Manipulation of Rheumatoid Arthritis Macrophages Primed for Inflammation

Written by Dr Megan Hanlon, Irish Research Council Research Fellow, Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin

Manipulation of Rheumatoid Arthritis Macrophages Primed for Inflammation

Arthritis is a leading cause of joint deformity that affects roughly 15% of the population. Rheumatoid Arthritis (RA) is a chronic and progressive form of inflammatory arthritis that typically affects 1 in 100 people and twice as many women as men. RA is associated significant co-morbidities including atherosclerosis, cardiovascular disease, diabetes and obesity and reduces patient mobility and quality of life. The economic cost of RA both individually and societally is an estimated cost of ¤19,596 per patient/year, and overall cost of ~¤544 million. Despite significant advances in the treatment of RA such as the development of new targeted biotherapies in recent years, there is still no cure for RA Patients of this debilitating disease require life-long treatment. In addition, it is currently impossible to predict which patients will develop severe, erosive disease and those who will respond well to treatments such as Methotrexate, Rituximab or Tofacitinib, resulting in a ‘trial and error’ approach to treatments. Therefore, better understanding of the disease at the site of inflammation ‘the synovial membrane’ will allow for the development of a ‘personalised medicine’ approach to therapy.

One of the hallmarks of RA pathology is inflammation of the synovial joint which results in swelling pain and subsequent joint damage. One such cell type that is a key player in joint destruction is the ‘macrophage’, with many studies demonstrating a correlation between increased numbers of sub-lining macrophages and RA disease activity. In fact, synovial macrophages are the only celltype identified to date that are consistently associated with treatment response, regardless of treatment type.

They can be derived from circulating monocytes and so in this study we isolated circulating monocytes from the blood of active RA patients and healthy individuals. Firstly, we demonstrate increased levels of pro-inflammatory mediators in RA monocytes compared with healthy individuals. Interestingly this distinctive hyper-inflammatory signature of RA circulating monocytes is maintained upon differentiation into macrophages. Ex vivo RA macrophages clearly memorise the inflammatory phenotype of their precursor cells as indicated by significant increases in inflammatory markers in RA macrophages compared to healthy. This suggests that if macrophages retain memory bias of their monocyte precursors, analysis of circulatory monocytes may be clinically translatable in terms of early diagnosis, disease stratification and treatment response.

Building upon this inflammatory data, we also examined the metabolic capacity of monocyte derived macrophages in RA and healthy controls. RA macrophages display heightened mitochondrial respiration along with increased frequency of elongated mitochondria compared with healthy macrophages. In addition, RA macrophages have boosted glycolysis with significant increased expression of key glycolytic markers. This data suggests that RA macrophages are in a highly energetic state in comparison to healthy macrophages. This hyper-energetic phenotype allows macrophages in disease to produce energy quickly to allow for rapid immune activation.

To further explore the underpinning mechanisms of these divergent macrophage activation states, we performed in depth transcriptional analysis pro and anti-inflammatory macrophages in RA patients. Here we demonstrated an enrichment of members of the JAKSTAT signalling pathway (Tofacitinib is a current target of this pathway), particularly STAT3 as well as enrichment of many members of the NAD salvage pathway particularly NAMPT enriched in RA proinflammatory macrophages. Using specific inhibitors for both STAT3 (STATTIC) and NAMPT (FK886), we investigated the role of these two molecules as central players in macrophage polarisation towards inflammatory functions. Here we found that both STAT3 and NAMPT inhibition resulted in inhibition of both the hyperinflammatory, and hypermetabolic phenotype observed in these RA macrophages. Interestingly, NAMPT inhibition also results in reciprocal inhibition of STAT3 gene expression suggesting interplay between these two signalling pathways. Finally phagocytic function of RA macrophages was assessed whereby pro-inflammatory macrophages display decreased phagocytic function compared with anti-inflammatory. This reduction in phagocytosis is reversed upon NAMPT inhibition, with little effect observed with STAT3 blockade.

Combined this data suggests that RA myeloid cells are imprinted with disease-specific hyperinflammatory and bioenergetic signatures and retain this functional commitment, such that differentiation into macrophages conserves this phenotype and results in impaired phagocytic ability. Mechanistically we have identified a key a role for a novel metabolite NAMPT whereby inhibition of NAMPT activity switches the inflammatory and metabolic phenotype of RA macrophages to promote resolution of inflammation. Thus, this study highlights the potential role of circulating monocytes as a blood surrogate marker for tissue inflammation and also identifies new candidate targetable pathways for better treatment options.

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