Role of myeloid regulatory cells (MRCs) in maintaining tissue homeostasis and promoting tolerance in autoimmunity, inflammatory disease and transplantation

Abstract

Myeloid cells play a pivotal role in regulating innate and adaptive immune responses. In inflammation, autoimmunity, and after transplantation, myeloid cells have contrasting roles: on the one hand they initiate the immune response, promoting activation and expansion of effector T-cells, and on the other, they counter-regulate inflammation, maintain tissue homeostasis, and promote tolerance. The latter activities are mediated by several myeloid cells including polymorphonuclear neutrophils, macrophages, myeloid-derived suppressor cells, and dendritic cells. Since these cells have been associated with immune suppression and tolerance, they will be further referred to as myeloid regulatory cells (MRCs). In recent years, MRCs have emerged as a therapeutic target or have been regarded as a potential cellular therapeutic product for tolerance induction. However, several open questions must be addressed to enable the therapeutic application of MRCs including: how do they function at the site of inflammation, how to best target these cells to modulate their activities, and how to isolate or to generate pure populations for adoptive cell therapies. In this review, we will give an overview of the current knowledge on MRCs in inflammation, autoimmunity, and transplantation. We will discuss current strategies to target MRCs and to exploit their tolerogenic potential as a cell-based therapy.

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

“…The immunosuppression present in the SIRS/CARS states, e.g., in sepsis and many autoimmune diseases, can increase the risk for persistent infections and multiple organ failure. However, not only severe insults but all chronic inflammatory disorders can provoke an immunosuppressive condition which counteracts the pro-inflammatory responses, thus alleviating the destructive effects of persistent inflammation [4,111,126]. Many pathological conditions involving chronic inflammation display both pro-inflammatory and anti-inflammatory characteristics, i.e., they create a local SIRS/CARS state.…”

“…Recently, it has been observed that both myeloid and lymphoid cells are able to exhibit extensive plasticity; for instance many immune cells display both the pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner, e.g., after infiltration of these cells into stressed tissues. The immune suppressive phenotypes are commonly called regulatory subtypes since they can inhibit the functions of immune effector cells [4,5]. The best characterized immunosuppressive subtypes of myeloid cells include immature myeloidderived suppressor cells (MDSC) as well as regulatory macrophages (Mreg/M2c) and dendritic cells (DCreg/ tolDC).…”

Induction of Antigen-Specific Tolerance in T Cell Mediated Diseases

“…A better understanding of the biology of tolDC and the development of protocols for the generation of tolDC in vitro , opened the possibility to translate their use as immunotherapy in clinical trials for immune-mediated diseases ( 115 , 116 ). These therapies are not simple alternatives to Treg-based therapies, but they are complementary.…”

LDK378 inhibits the recruitment of myeloid‐derived suppressor cells to spleen via the p38–GRK2–CCR2 pathway in mice with sepsis

“…A number of studies have demonstrated that MDSCs support tumor progression and metastasis in the development of tumor‐associated immunosuppressive microenvironment . More recently, MDSCs have been reported to accumulate and expand in infectious disease conditions, such as trauma, burns, and inflammation . In particular, MDSCs were found to be dramatically increased in number, which remained elevated in the spleen, lymph nodes and bone marrow during polymicrobial sepsis, which contributes to sepsis‐induced T‐cell suppression and preferential polarization of T‐helper 2 cells .…”

“…6,7 More recently, MDSCs have been reported to accumulate and expand in infectious disease conditions, such as trauma, burns, and inflammation. 8,9 In particular, MDSCs were found to be dramatically increased in number, which remained elevated in the spleen, lymph nodes and bone marrow during polymicrobial sepsis, which contributes to sepsis-induced T-cell suppression and preferential polarization of T-helper 2 cells. 10 In a recent study, it was shown that the number of circulating MDSCs is persistently increased in sepsis patients and associated with adverse outcomes.…”