Mesenchymal Stem Cell-Derived Interleukin 1 Receptor Antagonist Promotes Macrophage Polarization and Inhibits B Cell Differentiation

Abstract

The role of interleukin 1 receptor antagonist (IL1RA) in mediating the immunosuppressive effect of mesenchymal stem/stromal cells (MSCs) has been reported in several studies. However, how MSC-derived IL1RA influences the host response has not been clearly investigated. We therefore derived MSCs from the bone marrow of IL1RA knockout mice and evaluated their immunosuppressive effect on different immune cell subsets. IL1RA deficient (IL1RA 2/2 ) or wild type (wt) MSCs inhibited to the same extend the proliferation of T lymphocytes. On the contrary, IL1RA 2/2MSCs were less effective than wt MSCs to induce in vitro the macrophage polarization from M1 to M2 phenotype secreting IL10 and exerting a suppressive effect on CD4 1 T cells. Moreover compared with wt MSCs, IL1RA 2/2 MSCs did not efficiently support the survival of quiescent B lymphocytes and block their differentiation toward CD19 1 CD1381 plasmablasts secreting IgG antibodies. The effectiveness of IL1RA secreted by MSCs in controlling inflammation was further shown in vivo using the collagen-induced arthritis murine model. MSCs lacking IL1RA expression were unable to protect mice from arthritic progression and even worsened clinical signs, as shown by higher arthritic score and incidence than control arthritic mice. IL1RA 2/2 MSCs were not able to decrease the percentage of Th17 lymphocytes and increase the percentage of Treg cells as well as decreasing the differentiation of B cells toward plasmablasts. Altogether, our results provide evidence of the key role of IL1RA secreted by MSCs to both control the polarization of macrophages toward a M2 phenotype and inhibit B cell differentiation in vivo. STEM CELLS 2016;34:483-492 SIGNIFICANCE STATEMENTIn the present study, we present evidence that IL1RA is a key mediator of MSC immunosuppressive effect, which could account for the polarization of macrophages toward the M2 phenotype, together with the already described factors PGE2, IL6 and GM-CSF. We also show that MSC-derived IL1RA impacts on the inhibition of B cell differentiation and the induction of Breg-like cells. The novelty of our study is the conclusion that this effect is at least partly mediated by IL1RA.

Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles

“…Immunomodulatory role of murine BM-MSCs was reported to be dependent on the expression of IL-6-dependent PGE2, IL1-RA and glucocorticoid-induced leucine zipper (GILZ) while inducible nitric oxide synthase (iNOS) expression was dispensable [49,50,51]. However, some studies failed to demonstrate any improvement with MSC treatment, probably related to mouse strain genetic background, or use of immortalized murine MSCs [52,53,54].…”

Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease

“…One of their key immunomodulatory factors is indoleamine 2,3-dioxygenase (IDO), which deprives the environment of L-tryptophan thereby inhibiting lymphocyte proliferation [18], has been demonstrated to promote graft acceptance after solid organ transplantation [19]. In addition, prostaglandin E 2 (PGE 2 ), CCL2 and interleukin 1 receptor antagonist (IL1RA), which are produced by MSC have shown to have an important role in the therapeutic effects of MSC on autoimmune diseases, such as rheumatoid arthritis [3, 4, 20–23]. Besides secretion of anti-inflammatory factors, MSC express cell surface proteins that are known for their immunoregulatory function, such as programmed death-ligand 1 (PD-L1), which inhibits lymphocyte proliferation [24].…”

Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

“…Indeed, MSCs inhibit the activation of dendritic cells (DCs), proinflammatory M1-like macrophages, natural killer (NK) cells, and B and T cells while inducing the generation of cells with anti-inflammatory phenotypes [15–18]. Based on these broad immunomodulatory abilities, the therapeutic potential of MSCs in autoimmune and inflammatory disorders has been intensively investigated in experimental mouse models [19–23].…”

“…TSG-6 will then prevent the interaction of the Toll-like receptor 2 (TLR-2) on macrophages by interacting with their CD44 receptor and thus modulate TLR-2-mediated NF- κ B signaling and decrease macrophage inflammatory response [44]. We and others have shown that IL-1 receptor antagonist (IL-1RA) produced by MSCs is involved in the modulation of the plasticity of macrophages promoting their differentiation toward an M2 phenotype [18, 45]. …”

“…MSCs directly promote the development of CD19 + CD24 high CD38 high IL-10-secreting regulatory B cells through the chemokine stromal derived factor-1 α (SDF-1 α ) and its receptor, CXCR7, which contribute to the generation of an immunosuppressive environment [70, 71]. Finally, in arthritis, we have shown that MSCs inhibit plasmoblasts generation in vivo in CIA through the expression of the IL-1 receptor antagonist (IL-1RA) on MSCs [18]. …”