The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis

Abstract

The identification of “trained immunity/tolerance” in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeutic agents in cancer and rheumatoid arthritis (RA). We have previously showed that MTX promotes trained immunity in human macrophages. In the present manuscript, we have assessed the anti-inflammatory effects of PMX and MTX and found that OCM blockers alter the functional and gene expression profile of human macrophages and that OCM blockade reprograms macrophages towards a state of lipopolysaccharide (LPS) tolerance at the signaling and functional levels. Moreover, OCM blockade reduced macrophage LPS responsiveness by impairing the expression of membrane-bound and soluble CD14 (sCD14). The therapeutic relevance of these results was later confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. As a whole, our results demonstrate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance and positions sCD14 as a valuable tool to predict MTX response in RA patients.

Folate Receptor Beta for Macrophage Imaging in Rheumatoid Arthritis

“…PMX was originally developed to overcome MTX resistance in cancer chemotherapy (55) by harboring more efficient transport properties via RFC, PCFT and FR than MTX (Figure 1C). PMX has shown anti-arthritic effects by suppressing cytokine production in activated T cells of RA patients (75), experimental arthritis models (74) and polarized macrophages in vitro (28). Together, these preclinical studies demonstrate the suitability and feasibility of macrophage PET with [ 18 F]fluoro-PEG-folate for arthritis disease monitoring and therapy response monitoring thereby supporting clinical studies in RA.…”

“…Also FRb functions as one of three transport proteins for folates and antifolates, the two others are the reduced folate carrier (RFC, SLC19A1) and proton-coupled folate transporter (PCFT, SLC46A1) (57) (Figure 1E). The expression of these 3 folate transporters does vary between polarized macrophages; in ex vivo skewed monocytes to M1-type macrophages by GM-CSF and M2-type macrophage by M-CSF, RFC gene expression is differentially higher in M1-type macrophages, whereas FRb and PCFT expression are markedly higher in M2-type macrophages (27,28). Given that FRa/b also retain a high affinity binding profile for folate conjugates, this allowed the design of folate conjugates which could serve as folate based imaging agents like [ 18 F]fluoro-PEG-folate (Figure 1F) (58-60).…”

“…In the context of this review, FRb expression has long been recognized on macrophages that are triggered by inflammatory stimuli and on activated macrophages in inflamed joints of RA patients (24,25). In exvivo M-CSF skewed monocyte-derived macrophages, FRb is differentially expressed on M2-type macrophages (26)(27)(28). However, in inflamed RA synovium, these FRb-expressing M2macrophages can produce pro-inflammatory cytokines when exposed to either pro-inflammatory stimuli (i.e.…”

Predictors of improvement in disease activity in first hospitalized patients with systemic lupus erythematosus: a multicenter retrospective study of a Chinese cohort

“…Apart from it, leflunomide also favored renal function, especially regarding 24-h proteinuria and serum creatinine[ 26 ]. Methotrexate is a kind of antifolate that inhibit nucleotide synthesis and DNA replication and is commonly used in rheumatoid arthritis treatment[ 27 ]. A meta-analysis indicated that methotrexate was also effective in reducing SLEDAI score and alleviating active arthritis and cutaneous manifestations[ 28 ].…”

Role of CD14 in human disease

“…Elevated levels of CD14 in patients associates with higher levels of cholesterol coupled with greater risks of myocardial infarction and cardiovascular‐associated death [71]. CD14 also appears to enhance the severity of cardiomyopathic conditions that result from third degree burn injury [72] and Chagas disease [73]. Finally, CD14 levels have been suggested to predict patient outcomes following acute myocardial infarction [74].…”