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Epigenetic Regulation of Macrophage-Induced Inflammation by Glutamine During Tissue Repair
Epigenetic Regulation of Macrophage-Induced Inflammation by Glutamine During Tissue Repair
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103023
- ISBN
- 9798286445158
- DDC
- 574
- 저자명
- Xu, Yiting.
- 서명/저자
- Epigenetic Regulation of Macrophage-Induced Inflammation by Glutamine During Tissue Repair
- 발행사항
- [Sl] : Yale University, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 106 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 86-12, Section: B.
- 주기사항
- Advisor: Horsley, Valerie.
- 학위논문주기
- Thesis (Ph.D.)--Yale University, 2025.
- 초록/해제
- 요약Introduction:Delayed wound healing is a major healthcare challenge, creating a significant financial burden and impacting patient quality of life by increasing risks of infections, chronic wounds, and impaired tissue regeneration. Macrophages are key mediators in wound healing, where they transition from a pro-inflammatory to an anti-inflammatory state, balancing inflammation resolution and tissue repair. Dysregulated macrophage function, as seen in chronic wounds, leads to persistent inflammation and poor healing outcomes. Recent studies indicate that glutamine metabolism in macrophages may be crucial for this phenotypic transition by influencing gene expression and epigenetic regulation. However, the specific role of glutamine metabolism in modulating macrophage-driven wound healing remains underexplored.Methods:We used an excisional wound model on dorsal skin to create full-thickness wounds in mice. To investigate the changes in macrophage metabolism in wound healing, we utilized integrative metabolomics and transcriptomics analysis. To further assess the role of glutamine metabolism in wound healing, we utilized dietary and genetic approaches. Mice were fed either a glutamine/glutamate-deficient diet or an isocaloric control diet, and wound healing was assessed. Additionally, we generated LysMCre-expressing glutaminase knockout (Gls cKO) mice to specifically ablate glutamine metabolism in macrophages. Bulk RNA sequencing was used to examine gene expression changes, and DOGMA-seq combined with CUT&Tag assays was employed to assess chromatin accessibility and histone modifications.Results:Metabolomic and transcriptomics analyses revealed metabolic and gene expression shifts in macrophages from glycolysis to TCA cycle intermediates, particularly glutamine/glutamate pathways, at later healing stages. Mice on the Glu/Gln-deficient diet and Gls cKO mice both displayed delayed wound healing, characterized by prolonged inflammation and reduced re-epithelialization. Flow cytometry confirmed increased pro-inflammatory macrophages (CD45+CD11b+F4/80+Ly6C+) and neutrophil recruitment in Gls cKO wounds. Transcriptomic data showed upregulation of genes involved in neutrophil chemotaxis and inflammation in Gls cKO macrophages. Epigenetic profiling demonstrated hypermethylation near pro-inflammatory gene loci and increased chromatin accessibility at inflammatory markers, indicating glutamine's role in modulating macrophage gene expression during healing.Conclusions:Our findings highlight that glutamine metabolism is essential for macrophage function during wound healing, supporting the transition from inflammation to tissue repair. Disrupted glutamine metabolism leads to sustained inflammation, impaired angiogenesis, and compromised tissue remodeling. This study underscores the potential therapeutic value of targeting macrophage glutamine metabolism to enhance wound healing, particularly in chronic, non-healing wounds. Future research should investigate the molecular pathways linking glutamine metabolism with epigenetic regulation in macrophages and explore its clinical applications in wound management.
- 일반주제명
- Cellular biology
- 일반주제명
- Molecular biology
- 일반주제명
- Microbiology
- 키워드
- Macrophage
- 키워드
- Metabolism
- 키워드
- Neutrophil
- 키워드
- Tissue repair
- 기타저자
- Yale University Molecular Cellular and Developmental Biology
- 기본자료저록
- Dissertations Abstracts International. 86-12B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
008260126s2025 us c eng d■001000017356720
■00520260202103023
■006m o d
■007cr#unu||||||||
■020 ▼a9798286445158
■035 ▼a(MiAaPQ)AAI31844862
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aXu, Yiting.
■24510▼aEpigenetic Regulation of Macrophage-Induced Inflammation by Glutamine During Tissue Repair
■260 ▼a[Sl]▼bYale University▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a106 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 86-12, Section: B.
■500 ▼aAdvisor: Horsley, Valerie.
■5021 ▼aThesis (Ph.D.)--Yale University, 2025.
■520 ▼aIntroduction:Delayed wound healing is a major healthcare challenge, creating a significant financial burden and impacting patient quality of life by increasing risks of infections, chronic wounds, and impaired tissue regeneration. Macrophages are key mediators in wound healing, where they transition from a pro-inflammatory to an anti-inflammatory state, balancing inflammation resolution and tissue repair. Dysregulated macrophage function, as seen in chronic wounds, leads to persistent inflammation and poor healing outcomes. Recent studies indicate that glutamine metabolism in macrophages may be crucial for this phenotypic transition by influencing gene expression and epigenetic regulation. However, the specific role of glutamine metabolism in modulating macrophage-driven wound healing remains underexplored.Methods:We used an excisional wound model on dorsal skin to create full-thickness wounds in mice. To investigate the changes in macrophage metabolism in wound healing, we utilized integrative metabolomics and transcriptomics analysis. To further assess the role of glutamine metabolism in wound healing, we utilized dietary and genetic approaches. Mice were fed either a glutamine/glutamate-deficient diet or an isocaloric control diet, and wound healing was assessed. Additionally, we generated LysMCre-expressing glutaminase knockout (Gls cKO) mice to specifically ablate glutamine metabolism in macrophages. Bulk RNA sequencing was used to examine gene expression changes, and DOGMA-seq combined with CUT&Tag assays was employed to assess chromatin accessibility and histone modifications.Results:Metabolomic and transcriptomics analyses revealed metabolic and gene expression shifts in macrophages from glycolysis to TCA cycle intermediates, particularly glutamine/glutamate pathways, at later healing stages. Mice on the Glu/Gln-deficient diet and Gls cKO mice both displayed delayed wound healing, characterized by prolonged inflammation and reduced re-epithelialization. Flow cytometry confirmed increased pro-inflammatory macrophages (CD45+CD11b+F4/80+Ly6C+) and neutrophil recruitment in Gls cKO wounds. Transcriptomic data showed upregulation of genes involved in neutrophil chemotaxis and inflammation in Gls cKO macrophages. Epigenetic profiling demonstrated hypermethylation near pro-inflammatory gene loci and increased chromatin accessibility at inflammatory markers, indicating glutamine's role in modulating macrophage gene expression during healing.Conclusions:Our findings highlight that glutamine metabolism is essential for macrophage function during wound healing, supporting the transition from inflammation to tissue repair. Disrupted glutamine metabolism leads to sustained inflammation, impaired angiogenesis, and compromised tissue remodeling. This study underscores the potential therapeutic value of targeting macrophage glutamine metabolism to enhance wound healing, particularly in chronic, non-healing wounds. Future research should investigate the molecular pathways linking glutamine metabolism with epigenetic regulation in macrophages and explore its clinical applications in wound management.
■590 ▼aSchool code: 0265.
■650 4▼aCellular biology
■650 4▼aMolecular biology
■650 4▼aMicrobiology
■653 ▼aMacrophage
■653 ▼aMetabolism
■653 ▼aNeutrophil
■653 ▼aSkin wound healing
■653 ▼aTissue repair
■690 ▼a0379
■690 ▼a0307
■690 ▼a0410
■690 ▼a0769
■71020▼aYale University▼bMolecular, Cellular, and Developmental Biology.
■7730 ▼tDissertations Abstracts International▼g86-12B.
■790 ▼a0265
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17356720▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
