Targeting Innate Immune Memory to Alleviate Monocyte Exhaustion and Chronic Inflammation

Sepsis and chronic inflammation remain unresolved clinical challenges due to immune dysregulation. Innate immune cells, particularly monocytes, are key regulators of inflammation and its resolution. However, unbalanced or prolonged stimulation can drive these cells into dysfunctional states. These cells may enter dysfunctional "exhausted" or "low-grade inflammatory" states, resulting in impaired immune memory and unresolved inflammation This dissertation explores two parallel models of immune exhaustion and low-grade inflammation. In the first project, we reported that co-treatment of monocytes with methoxy-mycolic acid (M-MA) effectively impedes the phenotype of exhausted monocytes induced by repeated exposure to LPS, including blocking the expansion of exhausted Ly6Chi/CD38hi/PD-L1hi monocytes and restoring the expression of CD86. Functionally, M-MA treatment rejuvenates the mitochondrial function of exhausted monocytes and alleviates their suppressive effect on T cells. Mechanistically, M-MA ameliorates cellular stress signaling by inhibiting Src-STAT1 mediated pathogenic inflammatory polarization and reduces the production of compensatory immune suppressors TAX1BP1 and PLAC8. The whole genome methylation analyses further demonstrate that M-MA effectively erases the methylation memory of exhausted monocytes, with confirmed restoration of Plac8 methylation by M-MA. In the second project, we showed that sustained stimulation with oxidized low-density lipoprotein (oxLDL) or free cholesterol induces a low-grade inflammatory phenotype, characterized by elevated expression of CD49d, CD86, CD74, and CD38, but these features were not observed during the acute phase. The low-grade inflammation is marked by enhanced monocyte-endothelial adhesion, as oxLDL or cholesterol increases adhesion molecule expression on both cell types. Unlike monocyte exhaustion, in a monocyte-T cell co-culture system, we report that T cells cultured with cholesterol-treated monocytes exhibited significantly higher proliferative capacity compared to those cultured with PBS-treated monocytes. Mechanistically, prolonged stimulation with oxLDL or cholesterol led to distinct activation of the Src/SYK/mTORC1/S6K/STAT5 signaling pathway over time, supporting the establishment of a persistent inflammatory state. Notably, Fumagillin and DHA, which target membrane-associated processes, could reverse this phenotype. Collectively, our work uncovers distinct molecular mechanisms underlying innate immune dysregulation and identifies strategies to restore immune homeostasis in sepsis and chronic inflammation.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Biological Sciences

Department dc:contributor.department

Biological Sciences

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2025

Author dc:creator

• Yajun, Wu

Chair dc:contributor.committeechair

• Li, Liwu

Committee members dc:contributor.committeemember

• Geng, Shuo
• Chen, Jing
• Luo, Xin

• monocytes
• exhaustion
• mycolic acid
• low-grade inflammation
• intervention

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:44500

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/137560