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Programmed Cell Death in Immune Modulation: Insights from Antimicrobial and Immunosuppressive Responses

Liu, Zihao
http://orcid.org/0009-0007-5921-7684
http://rave.ohiolink.edu/etdc/view?acc_num=osu1732532815291714

Abstract Details

2024, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
My research focuses on the diverse roles of programmed cell death (PCD) in host innate immune responses. My dissertation explores how PCD assists host antimicrobial defense, as well as contributes to the progression of sepsis-induced immunosuppression. The dissertation could be divided into two main sections and one derivative section. Firstly, I have identified a novel interaction between Pseudomonas aeruginosa and host necroptosis during in vitro and in vivo infection. Secondly, I have characterized the impact of a novel PCD regulator, NINJ1, in improving sepsis-induced immunosuppression by partially restoring the host defense to secondary infections. Quorum sensing (QS), a communication system evolved by Pseudomonas aeruginosa to monitor its density, is well-acknowledged to be involved in multiple activities during bacterial infection. Recent studies have revealed clues about link between Pseudomonas aeruginosa QS and host programed cell death. However, it remains limited understanding whether QS plays a role in host PCD process during the infection. In this study, I used rhl mutants of Pseudomonas aeruginosa to in vitro challenge multiple genetic knockout macrophages to explore the connection between QS and programmed cell death. According to the data from cell death assays and immunoblotting, I discovered these rhl mutants significantly promoted necroptosis which was unknown in this field. Additionally, I found that the increased necroptosis activation was caused by the upregulation of another QS subsystem, pqs, because the deletion of pqs in rhl-deficient Pseudomonas aeruginosa abolished macrophage necroptosis in vitro and in vivo. Therefore, this study revealed a novel rhl-pqs-necroptosis pathway. Sepsis is characterized by two dynamic stages occur during the initiation and progression, which are system inflammatory response syndrome (SIRS) in the acute phase and compensatory anti-inflammatory response syndrome (CARS) in the later phase. Recent study revealed that inhibiting HMGB1 release reduced pyroptosis-related effector cell loss in septic mice. As a newly discovered PCD component, NINJ1-mediated plasma membrane rupture has becoming increasingly important in preclinical studies. However, it is totally unclear whether NINJ1 plays a role in sepsis-induced immunosuppression. In this study, I obtained Ninj1-/- mice and induced sepsis through cecal ligation and puncture (CLP) surgery. I discovered that NINJ1 deficiency significantly reduced the mortality of septic mice. In addition, by using a two-hit model, I found that NINJ1 deficiency also partially restored host defense to bacterial infection under immunosuppression circumstance. These findings provide us with novel therapeutic target in developing clinical treatments for patients suffered with sepsis. Inspired by the findings and approaches of my second study, I extended my research to investigate whether NINJ1 has an impact on tumor-mediated immunosuppression. The immunosuppressive status in TME is mainly due to type 2 transition of immune effector cells regulated by tumor cells and immune regulator cells. By exerting the function of NINJ1 in modulating membrane rupture, we hypothesize that targeting NINJ1 in tumor cells can inhibit the pro-tumor transition of immune cells in TME. To test the hypothesis, I collaborated with Dr. Xiang Chen to generate Ninj1-/- tumor cells and reconfirmed NINJ1’s function in tumor cells. By co-culturing macrophages with supernatants from WT and Ninj1-/- tumor cells, I found both the M2-associated gene expression and M2-related signaling pathway were remarkably suppressed in macrophages treated with Ninj1-/- sup, indicating loss of NINJ1 in tumor cells restrains the transition of pro-tumor immune cells and can be function as a potential therapeutic target.
Haitao Wen (Advisor)
Patrick Collins (Committee Member)
Amal Amer (Committee Member)
Daniel Wozniak (Committee Member)
117 p.
Immunology
programmed cell death; Pseudomonas aeruginosa; sepsis; immunosuppression; NINJ1

Recommended Citations

Citations

  • Liu, Z. (2024). Programmed Cell Death in Immune Modulation: Insights from Antimicrobial and Immunosuppressive Responses [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1732532815291714

    APA Style (7th edition)

  • Liu, Zihao. Programmed Cell Death in Immune Modulation: Insights from Antimicrobial and Immunosuppressive Responses. 2024. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1732532815291714.

    MLA Style (8th edition)

  • Liu, Zihao. "Programmed Cell Death in Immune Modulation: Insights from Antimicrobial and Immunosuppressive Responses." Doctoral dissertation, Ohio State University, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1732532815291714

    Chicago Manual of Style (17th edition)

osu1732532815291714
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© 2024, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.