Mesenchymal Stromal Cells and Their Extracellular Vesicles Enhance the Anti-Inflammatory Phenotype of Regulatory Macrophages by Downregulating the Production of Interleukin (IL)-23 and IL-22

Abstract

Resolution-phase macrophage population orchestrates active dampening of the inflammation by secreting anti-inflammatory and proresolving products including interleukin (IL)-10 and lipid mediators (LMs). We investigated the effects of both human bone marrow-derived mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) on mature human regulatory macrophages (Mregs). The cytokines and LMs were determined from cell culture media of Mregs cultivated with MSCs and MSC-EVs. In addition, the alterations in the expression of cell surface markers and the phagocytic ability of Mregs were investigated. Our novel findings indicate that both MSC coculture and MSC-EVs downregulated the production of IL-23 and IL-22 enhancing the anti-inflammatory phenotype of Mregs and amplifying proresolving properties. The levels of prostaglandin E2 (PGE2) were substantially upregulated in MSC coculture media, which may endorse proresolving LM class switching. In addition, our results manifest, for the first time, that MSC-EVs mediate the Mreg phenotype change via PGE2. These data suggest that both human MSC and MSC-EVs may potentiate tolerance-promoting proresolving phenotype of human Mregs.

Immunoregulatory Effects of Stem Cell-Derived Extracellular Vesicles on Immune Cells

“…(47) or prevent the migration of pro-inflammatory M1 macrophages through interaction with chemokine ligands expressed on other tissues and cells (28,41,42,47) (Table 1). In addition, as reported by a study, SC-EVs downregulate the production of IL-23 and IL-22 and upregulate anti-inflammatory prostaglandin E2 (PGE2) by indirectly repressing the function of T helper type 17 (Th17) cell or by inducing conversion of Th17 cells into regulatory T cells (Tregs) (102). As a result, SC-EVs induced conversion of activated regulatory macrophages (Mregs) from a proinflammatory phenotype to an alternative anti-inflammatory phenotype and eventually promoted the reduction of severe inflammation (102).…”

Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Dendritic Cell Maturation and Function

“…This phenotype change was accompanied with a functional shift in DC cytokine production profile from inflammatory to immunoregulatory. MSC-EVs have been reported to induce regulatory macrophage phenotype change and skew their cytokine production toward a regulatory profile with increased production of anti-inflammatory cytokines and downregulation of inflammatory cytokine production ( 11 , 33 , 38 ). A recent study by Tung et al ( 39 ) also demonstrated that regulatory T cell-derived EVs (Treg-EVs) induced anti-inflammatory cytokine secretion by DCs, with an increased IL-10 and decreased IL-6 production following LPS stimulation ( 39 ).…”

“…The analysis revealed that miR-223-3p targets the CD83 gene, while miR-142-3p has been experimentally observed as an inhibitor of IL-6 expression ( 54 ). Recent evidence also showed that Treg-EV enclosed miR-142-3p can be acquired by DCs resulting in the induction of a tolerogenic phenotype in DC ( 38 ). Moreover, miR-126-3p targets genes upstream TLR signaling, such as Tsc1 , a negative regulator of the mTOR kinase ( 55 ) and miR-29b targets Bcl-2 gene, which is involved in the maintenance of DC longevity in vivo ( 56 ).…”

Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

“…Similarly, using in vitro cell models and an in vivo model of cardiotoxin induced-skeletal muscle injury, Lo Sicco and colleagues demonstrated that adipose tissue derived-MSCs release EVs endowed with potent anti-inflammatory capacities to balance macrophage polarization toward an “M2-like” profile [ 112 ]. More recently, Hyvärinen and coworkers demonstrated that MEx enhance the anti-inflammatory phenotype of regulatory (‘M2-like’) macrophages by downregulating the production of interleukin (IL)-23 and IL-22 [ 113 ]. Of interest, other studies have found that exosomes isolated from MSCs preconditioned by lipopolysaccharide (LPS) may have superior ‘regulatory’ abilities for macrophage polarization and resolution of chronic inflammation by shuttling microRNA let-7b [ 114 ].…”