HBEGF⁺ macrophages in rheumatoid arthritis induce fibroblast invasiveness

Area of Science:

• Immunology
• Rheumatology
• Cell Biology

Background:

• Macrophages exhibit diverse phenotypes influenced by tissue microenvironments.
• Understanding macrophage phenotypes in human tissues, particularly in autoimmune diseases like rheumatoid arthritis (RA), remains limited.

Purpose of the Study:

• To define distinct macrophage subsets in the joints of RA patients.
• To investigate the role of specific macrophage subsets in RA pathogenesis and their interaction with fibroblasts.
• To evaluate the impact of RA medications on these macrophage subsets.

Main Methods:

• Single-cell RNA sequencing was employed to analyze macrophage populations in human RA joint tissues.
• Ex vivo synovial tissue assays were conducted to assess cellular interactions and drug effects.

Main Results:

• A distinct subset, HBEGF+ inflammatory macrophages, was enriched in RA joints.
• These macrophages were shaped by resident fibroblasts and tumor necrosis factor (TNF).
• HBEGF+ macrophages promoted fibroblast invasiveness via epidermal growth factor receptor (EGFR) signaling, contributing to joint destruction.
• RA medications targeted HBEGF+ macrophages, but some treatments redirected them to a non-resolving inflammatory state.

Conclusions:

• Intercellular crosstalk between fibroblasts and HBEGF+ macrophages reshapes cell functions in RA, driving joint destruction.
• Current RA treatments may have unintended consequences on macrophage phenotypes, potentially hindering inflammation resolution.
• Studying local macrophage phenotypes and interactions is crucial for understanding inflamed tissues and optimizing RA therapies.