Author

Asako Itakura

Date

October 2013

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Cell and Developmental Biology

Institution

Oregon Health & Science University

Abstract

Neutrophils, the most abundant white blood cell in the human circulation, play an indispensable role as the first line of innate immune host defense. When circulating neutrophils encounter the signs of infection and/or tissue damage, they rapidly extravasate into the target tissue in order to locally eliminate invading pathogens using their potent microbicidal activity at the cost of their lives. However, improper activation of neutrophils has been shown to mediate the pathological processes of inflammatory diseases and thrombotic complications. This thesis is centered on identifying the key molecular mechanisms that underlie neutrophil activation, migration and death. Neutrophil migration into/within the inflamed tissue is driven by the cell function termed chemotaxis, in which cell migration is guided by a gradient of chemotatic factors derived from injured tissue or pathogens. For efficient chemotaxis, activated neutrophils develop and maintain the morphological polarization with distinct front and back structures, owing to their highly-coordinated cytoskeletal machinery. While studies have shown that the Rho-family GTPases, such as Rac, Cdc42 and RhoA GTPases, act as an important cellular compass downstream of chemoattractant receptors, the complex network of signaling pathways downstream of Rho GTPases regulating cytoskeletal dynamics has not been fully characterized. Studies in this thesis suggest that p21-activated kinase (PAK) serves to orchestrate the crosstalk between “frontness” and “backness” signals mediated by Rac/Cdc42 and RhoA, respectively, during neutrophil chemotaxis induced by the bacteria-derived formyl peptide, fMLP. Upon their arrival to the target tissue, neutrophil activation triggers their professional microbicidal program, including an active form of cell death by the release of neutrophil extracellular traps (NETs). NETs consist of decondensed nuclear chromatin decorated with antibacterial proteins that together form a physical trap for pathogen killing; however, physiological stimuli and cellular events required for NETs formation are ill-defined. We show that the mammalian target of rapamycin (mTOR) pathway, downstream of fMLP signaling, plays a central role in the regulation of neutrophil fate towards NETs formation. The activation of innate immunity and blood coagulation is linked as effectors of host defense response, where local accumulation of neutrophils is shown to promote prothrombotic conditions. In this thesis, studies reveal that the activated coagulation factor XI (FXIa) displays an inhibitory effect on neutrophil activation and chemotaxis triggered by chemotactic stimuli including fMLP. This novel interaction between neutrophils and FXIa implicates a potential role of FXIa in modulating innate immunity at the interphase of inflammation and thrombosis. Collectively, this dissertation provides novel insights into the tight regulation of neutrophil activation, migration and fate decision, which constitute a crucial mechanism in health and disease.

Identifier

doi:10.6083/M43T9F7Z

School

School of Medicine

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