would normally be chelated by 24p3. Specific granule deficiency (SGD) is a rare congenital disorder characterized by complete absence of proteins in secondary granules. Neutrophils from SGD patients, who are prone to bacterial infections, lack normal functions but the potential role of 24p3 in neutrophil dysfunction in SGD is not known. Here we show that neutrophils from 24p3-deficient mice are defective in many neutrophil functions. Specifically, neutrophils in 24p3-deficient mice do not extravasate to sites of infection and are defective for chemotaxis. A transcriptome analysis revealed that genes that control cytoskeletal reorganization are selectively suppressed in 24p3-deficient neutrophils. Additionally, small regulatory RNAs (miRNAs) that control upstream regulators of cytoskeletal proteins are also increased in 24p3-deficient neutrophils. Further, 24p3-deficient neutrophils failed to phagocytose bacteria, which may account for the enhanced sensitivity of 24p3-deficient mice to both intracellular (Listeria monocytogenes) and extracellular (Candida albicans, Staphylococcus aureus) pathogens. Interestingly, Listeria does not secrete siderophores and additionally, the siderophore secreted by Candida is not sequestered by 24p3. Therefore, the heightened sensitivity of 24p3-deficient mice to these pathogens is not due to sequestration of siderophores limiting iron availability, but is a consequence of impaired neutrophil function. Key words: Lipocalin, 24p3, neutrophils, cell motility, chemotaxis, MIRNA-362-3p To address the role of lipocalin 2 in regulating miRNA expression profiling in neutrophils derived from mouse bone marrow, we performed microarray analysis of miRNAs in wild type (N=2) and lcn2 knockout (N=2) neutrophils.

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Phenotypic changes in PMN from production to site of infecction

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