# Evidence for Pro-Inflammatory Activity of LTα3 on Macrophages: Significance for Experimental Arthritis and for Therapeutic Switching in Rheumatoid Arthritis Patients

## TL;DR

This study shows that LTα3 promotes inflammation in macrophages and suggests that blocking it may not help treat rheumatoid arthritis.

## Contribution

The study reveals a new pro-inflammatory role of LTα3 in macrophages and challenges its therapeutic potential in rheumatoid arthritis.

## Key findings

- LTα3 directs mouse and human macrophages toward a pro-inflammatory M1 phenotype.
- Blocking LTα3 reduced arthritis only in TNF-KO mice, not in wild-type mice.
- Switching RA patients from anti-TNF monoclonal antibodies to etanercept did not improve clinical outcomes.

## Abstract

Lymphotoxin-alpha (LTα3) is a soluble cytokine of the TNF superfamily. Its role in inflammation and arthritis is not well known. Macrophages are important in K/BxN Serum-Transfer Arthritis (STA) and rheumatoid arthritis (RA). Anti-TNF monoclonal antibodies as well as etanercept (ETA), a soluble TNF receptor II that also neutralizes LTα3, are efficient in the treatment of RA. Objectives: To evaluate the role of LTα3 in macrophage phenotypes and in arthritis. Methods: Macrophages were cultured in the presence of recombinant LTα3, and their phenotypes were studied. The clinical effect of blocking LTα3 in STA was evaluated, as well as the effect of switching from anti-TNF monoclonal antibodies to etanercept in the “ROC” register of RA patients. Results: We showed that recombinant LTα3 was capable of directing mouse and human macrophages towards a pro-inflammatory “M1” phenotype. In K/BxN STA, ETA decreased clinical score and joint swelling. Anti-LTα3 reduced arthritis only in TNF-KO mice, indicating that the effect of LTα3 was visible in the absence of TNF. The “ROC” register indicated that switching anti-TNF mAb to ETA did not induce clinical and biological improvement in RA. Conclusion: We show a pro-inflammatory role for LTα3 in murine and human macrophages. The neutralization of both TNF and LTα3 is not beneficial in the treatment of RA.