Regulatory macrophages

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Regulatory macrophages (Mregs) represent a subset of anti-inflammatory macrophages. In general, macrophages are a very dynamic and plastic cell type and can be divided into two main groups: classically activated macrophages (M1) and alternatively activated macrophages (M2). [1] M2 group can further be divided into sub-groups M2a, M2b, M2c, and M2d. [2] Typically the M2 cells have anti-inflammatory and regulatory properties and produce many different anti-inflammatory cytokines such as IL-4, IL-33, IL-10, IL-1RA, and TGF-β. [3] [4] M2 cells can also secrete angiogenic and chemotactic factors. [5] These cells can be distinguished based on the different expression levels of various surface proteins and the secretion of different effector molecules. [4]

Contents

M2a, mainly known as alternatively activated macrophages, are macrophages associated with tissue healing due to the production of components of extracellular matrix. M2a cells are induced by IL-4 and IL-13. [2] M2b, generally referred to as regulatory macrophages (Mregs), are characterized by secreting large amounts of IL-10 and small amounts of IL-12. [6] [7] M2c, also known as deactivated macrophages, secrete large amounts of IL-10 and TGF-β. M2c are induced by glucocorticoids and TGF-β. [8] M2d are pro-angiogenic cells that secrete IL-10, TGF-β, and vascular endothelial growth factor and are induced by IL-6 and A2 adenosine receptor agonist (A2R). [4] [9]

Mreg origin and induction

Mregs can arise following innate or adaptive immune responses. Mregs were first described after FcγR ligation by IgG complexes in the occurrence of pathogen-associated molecular patterns (e. g. lipopolysaccharide or lipoteichoic acid) acting through Toll-like receptors. [10] Coculture of macrophages with regulatory T cells (Tregs) caused differentiation of macrophages toward Mreg phenotype. [11] Similar effect provoked interaction of macrophages and B1 B cells. [12] Mregs can even arise following stress responses. Activation of the hypothalamic-pituitary-adrenal axis leads to production of glucocorticoids that cause decreased production of IL-12 by macrophages. [13]

Many cell types including monocytes, M1, and M2 can in a specific microenvironment differentiate to Mregs. [7] Induction of Mregs is strongly linked with the interaction of Fc receptors located on the surface of Mregs with Fc fragments of antibodies. [14] It has been shown that anti-TNF monoclonal antibodies interacting with Fcγ receptor of Mregs induce differentiation of Mregs through activation of STAT3 signaling pathway. [15] [16] Some pathogens can promote the transformation of cells into Mregs as an immune evasion mechanism. [7] [17] Two signals are needed for Mregs inducement. The first signal is stimulation by M-CSF, GM-CSF, PGE2, adenosine, glucocorticoid, or apoptotic cells. [9] [18] The second signal can be stimulation with cytokines or toll-like receptor ligands. The first signal promotes the differentiation of monocytes to macrophages and the second signal promotes immunosuppressive functions. [8] In vitro, M-CSF, IFNγ, and LPS are used for the inducement of Mregs. [7]

Other cells such as eosinophils and innate lymphoid cells type 2 (ILC2) can promote M2 polarization by cytokine secretion. IL-9 can function as a growth factor for ILC-2 and thereby assist in the induction of Mregs. Another cytokine that helps the induction of Mregs is IL-35 which is produced by Tregs. [7]

Characterization and determination of Mregs

Surprisingly, Mregs resemble classically activated macrophages more than alternatively activated macrophages, due to higher biochemical similarity. [19] The difference between M1 macrophages and Mregs is, inter alia, that Mregs secrete high levels of IL-10 and simultaneously low levels of IL-12. Out of all macrophages, Mregs show the highest expression of MHC II molecules and co-stimulatory molecules (CD80/CD86), which differentiates them from the alternatively activated macrophages, which show a very low expression of these molecules. Mregs also differ from alternatively activated macrophages by producing high levels of nitric oxide and low arginase activity. [7] [16] [19] Lastly, they differ in the expression of FIIZ1 (Resistin-like molecule alpha1) and YM1 which are differentiation markers present on alternatively activated macrophages. [4] Mregs are recognized by the expression of PD-L1, CD206, CD80/CD86, HLA-DR, and DHRS9 (dehydrogenase/reductase 9). [4] [20] DHRS9 has been recognized as a stable marker for Mregs in humans. [20]

Biochemical and functional characterization of Mregs

The physiological role of Mregs is to dampen the immune response and immunopathology. Unlike classically activated macrophages, Mregs produce low levels of IL-12, which is important because IL-12 induces differentiation of naïve helper T cells to Th1 cells which produce high levels of IFNγ. Mregs do not contribute to the production of extracellular matrix because they express low levels of arginase. [12] [4]

Mregs show up-regulation of IL-10, TGFβ, PGE2, iNOS, IDO, and down-regulation of IL-1β, IL-6, IL-12, and TNF-α. [21] By secreting TGF-β they help with the induction of Tregs and by producing IL-10 they contribute to the induction of tolerance and regulatory cell types. Mregs can directly inhibit the proliferation of activated T cells. It has been shown that Mregs co-cultured with T cells have a negative effect on the T-cellular ability to secrete IL-2 and IFN-γ. [22] Mregs can also inhibit the arginase activity of alternatively activated macrophages, the proliferation of fibroblasts, and can promote angiogenesis. [23] The use of Mregs is widely studied as a potential cell-based immunosuppressive therapy after organ transplantation. Mregs could potentially solve the problems (susceptibility to infectious diseases and cancer diseases) associated with the current post-transplant therapy. Since Mregs are still producing nitric oxide they may be more suitable than current treatments, when appropriately stimulated. [22]

Related Research Articles

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the 'B' stands for bursa and not bone marrow as commonly believed.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

<span class="mw-page-title-main">Transforming growth factor beta</span> Cytokine

Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms and many other signaling proteins. TGFB proteins are produced by all white blood cell lineages.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

Understanding of the antitumor immunity role of CD4+ T cells has grown substantially since the late 1990s. CD4+ T cells (mature T-helper cells) play an important role in modulating immune responses to pathogens and tumor cells, and are important in orchestrating overall immune responses.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance prevents immune response to harmless food antigens and allergens, too.

<span class="mw-page-title-main">CD69</span>

CD69 is a human transmembrane C-Type lectin protein encoded by the CD69 gene. It is an early activation marker that is expressed in hematopoietic stem cells, T cells, and many other cell types in the immune system. It is also implicated in T cell differentiation as well as lymphocyte retention in lymphoid organs.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

T helper 3 cells (Th3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. Th3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). Th3 have been described both in mice and human as CD4+FOXP3− regulatory T cells. Th3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4+CD25−FOXP3−LAP+ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that play a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment (TME) is the environment around a tumor, including the surrounding blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment. This ability is connected to their multiple roles in the organism: they are powerful effector cells of the innate immune system, but also important in removal of cellular debris, embryonic development and tissue repair.

Type 1 regulatory cells or Tr1 (TR1) cells are a class of regulatory T cells participating in peripheral immunity as a subsets of CD4+ T cells. Tr1 cells regulate tolerance towards antigens of any origin. Tr1 cells are self or non-self antigen specific and their key role is to induce and maintain peripheral tolerance and suppress tissue inflammation in autoimmunity and graft vs. host disease.

Tolerogenic dendritic cells are heterogenous pool of dendritic cells with immuno-suppressive properties, priming immune system into tolerogenic state against various antigens. These tolerogenic effects are mostly mediated through regulation of T cells such as inducing T cell anergy, T cell apoptosis and induction of Tregs. Tol-DCs also affect local micro-environment toward tolerogenic state by producing anti-inflammatory cytokines.

References

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