Folate Receptor Beta for Macrophage Imaging in Rheumatoid Arthritis

Abstract

Non-invasive imaging modalities constitute an increasingly important tool in diagnostic and therapy response monitoring of patients with autoimmune diseases, including rheumatoid arthritis (RA). In particular, macrophage imaging with positron emission tomography (PET) using novel radiotracers based on differential expression of plasma membrane proteins and functioning of cellular processes may be suited for this. Over the past decade, selective expression of folate receptor β (FRβ), a glycosylphosphatidylinositol-anchored plasma membrane protein, on myeloid cells has emerged as an attractive target for macrophage imaging by exploiting the high binding affinity of folate-based PET tracers. This work discusses molecular, biochemical and functional properties of FRβ, describes the preclinical development of a folate-PET tracer and the evaluation of this tracer in a translational model of arthritis for diagnostics and therapy-response monitoring, and finally the first clinical application of the folate-PET tracer in RA patients with active disease. Consequently, folate-based PET tracers hold great promise for macrophage imaging in a variety of (chronic) inflammatory (autoimmune) diseases beyond RA.

Recent advances in nano-targeting drug delivery systems for rheumatoid arthritis treatment

“…Folate receptors are glycopolypeptides with high affinity for folic acid that have four isoforms (FR-α, FR-β, FR-γ and FR-δ) that are differentially expressed among tissues [144]. FR-β is widely expressed on the surfaces of activated synovial macrophages in patients with RA and therefore may be a potential target for disease treatment [145]. MTX encapsulated in hydrophobically modified ethylene glycol chitosan nanoparticles conjugated to folic acid, compared with nanoparticles without folic acid conjugation, has been found to result in significantly lower pro-inflammatory cytokine expression, paw thickness and arthritic scores in CIA mice [130].…”

On the origin of the functional versatility of macrophages

“…The folate gradient is perceived via a G-protein coupled folate receptor at nanomolar concentrations and leads to the activation of chemotaxis and machinery required for phagocytosis and bacterial processing in the phagolysosome (Pan et al, 2016). Interestingly, increased expression of folate receptors are a hallmark of pro-inflammatory mammalian macrophages (Steinz et al, 2022). In particular, folate receptor β (FR-β) has been identified as a specific surface receptor for highly proinflammatory macrophages, such as those found in the synovial tissue of arthritic patients, in atherosclerotic plaques, or in pulmonary fibrosis (Chandrupatla et al, 2019).…”

Update on Imaging of Inflammatory Arthritis and Related Disorders

“…Another promising upcoming target for RA PET imaging is the folate receptor beta (FRb). 53 FRb is a high affinity binding protein for folates (i.e. folic acid and reduced folate cofactors) and is highly expressed on macrophages that are activated by inflammatory stimuli and on macrophages of RA synovial tissue.…”