Human Bone Marrow Mesenchymal Stromal/Stem Cells Regulate the Proinflammatory Response of Monocytes and Myeloid Dendritic Cells from Patients with Rheumatoid Arthritis.

Paula Laranjeira,Brígida Antunes,Tânia Ribeiro,Manuel Abecasis,António Martinho,Mónia Pedrosa,Susana Pedreiro,Cátia Duarte,Francisco Dos Santos,Margarida Fardilha,José António Pereira Da Silva,Artur Paiva,M Rosário Domingues

doi:10.3390/pharmaceutics14020404

Abstract

Rheumatoid arthritis (RA) is a disabling autoimmune disease whose treatment is ineffective for one-third of patients. Thus, the immunomodulatory potential of mesenchymal stromal/stem cells (MSCs) makes MSC-based therapy a promising approach to RA. This study aimed to explore the immunomodulatory action of human bone marrow (BM)-MSCs on myeloid dendritic cells (mDCs) and monocytes, especially on cytokines/chemokines involved in RA physiopathology. For that, LPS plus IFNγ-stimulated peripheral blood mononuclear cells from RA patients (n = 12) and healthy individuals (n = 6) were co-cultured with allogeneic BM-MSCs. TNF-α, CD83, CCR7 and MIP-1β protein levels were assessed in mDCs, classical, intermediate, and non-classical monocytes. mRNA expression of other cytokines/chemokines was also evaluated. BM-MSCs effectively reduced TNF-α, CD83, CCR7 and MIP-1β protein levels in mDCs and all monocyte subsets, in RA patients. The inhibition of TNF-α production was mainly achieved by the reduction of the percentage of cellsproducing this cytokine. BM-MSCs exhibited a remarkable suppressive action over antigen-presenting cells from RA patients, potentially affecting their ability to stimulate the immune adaptive response at different levels, by hampering their migration to the lymph node and the production of proinflammatory cytokines and chemokines. Accordingly, MSC-based therapies can be a valuable approach for RA treatment, especially for non-responder patients.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease, associated to Th1/Th17-mediated chronic inflammation of the joints, whose etiology is still elusive
To investigate how allogeneic bone marrow (BM)-mesenchymal stromal/stem cells (MSCs) regulate the immune function of PB monocytes and myeloid dendritic cells (mDCs) from RA patients, we evaluated the protein levels or mRNA expression of proinflammatory cytokines (TNF-α and IL-1β), proteins involved in cell migration (CCL3 or MIP-1α, CCL4 or MIP-1β, CCL5 or RANTES, CXCL9 or MIG, CXCL10 or IP-10, and CCR7), and the maturation marker CD83, in the presence/absence of BM-MSCs and stimulating agents (LPS plus IFNγ)
In order to assess the effect of BM-MSCs over TNFα and MIP-1β protein production, we used flow cytometry to measure the intracellular levels of these cytokines in monocytes and mDCs, using PBMCs cultured in the absence or in the presence of BM-MSCs

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease, associated to Th1/Th17-mediated chronic inflammation of the joints, whose etiology is still elusive. Several types of immune cells, namely monocytes/macrophages and dendritic cells (DCs), actively participate in RA pathophysiology and, together with Th1 and Th17 cells, infiltrate the RA joint There, they produce inflammatory mediators—namely interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, extracellular matrix-degrading enzymes, and free radicals—leading to chronic joint inflammation, with consequent cartilage destruction and bone erosion [1,3,4,5,6]. A recent clinical trial in RA, reported that the administration of umbilical cord blood MSCs resulted in the reduction DAS28 score and peripheral inflammatory parameters, including TNF-α, IL-1β, IL-6 and IL-8, accompanied by the increase of IL-10 expression. These data suggest MSC therapy influences the course of RA with evident clinical improvement [9]. Notwithstanding, clinical trials point out that multiple MSCs infusions at different time points will be probably needed and, in this scenario, immune sensitization against allogeneic MSCs may be a limitation for their use [15,16]

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