Rheumatology: rheumatoid arthritis macrophages respond to inflammation and exhibit changes in bioenergetic and functional

Objective: The presence of a large number of myeloid cells with monocytes/macrophage phenotypes in rheumatoid arthritis (RA) joints has made significant contributions to the disease, but its unique macrophage function has yet to be elucidated
.
This literature studies the metabolic activity of infiltrating polarized macrophages and their effect
on the pro-inflammatory response of RA.

Methods: CD14+ monocytes in RA and HC blood were isolated and examined
in vitro or after differentiation into "M1/M2" macrophages.
Quantification
of Inflammatory Response and Metabolic Analysis +/- Specific Inhibitors by RT-PCR, Western blot, Seahorse XFe technology, phagocytosis assay and transmission electron microscopy, and RNA-seq transcriptome analysis.

Results: Circulating RA monocytes were highly inflammatory after stimulation and significantly higher expression of key cytokines (p<0.
05) compared to HC, a phenotype that remained unchanged<b10> upon differentiation into mature in vitro polarized macrophages.
This induction in pro-inflammatory mechanisms goes hand in hand
with cellular bioenergetic changes.

RA macrophages are highly metabolic, with significant enhancement of oxidative phosphorylation and glycolysis in RA compared to healthy controls, and changes in mitochondrial morphology
.
RNA sequencing analysis revealed different transcriptional differences between nootropic and anti-inflammatory RA macrophages, revealing the role of
STAT3 and NMPT in driving macrophage activation states.

STAT3 and NAMPT inhibition resulted in a significant decrease
in pro-inflammatory gene expression observed in RA macrophages.
Interestingly, NAMPT inhibition specifically restores macrophage phagocytosis and leads to mutual STAT3 inhibition
connecting these two signaling pathways.

Conclusion: This study confirms the unique inflammatory and metabolic phenotype of RA monocytes-derived macrophages and identifies the key roles of NAMPT and STAT3 signaling in regulating this phenotype.

Sources:

Hanlon MM, McGarry T, Marzaioli V, et al.
Rheumatoid arthritis macrophages are primed for inflammation and display bioenergetic and functional alterations [published online ahead of print, 2022 Nov 18].
Rheumatology (Oxford).
2022; keac640.
doi:10.
1093/rheumatology/keac640.