TNF‐α and IL‐1β sensitize human MSC for IFN‐γ signaling and enhance neutrophil recruitment

Abstract

During inflammatory processes, tissue environmental cues are influencing the immunoregulatory properties of tissue‐resident mesenchymal stem/stromal cells (MSC). In this study, we elucidated one of the molecular and cellular responses of human MSC exposed to combinations of inflammatory cytokines. We showed that during multi‐cytokine priming by TNF‐α, IL‐1β, and IFN‐γ, IL‐1β further augmented the well‐established immunoregulatory activity induced by TNF‐α/IFN‐γ. On the molecular level, TNF‐α and IL‐1β enhanced the expression of IFN‐γ receptor (IFN‐γR) via NF 'kappa‐light‐chain‐enhancer' of activated B‐cells (NF‐κΒ) signaling. In turn, enhanced responsiveness to IFN‐γ stimulation activated STAT5 and p38‐MAPK signaling. This molecular feedback resulted in an increased IL‐8 release and augmented recruitment of polymorphonuclear granulocytes (PMN). Our study suggests the possibility that responses of MSC to multi‐cytokine priming regimens may be exploited therapeutically to fine‐tune inflammatory activity in tissues. This study elucidates molecular mechanisms underlying the immunological priming of mesenchymal stromal cells (MSC) and their interaction with neutrophils.

Research Progress on Strategies that can Enhance the Therapeutic Benefits of Mesenchymal Stromal Cells in Respiratory Diseases With a Specific Focus on Acute Respiratory Distress Syndrome and Other Inflammatory Lung Diseases

“…In a recent study, it was demonstrated that TNF-α/IFN-γ/IL-1β exposed MSCs had a stronger IL-8 secretion than MSCs exposed to TNF-α/IFN-γ only. Moreover, this increased expression of IL-8 enhanced neutrophil recruitment, a recruitment that was suggested to be mediated trough activation of STAT5 and p38-MAPK signaling (Hackel et al, 2020). This is but one example of potential means of pre-activating MSCs.…”

Metabolic Interdependency of Th2 Cell-Mediated Type 2 Immunity and the Tumor Microenvironment

“…Furthermore, injection of IL-4 enhanced tumor clearance and correlated with increased infiltration of eosinophils, macrophages, neutrophils and in part lymphocytes. In addition, neutralizing IL-5 by monoclonal antibodies restored tumor growth (50,57,58,62,65). The latter studies demonstrated that Th2 cytokines are important in anti-tumor immunity, although they do not provide direct evidence for an involvement of Th2 cells.…”

“…While, traditionally, type 2 immunity was implicated in an inhibition of anti-tumor responses, a number of studies provide convincing evidence demonstrating that Th2 cells indeed mediate anti-tumor immunity. Of note, these studies do not only provide correlative analyses, but apply adoptive Th2 cell transfer experiments (49,56,61) or perform pharmacological administration of Th2 cytokines to tumor bearing mice (50,57,58,62,66). Some of the anti-tumor effects of Th2 cells in addition were attributed to an indirect effect of Th2 cells and their cytokines on Th9 cells (98,99).…”

Current Status of Cell-Based Therapies for COVID-19: Evidence From Mesenchymal Stromal Cells in Sepsis and ARDS

“…Senescent MSCs were also unable to show protection in a murine model of LPS-induced lethal endotoxemia (155). In some reports, MSCs were indicated to enhance neutrophil recruitment and its bactericidal functions through TNF-a and IL-1b signaling (156,157). However, these findings highlight MSCs as a potential risk factor because aberrant neutrophil activation contributes to disease severity and local tissue damage in COVID-19 through the amplification of hypercytokinemia and the formation of neutrophil extracellular traps (NETs) (158).…”