A Pathogenic Th17/CD38⁺ Macrophage Feedback Loop Drives Inflammatory Arthritis through TNF-α

Area of Science:

• Immunology
• Rheumatology
• Cell Biology

Background:

• Rheumatoid arthritis (RA) pathogenesis involves complex immune cell interactions.
• Single-cell studies have identified RA-associated cell subsets but not their functional interplay.
• Understanding cell-cell communication is crucial for elucidating inflammatory arthritis mechanisms.

Purpose of the Study:

• To temporally profile murine arthritic synovial cells using single-cell analysis.
• To identify and characterize interactions between immune cells in inflammatory arthritis.
• To elucidate the role of macrophage-Th17 cell axis in driving arthritis.

Main Methods:

• Single-cell RNA sequencing of murine arthritic synovial isolates.
• In vitro co-culture experiments to assess macrophage-Th17 cell interactions.
• In vivo studies involving macrophage depletion and TNF-α blockade.

Main Results:

• Murine macrophage subtypes expanded in arthritis, promoting Th17 cell function.
• Macrophages maintain Th17 cell functionality and expansion in vitro.
• A reciprocal feedback loop exists where Th17-derived TNF-α induces CD38+ macrophages, enhancing Th17 function.
• CD38+ macrophages are expanded in arthritis; their depletion or TNF-α blockade alleviates disease.

Conclusions:

• A novel TNF-α-mediated feedback loop between macrophages and Th17 cells drives inflammatory arthritis.
• Targeting this macrophage-Th17 cell axis, particularly CD38+ macrophages, holds therapeutic potential for RA.
• This study provides new insights into the cellular mechanisms underlying inflammatory arthritis pathogenesis.