Macrophage re-programming by JAK inhibitors relies on MAFB

Area of Science:

• Immunology
• Rheumatology
• Pharmacology

Background:

• Monocyte-derived macrophages are key in inflammatory diseases like rheumatoid arthritis (RA).
• Specific macrophage subsets in RA synovium correlate with disease activity or resolution.
• Janus kinase inhibitors (JAKi) are effective RA treatments, but their impact on macrophage differentiation is unknown.

Purpose of the Study:

• To investigate the effects of JAK inhibitors (JAKi) on macrophage specification and differentiation in rheumatoid arthritis (RA).
• To analyze the transcriptional and functional impact of JAKi on human monocyte subsets and monocyte-derived macrophages.

Main Methods:

• Analysis of transcriptional and functional effects of JAKi on human peripheral blood monocyte subsets from RA patients.
• Assessment of monocyte-derived macrophage differentiation promoted by granulocyte-macrophage colony-stimulating factor (GM-CSF).
• Dose-dependent evaluation of Upadacitinib, baricitinib, tofacitinib, and deucravacitinib effects.

Main Results:

• Upadacitinib restored peripheral blood monocyte balance in RA patients.
• JAKi skewed macrophages towards an anti-inflammatory profile, enhancing MAFB expression and inhibitory GSK3β phosphorylation.
• Upadacitinib-treated macrophages showed increased phagocytosis, an anti-inflammatory cytokine profile, and enrichment of homeostasis-associated genes.
• These effects were observed with other JAKi but not the TYK2 inhibitor deucravacitinib.

Conclusions:

• JAK inhibitors reprogram macrophages to an anti-inflammatory and pro-resolution phenotype.
• This reprogramming is linked to enhanced MAFB expression, offering a new therapeutic perspective for RA.
• JAKi may modulate macrophage function to promote inflammation resolution in RA.