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The Influence of Macrophages on Mesenchymal Stromal Cell Therapy: Passive Or Aggressive Agents?

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The Influence of Macrophages on Mesenchymal Stromal Cell Therapy: Passive Or Aggressive Agents? Clinical and Experimental Immunology REVIEW ARTICLE doi:10.1111/cei.12929 The influence of macrophages on mesenchymal stromal cell therapy: passive or aggressive agents? F. Carty, B. P. Mahon and K. English Summary Institute of Immunology, Department of Biology, Maynooth University, Maynooth, Mesenchymal stromal cells (MSC) have emerged as promising cell therapies County Kildare, Ireland for multiple conditions based on demonstrations of their potent immunomodulatory and regenerative capacities in models of inflammatory disease. Understanding the effects of MSC on T cells has dominated the majority of work carried out in this field to date; recently, however, a number of studies have shown that the therapeutic effect of MSC requires the presence of macrophages. It is timely to review the mechanisms and manner by which MSC modulate macrophage populations in order to design more effective MSC therapies and clinical studies. A complex cross- talk exists through which MSC and macrophages communicate, a communication that is not controlled exclusively by MSC. Here, we examine the evidence that suggests that MSC not only respond to inflammatory macrophages and adjust their secretome accordingly, but also that macrophages respond to encounters with MSC, creating a feedback Accepted for publication 16 January 2017 loop which contributes to the immune regulation observed following MSC Correspondence: Bernard P. Mahon, Institute therapy. Future studies examining the effects of MSC on macrophages of Immunology, Department of Biology, should consider the antagonistic role that macrophages play in this Maynooth University, Maynooth, County. exchange. Kildare, Ireland. E-mail: [email protected] Keywords: inflammation, macrophage, mesenchymal stem cells Introduction (Treg) simultaneously [6,9,10]. MAPC and MSC that have been activated or licensed by inflammatory signals such as Adult progenitor cells such as mesenchymal stromal cells interferon (IFN)-g suppress the proliferation of T helper (MSC) and multi-potent adult progenitor cells (MAPC) type 1 (Th1) cells via production of indoleamine 2,3-dioxy- are heterogeneous populations present in a range of adult genase (IDO) [11], while prostaglandin E2 (PGE2) and pro- tissues, often derived from bone marrow (BM) or adipose grammed death ligand 1 (PDL-1) are required for the tissue (AT) for experimental use [1]. While both MSC and suppression of Th17 activity [5,9,12–14]. The combination MAPC can protect and repair damaged tissues [2–4], it is of these effects, with suppression of the inflammatory their immunomodulatory action that has garnered most storm, make MSC and similar therapies important candi- attention over the past decade, with a large number of dates for intervention against chronic immune pathologies. studies demonstrating that MSC can suppress inflamma- The features of the MSC interaction with innate immune tion and adaptive immunity [5–8]. Understandably, the cells are becoming clear. MSC-derived PGE2, the products focus of MSC research has centred on interactions between of IDO and tumour necrosis factor-inducible gene 6 (TSG- MSC and T cells; however, there is now substantial evi- 6) promote the conversion of monocytes and proinflam- dence to suggest that MSC-derived soluble factors also sup- matory macrophages into anti-inflammatory populations press activation and maturation of innate immune cells, producing interleukin (IL)-10 [15–20]. Proliferation, IFN- while skewing early innate reactions towards an anti- g production and the cytotoxic action of natural killer inflammatory phenotype. Studies of adaptive immune (NK) cells is inhibited during co-culture with MSC, with modulation have shown that MSC suppress proliferation IDO, PGE2 and human leucocyte antigen G5 (HLA-G5) and activation of proinflammatory T cells preferentially, playing important roles [21–25]. MSC also suppress adapt- while promoting anti-inflammatory regulatory T cells ive immunity indirectly through shaping the response VC 2017 British Society for Immunology, Clinical and Experimental Immunology, 188: 1–11 1 F. Carty et al. Fig. 1. Mesenchymal stromal cells (MSC) and macrophages cross-communicate. Macrophages are activated by stimuli to produce proinflammatory factors. This creates a feedback loop whereby proinflammatory cytokines produced by macrophages stimulate MSC to produce prostaglandin E2 (PGE2) and interleukin (IL)21RA, among other immune modulators. patterns of dendritic cells (DC). Initially these MSC–DC that an intricate communication exists with cells of the interactions appeared bewildering; however, the mecha- immune system requiring direct cell–cell contact involving nisms by which MSC direct DC towards a regulatory phe- signals such as Notch-Jagged or PDL-1 for MSC to support notype through IL-6 secretion and Notch signalling have Treg and regulatory DC populations. The implication from been clarified recently and characterized by a number of these studies is that suppression of innate immune proc- teams [8,26–29]. esses contributes to the beneficial effects seen when MSC The studies summarized above suggest that MSC action are deployed therapeutically in conditions where an inflam- during cell therapy is complex, and involves more than matory/cytokine storm is prominent. shaping adaptive immunity: MSC therapy is not a simple Clinical trials using MSC and MAPC have been justified form of global immune suppression that can be reduced to, and performed targeting a range of ischaemic and inflam- or replaced by, a single soluble factor. A complex interac- matory conditions including chronic obstructive pulmo- tion occurs whereby MSC seem to be licensed or primed by nary disease (COPD), graft-versus-host disease (GVHD) an inflammatory milieu and respond by producing anti- and Crohn’s disease, with varying levels of success (www. inflammatory soluble factors and surface molecules (Fig. clinicaltrials.gov) [31–33]. While much has been done to 1), suggesting that the early MSC–innate interaction might understand MSC biology, it is evident from the clinical trial be central to successful design of effective therapies. For data that mechanistic understanding lags behind the phe- example, IDO, which converts tryptophan to kynurenine, nomenological observations of MSC efficacy. The gap in is not produced by MSC under basal conditions, but is our understanding is perhaps most evident with regard to induced in human MSC by exposure to IFN-g [20]. Simi- the cross-talk between MSC and macrophages, although a larly, TNF-a induces cyclooxygenase 2 (COX-2) expression number of interesting studies have addressed this issue by murine BM-MSC [30], and IL-1b has been shown to recently. Multiple and varied mechanisms are emerging by prime human MAPC to generate PGE2 [5]. It is also likely which MSC modulate macrophage populations; however, 2 VC 2017 British Society for Immunology, Clinical and Experimental Immunology, 188: 1–11 Cross-talk between macrophages and MSC the priority, redundancy and species specificity of these regulatory capacity of macrophages following cell therapy interactions is still unclear. The remainder of this paper through introduction of MSC-influenced macrophages concentrates on the mechanisms by which MSC promote into different functional assays which have helped to anti-inflammatory macrophage populations, with a partic- advance and clarify our understanding [38,39]. ular focus on the ways in which macrophages and MSC An array of studies have demonstrated the capacity for interact. MSC to modulate inflammatory M1 macrophages and pro- mote anti-inflammatory M2 macrophages [15,37,40]. The recent progress made in the field of immunometabolism Characterizing macrophage phenotypes has been reflected in the MSC field, with Selleri et al. [39] The measurement of the effect of MSC on the inflamma- reporting the capacity of umbilical cord MSC (UC-MSC) tory signature of isolated macrophage populations has to promote an M2 phenotype in a lactate-dependent man- been an important initial topic for study. Macrophages and ner. The M2 gene expression signature was confirmed by their monocytic precursors are professional phagocytes expression of typical macrophage and M2 gene transcripts responsible for the clearance of pathogens and apoptotic such as CD14, CD16, CD68 and IL-10. Furthermore, these cells. Macrophages can further acquire specialized roles MSC influenced monocytes showed a greater capacity to based on their anatomical location. For example, the pre- skew activated T cells towards a Th2 phenotype than dominant function of alveolar macrophages is the elimina- monocytes differentiated in the absence of MSC. While no tion of particulates, allergens and microbes from the role was attributed to IDO or IL-6 in this study, inhibition alveolar surfaces of the lung, while microglia in the brain of lactate production by MSC resulted in lower expression are responsible for tissue remodelling and homeostasis of CD14, CD16 and CD163 and higher expression of [34]. These issues of macrophage diversity give rise to CD1a. In the presence of UC-MSC, monocytes undergoing problems of interpretability and questions of how applica- differentiation into DC show decreased mitochondrial ble data from macrophage cell lines, or from different tis- mass and increased spare respiratory capacity, indicating sues, can be broadly interpreted and applied. that MSC-derived lactate shifts the metabolic programming Regardless of their anatomical location, macrophages are of monocytes undergoing differentiation towards
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