CD83 as Checkpoint Molecule Controlling Resolution of Inflammation: Comparison
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Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively.

  • CD83
  • resolution of inflammation
  • IDO/TGF-β-axis
  • pro-resolving macrophages
  • transplantation

1. Introduction

Inflammation is a tightly controlled mechanism that ensures an effective response of houman beings' r organism to potential injuries. Tissue damage, either sterile or after infection, leads to the release of exogenous or endogenous danger signals, which trigger the initial induction phase of inflammation. Tissue resident cells, such as macrophages (Mφ), sense an inflammatory stimulus via pattern-recognition receptors, such as toll-like receptors (TLRs), which causes activation of pro-inflammatory signaling cascades, such as the nuclear factor kappa B (NF-κB) pathway [1]. This activation culminates in secretion of pro-inflammatory cytokines and chemokines, which then orchestrate a sequential recruitment of circulating immune cells to initiate an inflammatory response.
The first cellular response team is formed by neutrophil granulocytes, which invade the inflamed tissue in a swarm-like fashion and potentiate inflammation [2]. Neutrophils also recruit circulating inflammatory monocytes that differentiate into Mφ, which clear potential pathogens as well as cellular debris [1][3]. Either the effector cells of the innate immune system suffice to clear the cause of activation or call on the adaptive immune system for aid. For instance, dendritic cells (DCs), which are the most potent antigen-presenting cells of the immune system, mature upon encounter with inflammogens and migrate to the lymph nodes where they activate naïve T cells, which subsequently differentiate into effector T cells. DCs function as a control center at the interface between innate and adaptive immunity, fine-tuning initiation and eventual confinement of inflammatory processes. Furthermore, specific subsets of these cells promote and maintain immunological tolerance by induction of regulatory T cells (Treg), and thus can restrain inflammation [4].
Once the original harmful stimulus has been successfully cleared, it is of utmost importance to confine the inflammatory reaction to prevent excessive tissue damage. This phase is termed resolution of inflammation and it depends on a switch of specific gene expression profiles towards anti-inflammatory mediators and tissue remodeling [5][6]. One key event in the transition to the resolution phase is reprogramming of Mφ phenotype and function [7]. After the first infiltration wave, neutrophils eventually undergo apoptosis, for instance after phagocytosis of pathogenic threats [8]. During the initial inflammatory response, recruited pro-inflammatory Mφ ingest apoptotic neutrophils via a process called efferocytosis. In contrast to phagocytosis of cellular debris or pathogens, efferocytosis of neutrophils modulates Mφ activation and switches Mφ from an inflammatory to an anti-inflammatory and pro-resolving gene profile [9]. In addition, Tregs that have infiltrated the inflamed tissue can skew the Mφ phenotype to a reparative one [6][7]. Pro-inflammatory Mφ are often termed as classically activated cells (CAM or M1-like), whereas reparative Mφ are referred to as alternatively activated (AAM or M2-like), which is a correlate of stimulation with LPS+IFN-γ or IL4, respectively. However, it has become increasingly clear that the rigid M1/M2 dichotomy is an in vitro phenomenon and not sufficient to describe the entire complexity of Mφ polarization [10]. Mφ rather integrate several environmental cues to adopt the perfect phenotype that is needed to promote a regular course of inflammation—including the resolution phase [7]. The functional switch of Mφ is further supported by a finely concerted sequential expression of pro- and anti-inflammatory cytokines and growth factors. While TNF-α and IFN-γ dominate the initial phase of inflammation, resolution of inflammation is carried by expression of IL-10, IGF-1, and TGF-β [11][12][13].
Since a precise succession of initiation and resolution phase is a prerequisite for eliminating the inflammogen without causing immoderate damage, perturbation of this process can result in chronification of inflammation [6]. For instance, autoimmune disorders, such as rheumatoid arthritis (RA) or multiple sclerosis (MS), show a markedly disturbed resolution of inflammation due to constant triggering of immune responses by the respective autoantigen(s) [14][15]. Similarly, impaired resolution of inflammation fosters graft rejection after transplantation [16]. Treatment of such disorders, where proper shutdown of inflammation is disturbed, has relied on administration of broadly acting immunosuppressive drugs for a long time. However, this kind of treatment often comes with severe side effects, since it not only prevents unwanted but also desired immune responses, and even novel biologicals, such as antibodies against TNF-α, IL-6, or IL-12, bear the risk of an adverse impact on immune reactions [6]. Thus, current research focuses on deciphering molecular checkpoints and signaling pathways, whose modulation would rather directly promote resolution of inflammation than simply suppress the natural process of inflammation [17]. An ideal candidate compound for this purpose would be an endogenous modulator to minimize anti-drug responses, and it should not blunt the initiation of inflammation but rather bolster the resolution phase. Recent research revealed that the CD83 molecule possesses these qualities and is therefore perfectly suited as a putative immunomodulatory agent for future treatment of chronic inflammatory diseases.Therefore, thereinis review article will focus on the role of CD83 as an immunologic checkpoint molecule and will discuss future prospects of its use for “pro-resolution-therapies”

2. CD83: From Maturation Marker to Pro-Resolving Checkpoint Molecule

Since its discovery in 1992 as a surface molecule on activated immune cells such as DCs and B cells, the CD83 molecule has been intensively studied and characterized [18][19][20]: the CD83 protein is highly conserved among distinct species as murine, and human CD83 share 63% amino acid identity [21][22]. Membrane-bound CD83 (mCD83) is extensively glycosylated, which almost doubles its theoretical molecular weight from 23 kDa to 45 kDa, and it consists of three domains: an extracellular Ig-like domain, a transmembrane domain and a cytoplasmic domain [18]. A soluble isoform (sCD83) that consists largely of the extracellular domain is released into the supernatant of activated DCs and B cells [23]. This isoform is generated either by alternative splicing or by proteolytic cleavage of mCD83 [23][24]. The sCD83 molecule is present in low levels in sera of healthy donors, but its abundancy increases in sera of patients with hematological malignancies, e.g., multiple myeloma and acute myeloid leukemia, where it inversely correlates with progression-free survival [25]. In addition, patients with chronic inflammatory diseases, such as multiple sclerosis [26] and rheumatoid arthritis [27] show elevated sCD83 serum levels. Originally described as a marker for mature DCs (mDCs) [22][28][29][30][31], CD83 expression has been demonstrated on many other activated immune cells, including neutrophils [32], monocytes, macrophages (Mφ) [33], B/T cells [34], NK cells [35], and Tregs [36]. Moreover, also non-immune cells like epithelial cells of the thymus, airways, and intestine express CD83 [37][38][39]. Interestingly, CD83 is also a target of immune escape mechanisms. For instance, infection of DCs with herpes viruses results in proteasomal degradation of CD83, which leads to inhibition of potent antiviral immune responses [40][41][42]. Furthermore, Hodgkin lymphoma cells express CD83 to subvert anti-tumor T cell responses, in part by secretion of sCD83 [43]. In the past few years, various studies have elucidated the biological role of the mCD83 molecule in the context of homeostasis and immune pathologies. Within these studies, the mCD83 protein has emerged as a master regulator for CD4+ T cell development [44], and recently mCD83 was characterized as an immunoregulatory molecule, which contributes to maintenance of tolerance [30][36]. Moreover, the sCD83 isoform possesses striking capacities to induce the resolution of inflammation, shown in different pre-clinical models for chronic inflammatory/autoimmune diseases, food allergy and transplantation [39][45][46][47][48][49][50][51]. Within the following sections, we will summarize current knowledge on CD83 elicited signaling events and its pro-resolving function in homeostasis, autoimmune pathologies as well as in transplantation.

2.1. Biological Function of CD83 and Its Induced Signaling Events

For many years since its discovery, the signaling capacity of CD83 has remained enigmatic owing to the following problems: (i) the cytoplasmic tail of mCD83 lacks consensus motifs, which allow for binding of adaptor and signaling molecules, and (ii) CD83 has long been received as kind of an “orphan” receptor. While the latter issue was partially solved by identification of binding partners for sCD83 (see below), mCD83 signaling is still the subject of intensive investigations. TIn this section, we will focus on results demonstrating the importance of mCD83 for inflammation and then discuss still existing gaps in our knowledge regarding its signaling. The subsequent section will then deal with the immunomodulatory signaling capacity of sCD83.

2.2. Role of mCD83 in the Resolution of Inflammation

As mentioned above, the deleterious effect of complete CD83-deletion on CD4+ cell development has impeded clear predictions of the biological function of CD83 in inflammation for a long time. Due to their lack of peripheral CD4+ T cells, CD83−/− mice show reduced responses in a contact hypersensitivity model, which is dependent on proper T cell reaction [44][52], and their remaining T cells are hyperresponsive to stimulation [52]. Thus, employing these mice does not allow evaluation of the relevance of CD83 expression on different cell types for immune responses. To circumvent this problem, we generated mice where CD83 can be deleted by the Cre-LoxP system to enable investigations on its cell-specific biologic functions. Preliminary studies have revealed that CD83 deletion in B cells interferes with the proper formation of germinal center reaction and antibody production in response to bacterial infection [53]. Further data on conditional deletion of CD83 in DCs and Tregs have disclosed its vital role for the resolution of inflammation, which we will discuss in the following section.

3. Clinical Relevance of sCD83 for Therapeutic Purposes

There is an extensive body of evidence, demonstrating that sCD83 administration is a potent means to promote pro-resolution effects in preclinical disease models. Thus, in the following chapter, we will summarize the beneficial effects induced by sCD83 in these models, with a special focus on chronic inflammatory and autoimmune conditions as well as strategies to prevent organ transplant rejections.

3.1. sCD83 Promotes the Resolution of Chronic Inflammation

Inflammation is a tightly controlled physiological process of sequentially activated defense mechanisms. Imbalanced inflammation can lead to a misdirected anti-self-reaction that manifests as autoimmune disease, marked by chronic inflammation, destruction of healthy tissue and a loss of tissue functionality. Conventional therapy commonly relies on anti-inflammatory and immunosuppressive drugs to treat overshooting immune reactions. However, the low response rate and strong side effects of these therapies are not satisfying. Thus, new therapeutic concepts aim at modulating/manipulating cells involved in the autoimmune activation process or induce regulatory mechanisms to overcome the disease by enforcing the resolution process. Several independent groups have already proven the efficacy of sCD83 as such a “pro-resolution-compound” in preclinical models for chronic inflammatory and autoimmune diseases [39][45][46][47][48][50][51].

3.2. sCD83 Prevents Graft Rejection by Induction of Tolerogenic Mechanisms

In contrast to autoimmune diseases, in which the immune system reacts to self-antigens, unwanted inflammatory responses of innate and adaptive immune cells occur in the field of transplantation. Rejections of allografts occur due to fatal immune reactions of the recipient to the donor tissue. These inflammatory responses rely on differences of highly polymorphic MHC molecules between recipient and donor, resulting in tissue damage and finally rejection of the transplanted tissue. Current therapeutic approaches in patients receiving organ transplants often rely on a non-specific immunosuppressive medication, such as glucocorticoids, cytostatics, calcineurin inhibitors, or mTOR inhibitors with all known associated negative side effects [54]. Thus, patients after organ transplantation often suffer from drug-associated toxicity, reduced resistance to infections and development of malignancies. Consequently, new therapeutic agents, which establish or induce immune tolerance, promote tissue repair, contribute to resolution of inflammation are urgently needed. For this, researchers pursue amongst others the following strategies: (i) induction or transfer of Tregs, which are able to induce immune tolerance, and (ii) modulation of APC populations including DCs as well as Mφ towards regulatory cells, which can promote Treg differentiation and thus, induce immune tolerance. In this respect, regulatory Mφ, DCs, as well as Tregs, which are able to resolve inflammatory responses have been used in clinical trials as a cellular therapy in combination with immunosuppressive drugs in kidney transplantation [55]. Ijms 23 00732 g002 The sCD83 induced pro-resolving changes on Mφ are summarized in Figure 1.
Figure 1. sCD83 modulates Mφ towards an AAM-like phenotype with pro-resolving functions [56]. Administration of sCD83 during Mφ differentiation results in the secretion of AAM-associated chemokines CCL22 and CCL17, which are important for the recruitment of Tregs. In addition, F4/80, CD11b (black arrows) and the pro-resolving Msr-1 molecule were upregulated (dark blue arrows), while the costimulatory molecule CD86 was downregulated (red arrow). Coculture of sCD83-treated Mφ with allogeneic T cells results in inhibition of T cell proliferation, induction of Tregs as well as reduced IL-6 and TNF-α secretion. Administration of sCD83 during Mφ differentiation and subsequent skewing either towards CAMs or AAMs results in a prominent downregulation of CD86, OX40L (red arrow) on CAMs and in an upregulation of MSR-1 as well as downmodulation of CD86 on AAMs. Subsequently, both sCD83treated CAMs and AAMs enhance CD4+Foxp3+ T cell frequencies in MLR cocultures. Adoptive transfer of sCD83-treated Mφ results in the induction of tolerance in a fully MHC mismatched high-risk corneal transplantation model. Thus, in conclusion, sCD83 modulates Mφ towards an AAM phenotype, which promotes the resolution of inflammation. Figure was created using images from https://smart.servier.com/ (accessed on 29 November 2021) with adaptations.

4. sCD83: Conclusions, New Insights and Future Direction

In recent years, the CD83 molecule has been identified as an important immunological checkpoint, which contributes to the resolution of inflammation. The mCD83 isoform controls inflammatory responses via the induction of regulatory mechanisms in DCs as well as Tregs, while the sCD83 isoform induces resolution of inflammation in autoimmunity and promotes tolerance induction after transplantation. Importantly, a recent study paved the way for new therapeutic options in the field of transplantation: (i) pre-incubation of donor grafts with sCD83 is sufficient to induce tolerogenic mechanisms after transplantation, and (ii) adoptive transfer of sCD83-treated APCs improves graft survival. Since both regulatory DCs and Mφ have already been used in clinical trials after transplantation, the prospect of using sCD83-induced regulatory cells in transplantation is very exciting. Furthermore, this strategy could be combined with direct administration of the pro-resolving sCD83 molecule to modulate pro-inflammatory immune responses and to further promote resolution of inflammation. Similarly, sCD83-treated NK cells conferred immune modulation and disease amelioration in the EAU setting [48], highlighting the potency of sCD83 to boost cell-based therapy approaches. Regarding the role of mCD83 as pro-resolving mediator, adoptive transfer of antigen-specific T cells ectopically over-expressing mCD83 represents another very interesting approach. Collectively, further exploration of the potential of CD83 as a “pro-resolution” therapy may provide modern healthcare with an interesting tool to combat chronic and autoimmune diseases as well as to improve transplant acceptance. 

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