Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection

Table 2 Immunomodulation mechanisms of mesenchymal stromal cells

	Implicated biomolecules	Mechanism of action	Implicated immune cells	Result
Cell-cell contact	Fas/fas ligand	Fas/fas ligand death signaling pathway/FADD/caspases activation or TRAIL signaling pathway	Macrophages, DCs, T and B cells	Apoptosis
	PD-L1/ PD-1	PD-L1 induced death through binding with the inhibitory checkpoint protein PD-1	T and B cells	Reducing cell proliferation, reducing apoptosis of T reg
	HLA-G/LIRB2 (ILT4/CD85d) and KIR2DL4 (CD158d)	HLA-G/LIRB2 interaction /phosphorylation of TIMS/SHP phosphatases activation/ MAPK downregulation	DCs, NK cells and T cells	Inhibition of cellular proliferation
Soluble factors	PGE2	PGE2/cAMP production/ downregulation of IL-2, IL-2R expression. PGE2/ downregulation of PtdIn/ suppression of T cell receptor signaling	Macrophages, DCs, T and B cells	M2 macrophages switching; Prevention of DCs maturation, T and B cell inactivation
	IDO	IDO blocks the conversion of tryptophan to kyneurenin/in combination with TGF-β1 and HGF	DCs NK cells, T and B cells	G0/G1 cell cycle arrest
	NO	NO/suppression of STAT5 phosphorylation	Macrophages, T and B cells	Inhibition of cellular proliferation
	Galectins	Crosslinking with TCR/clustering prevention	T and B cells	Inhibition of T and B cell proliferation
	Soluble HLA-G isoforms	Similar interaction mechanism as membrane bound HLA-G isoforms	DCs, NK cells and T cells	Inhibition of cellular proliferation
ΕVs	miR-21-5p, miR-142-3p, miR-223-3p, and miR-126-3p	Interaction with JAG1, PDCD4, IL-12p35, downregulation of IL-6 expression	DCs	Inhibition of DC maturation
	miR-145, miR-146 and miR-155	Suppression of TRAF6 and IL-1 IRAK1 expression/down-regulation of NF-κB p65 phosphorylation/decrease in TNF- α, ΙL-1β and IL-6 production	Macrophages, T cells	Inactivation of M1 macrophages; Switching from Th1 to Th2 responses

FADD: Fas-associated death domain; PtdIn: Phosphatidylinositol; DCs: Dendritic cells; NK cells: Natural killer cells; PGE2: Prostaglandin E2; IL: Interleukin; TNF: Tumor necrosis factor; NO: Nitric oxide; STAT5: signal transducer and activator of transcription 5; TCR: T cell receptor; TRAIL: TNF-related apoptosis-inducing ligand; IDO: Indoleamine-2,3-dioxygenase; EVs: Extracellular vesicles; SHP: Src-homology 2 domain-containing protein tyrosine phosphatases; TRAF6: TNF receptor-associated factor 6; IRAK1: IL-1 receptor-associated kinase 1.