Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease; the clinical manifestations are correlated with continuum multiarticular synovitis, cartilage and bone damage, and defeat of joint function, that causes disability. Involvement of internal organs is also frequent. Between the inflammatory cells involved in RA, macrophages play a key role. These cells can polarize in different phenotype and mediate the immune/inflammatory reaction as well as the reparatory phase when possible. The properties of these cells are mediate by the body's environmental factors. In this systematic review, all English-speaking articles concerning the role of M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages in RA were systematically reviewed and categorized according to their polarized-function in RA, especially in the synovial tissue. Analyses of the endogenous molecules and the drugs that could modulate M1 and M2 activity in RA were achieved.

A sensitive search was developed in Pubmed, Web of Science, Ovid Med-Line, Embase Database and Science Direct Database (la both from Elsevier) to identify articles to increase the highlighting on the role of macrophages M1 and M2 in RA using the following terms: ((M1 AND M2) AND Rheumatoid Arthritis). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Relevant data were extracted and analyzed using a standardized template designed for this review.

In total 39 resulting articles were selected and categorized according to description of M1/M2's role in RA. Data from humans, mice and rats were subcategorized, thus in every section were highlighted the contribute, in peripheral blood and synovial tissue, of both polarized macrophages; section for endogenous molecules and drugs that favor the switch from M1 to M2 macrophages were carried out. The most evinced relevant results, were that in RA blood and in the synovial tissue, there isn't a clear distinction phase with M1 or M2 macrophages (by membrane marker analysis); rather there is M1 and M2 subset disequilibrium and by deeply analyses of mRNA gene and cytokine produced, it emerged that a non-coherent expression inner marker match with membrane molecules, and also the tissue section can define the marker expressed.

This systematic review emphasizes that the rigid classical subdivision of M1 and M2 macrophages, as well as the different samples' results comparison, might be questionable. In addition, it is suggested, when taking samples from RA patients, to carefully consider their therapies in order to analyze the M1 and M2 macrophages behavior without drug influence. In line with the advances in M1 and M2 knowledge, and the progression in the single-cell methodologies by identification of individual cell molecular markers, therapeutic approaches seem possible to favor the anti-inflammatory macrophage response in RA (e.g. M2 polarization).