The same result was obtained with M1 and M2 macrophages derived from blood of patients with RA (Fig. 3b, black bars). Because proteolytic pathways have a critical function in RA development, we were interested in MMP3 secretion upon TLR ligand stimulation in M1 and M2 macrophages derived from blood of HD or patients with RA. Somehow, unexpectedly, we found that TLR4 stimulation by LPS also led to prominent downregulation of these M2 genetic markers, even though signaling through TLR4 resulted in strong anti-inflammatory activity as measured by ratio of IL-10 to IL-6 and to IL-8 and as expected for M2 macrophages. [...]in conditions of abundant TLR2 stimulation, a “chimeric” M2 seems to emerge, displaying an M2-like phenotype defined by surface markers while obtaining M1-like functions as defined by genetic markers and cytokine secretion. Interestingly, several aspects are compatible with our M2-derived “chimeric” macrophages following TLR2 engagement. [...]they also demonstrated that FOLR2 and SLC40A1 gene expression levels in RA SF macrophages were low and corresponded to the generated M1 (GM-CSF) macrophages. [...]TLR stimulation might generate a broad MAPK signaling that then will subsequently be discriminated at different regulatory checkpoints, such as fine-tuning of downstream target gene expression by a specific set of microRNAs.