Frontiers in immunology · 2026
Empowered pro-inflammatory features in Ly6C monocytes and altered antigen-presenting capacity in Ly6Chigh monocytes in diabetic mice.
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Yang Pingping, Fang Pu, Sun Lizhe, Liu Lu, Fu Linghua, Xi Hang, Wang Xianwei, Bouchareb Rihab, Zhang Daqing, Wu Qinghua, Ji Yong, Yang Xiaofeng, Wang Hong
Аннотация
RATIONALE: Inflammatory monocyte (MC) subset polarization is a hallmark of systemic and tissue inflammatory feature in diabetes. The underlying molecular mechanism remains unclear.
METHODS AND RESULTS: Blood pro-inflammatory Ly6Chigh and anti-inflammatory Ly6Clow MC subsets were isolated from control (C57/BL6), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) mice by flow cytometry sorting and subjected to bulk high-throughput RNA-sequencing. Intensive and integrative functional bioinformatic studies were performed by analyzing the transcriptome through seven pairs of comparison between Ly6Chigh and Ly6Clow MC subsets and between different mouse groups. We examined molecular features of three key immune activation signals in innate and adaptive immune responses, including signal 1 antigen (Ag)-presenting, signal 2 immune checkpoint, and signal 3 cytokine, and their upstream transcription factors (TF). A total of 10 differentially expressed genes (DEG) of MHC-II molecules (signal 1) presented a low expression profile in Ly6Chigh MCs from all mice and mostly further reduced in T2DM Ly6Chigh MC. Ly6Chigh MCs show high intercellular inflammatory propagation based on immune checkpoint/cytokine-ligand expression but low intracellular inflammatory capacity based on immune checkpoint/cytokine-receptor expression, both further enhanced in T1/T2DM. In contrast, Ly6Clow MCs exhibit low intercellular propagation but high intracellular inflammatory capacity; both also increased in T1/T2DM. Furthermore, 921 upstream DEG transcription factors and 17 transcriptional axes were recognized in diabetic Ly6Chigh MCs by IPA upstream regulator analysis. Finally, three critical transcriptional axes that drove the altered immunological phenotype in Ly6Chigh MCs were recognized: ↓PAX5-↓CIITA-↓Cd74/H2-Eb2 for reduced Ag-presenting power, ↓MYC-↑Sema4a for elevated intercellular inflammatory propagation capacity, and ↑CEBPA/E-↑Csf2ra/3r for enhanced intracellular inflammatory propagation capacity in MC.
CONCLUSIONS: We have three major discoveries: 1) Ly6Chigh MCs exhibit lower Ag-presenting power, which was further suppressed in T2DM, mostly via ↓PAX5-↓CIITA-↓CD74 regulation. 2) Ly6Chigh MCs display high intercellular inflammatory propagation but low intracellular inflammatory capacity, both further enhanced in T1/T2DM, mostly via ↓MYC-↑Sema4a and ↑CEBPA/E-↑Csf2ra/3r regulation. 3) Ly6Clow MCs acquired additional intercellular and intracellular inflammatory capacity in T1/T2DM.
METHODS AND RESULTS: Blood pro-inflammatory Ly6Chigh and anti-inflammatory Ly6Clow MC subsets were isolated from control (C57/BL6), type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) mice by flow cytometry sorting and subjected to bulk high-throughput RNA-sequencing. Intensive and integrative functional bioinformatic studies were performed by analyzing the transcriptome through seven pairs of comparison between Ly6Chigh and Ly6Clow MC subsets and between different mouse groups. We examined molecular features of three key immune activation signals in innate and adaptive immune responses, including signal 1 antigen (Ag)-presenting, signal 2 immune checkpoint, and signal 3 cytokine, and their upstream transcription factors (TF). A total of 10 differentially expressed genes (DEG) of MHC-II molecules (signal 1) presented a low expression profile in Ly6Chigh MCs from all mice and mostly further reduced in T2DM Ly6Chigh MC. Ly6Chigh MCs show high intercellular inflammatory propagation based on immune checkpoint/cytokine-ligand expression but low intracellular inflammatory capacity based on immune checkpoint/cytokine-receptor expression, both further enhanced in T1/T2DM. In contrast, Ly6Clow MCs exhibit low intercellular propagation but high intracellular inflammatory capacity; both also increased in T1/T2DM. Furthermore, 921 upstream DEG transcription factors and 17 transcriptional axes were recognized in diabetic Ly6Chigh MCs by IPA upstream regulator analysis. Finally, three critical transcriptional axes that drove the altered immunological phenotype in Ly6Chigh MCs were recognized: ↓PAX5-↓CIITA-↓Cd74/H2-Eb2 for reduced Ag-presenting power, ↓MYC-↑Sema4a for elevated intercellular inflammatory propagation capacity, and ↑CEBPA/E-↑Csf2ra/3r for enhanced intracellular inflammatory propagation capacity in MC.
CONCLUSIONS: We have three major discoveries: 1) Ly6Chigh MCs exhibit lower Ag-presenting power, which was further suppressed in T2DM, mostly via ↓PAX5-↓CIITA-↓CD74 regulation. 2) Ly6Chigh MCs display high intercellular inflammatory propagation but low intracellular inflammatory capacity, both further enhanced in T1/T2DM, mostly via ↓MYC-↑Sema4a and ↑CEBPA/E-↑Csf2ra/3r regulation. 3) Ly6Clow MCs acquired additional intercellular and intracellular inflammatory capacity in T1/T2DM.