Systemic reprogramming of monocytes in Crohn's disease promotes their intestinal inflammatory function

Area of Science:

• Immunology
• Gastroenterology
• Genomics

Background:

• Intestinal macrophages are replenished by circulating monocytes, but their dysregulation in inflammatory bowel disease (IBD) is poorly understood.
• Understanding the origins of monocyte dysregulation is crucial for IBD pathology.
• Previous research has not fully elucidated the systemic changes in monocytes prior to intestinal recruitment.

Purpose of the Study:

• To investigate the reprogramming of circulating monocytes in IBD before they infiltrate tissues.
• To characterize blood monocyte heterogeneity in newly diagnosed, treatment-naïve IBD patients compared to healthy controls.
• To identify molecular mechanisms driving monocyte dysregulation in IBD.

Main Methods:

• Single-cell transcriptomic analysis of blood monocytes.
• Epigenomic profiling (chromatin accessibility).
• Functional assays to assess monocyte behavior and response to cytokines.

Main Results:

• Crohn's disease (CD) monocytes exhibit distinct transcriptional profiles and altered developmental trajectories compared to healthy controls and ulcerative colitis (UC) patients.
• CD-associated transcriptional changes correlate with altered chromatin accessibility, implicating transcription factors like NF-κB, EGR, KLF, and AP-1.
• Interferon-gamma (IFN-γ) may prime CD monocytes for inflammation by reducing IL-10 responsiveness, with these changes persisting in intestinal macrophages.

Conclusions:

• Monocyte dysfunction in CD is, in part, systemically pre-established before tissue recruitment.
• Systemic signals in CD alter monocyte programming, contributing to intestinal macrophage dysregulation.
• These findings highlight the importance of investigating circulating immune cells in understanding IBD pathogenesis.