IMMUNOSUPPRESSION
In pathological contexts other than cancer, paradoxically MET can have immunosuppressive effects, both on innate and adaptive immunity [45]. These effects are comprehensive and are schematically illustrated in Chart 2. The study by Diaz et al. (2017) involving obese patients with DMT2 deserves an observation. In it, it was observed that B-cell functions in response to vaccines were recovered and antibody response increased after MET treatment, although the pathological context of DMT2 has exactly the opposite effect to that observed. These effects, although they can be categorized as immuno-stimulators, are due to an anti-inflammatory action of the drug, capable of improving the functions of the B cells [53].
The role of AMPK in inflammation and polarization of macrophages was explored in a study using MET, compound C (an AMPK inhibitor) and AICAR for in vitro intervention. They found that in obese rats, AICAR apparently decreased the percentage of M1 macrophages and increased markedly M2 macrophages, suggesting that activation of AMPK plays a vital role in macrophage polarization [69]. Chung, Nicol, Cheng et al demonstrated the blocking of many effects caused by MET in the presence of compound C, suggesting that activation of AMPK is necessary to decrease pro-inflammatory cytokines, protective effect, decrease levels of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) [54].
Several studies report the action of MET on inflammatory mediators by reducing mRNA expression levels of inflammatory cytokines TNFα, IL-1α, IL-1β, IL-6, chemokines or by attenuating NF-κB activation [52, 55, 56] (Chart 2). This effect arouses great interest in severe cases of COVID-19, by the elevation of levels of inflammatory markers in the blood (C-reactive protein, ferritin and D-dimers), increase in the neutrophil/lymphocyte ratio and of several inflammatory cytokines and chemokines [70]. Mice with acute respiratory distress syndrome, accumulation of neutrophils and increased levels of inflammatory cytokines showed reduction of these indicators of lung damage after MET treatment (v.o. 50 mg/Kg for 7 days) [71]. Thus, the use of MET as a potential therapeutic tool for COVID-19 is highlighted. However, it is essential to understand, initially, the systemic inflammatory responses induced by SARS-CoV-2 and how these pathways are modulated by the different therapies used today.