Soluble CD83 modulates human-monocyte-derived macrophages toward alternative phenotype, function, and metabolism

Area of Science:

• Immunology
• Cell Biology
• Molecular Medicine

Background:

• Macrophage (Mφ) polarization and function are critical in chronic diseases like autoimmunity and fibrosis.
• Targeting Mφ biology offers a potential therapeutic strategy for inflammatory conditions.

Purpose of the Study:

• To investigate the effects of soluble CD83 (sCD83) on human monocyte-derived Mφ polarization and function.
• To elucidate the molecular mechanisms underlying sCD83-mediated Mφ modulation.

Main Methods:

• Treatment of human monocyte-derived Mφ with sCD83.
• Analysis of Mφ surface marker expression (e.g., ILT-2, ILT-4, ILT-5, CD163, MHC-II, MSR-1).
• Mixed lymphocyte reaction (MLR) assays to assess T cell stimulation capacity.
• Bulk RNA sequencing and pathway analysis.
• Pharmacological inhibition of the Liver X Receptor (LXR) pathway.

Main Results:

• sCD83 significantly increased inhibitory Mφ molecules (ILT-2, ILT-4, ILT-5, CD163) and decreased activation markers (MHC-II, MSR-1).
• sCD83 reduced Mφ capacity to stimulate alloreactive T cells in MLR assays.
• RNA sequencing revealed sCD83 downregulates pro-inflammatory pathways (HIF-1A, IL-6) and upregulates alternative Mφ activation and LXR pathways.
• sCD83-induced gene transcription (e.g., PPARG, ABCA1) is dependent on LXR activation.

Conclusions:

• sCD83 induces pro-resolving features in human Mφ, shifting them away from a pro-inflammatory phenotype.
• The LXR pathway is crucial for mediating the effects of sCD83 on Mφ.
• sCD83 represents a promising therapeutic candidate for inflammatory conditions, warranting further preclinical investigation.