Mesenchymal stromal cells and alpha-1 antitrypsin have a strong synergy in modulating inflammation and its resolution

Abstract

Many reasons, such as infection, injury, tissue transplantation, and cancer treatment, can cause dysregulated hyperinflammation. Immune cells become excessive and hyperactive, producing sustained, systemic and large quantities of cytokines. The systemic inflammation can rapidly progress to disseminated intravascular coagulation, endothelium damage, capillary leakage, multiorgan (e.g., liver, kidney, heart, and brain) dysfunction, ARDS, and fatality. Although the initial driver may differ, the late-stage clinical features of hyperinflammation and cytokine storm converge. Unfortunately, the outcome of current treatments is still unsatisfactory. Our body has regulatory mechanisms to prevent the over-activation of immune cells, but these mechanisms fail or are insufficient in patients with hyperinflammation. Logically, augmenting these regulators represents a promising approach. Among the various natural negative regulators, mesenchymal stromal cells (MSCs) and alpha-1 antitrypsin (A1AT) are attractive due to their unique characteristics. MSCs and A1AT have shown capabilities to modulate immune cells. However, the efficacy and potency of MSCs or A1AT alone are limited and cannot fully normalize hyperinflammation and cytokine storm. Considering MSCs are cells while A1AT is a protein, we hypothesize that they may suppress inflammation using different mechanisms and have additive or synergistic effects when combined. This report showed that the combination of MSCs and A1AT was much more effective than individual components in modulating inflammation of various immune cells in vitro and in animal models. Our results provide solid evidence to support clinical studies of the combinational use of MSCs and A1AT for normalizing inflammation under various disease conditions.