Immune Tolerance as the Physiologic Counterpart of Chronic Inflammation

Introduction

Chronic inflammation is linked to various diseases, including cancer, diabetes mellitus, obesity, and hypertension. The critical question—how is chronic inflammation linked to acute inflammation and are there any physiological counterparts to chronic inflammation ( 1 , 2 ). Answers to these questions are of paramount importance as they determine the treatment strategies of diseases associated with chronic inflammation.

In a simplistic approach, it is possible to divide acute inflammation into the two phases: the onset and the resolution (termination of inflammation and return to homeostasis) ( 3 , 4 ).

Chronic inflammation for various reasons lacks a complete resolution phase—it never ends. There are different reasons for it such as prolonged contact with infection or irritants and the presence of cells that continuously secrete inflammatory mediators. During chronic inflammation, anti-inflammatory cytokines are released continuously—along with pro-inflammatory cytokines ( 2 ). So, when the inflammatory stimulus becomes permanent, immunosuppression begins. This property can be used to achieve immune tolerance. For this aim, every immune-privileged site might contain the source of inflammatory factors ( 5 ). In this case, slightly elevated levels of inflammatory factors are linked to immune tolerance, while significantly elevated levels are linked to inflammatory exacerbations. Examples of Immune Regulatory Roles of Pro-Inflammatory Factors

According to recent studies, there is a long-lasting immune post-resolution phase even after acute inflammation, which might be essential for immune tolerance ( 6 ). It can be supposed that chronic inflammation significantly enhances this stage. Immune-privileged organs can acquire chronic inflammatory status to maintain immune tolerance. In pathology, e.g., cancer, chronic inflammatory status is also utilized to maintain immune tolerance ( Figure 1 ) ( 7 ).

Figure 1 . Low-grade constitutive inflammation might be the mechanism of immune tolerance. Various mechanisms of the transition to immune suppression during chronic inflammation exist. The figure depicts some of them. Inflammatory factors induce anti-inflammatory factors, which cause immune suppression ( 7 ). In the case of acute inflammation, the resolution of inflammation proceeds without suppressing immunity. It is necessary to stop an acute inflammation in time to prevent its transition to the chronic form. In the treatment of diseases linked to chronic inflammation, there may be two methods to utilize—anti-inflammatory and pro-inflammatory therapy. Both of these therapies are aimed at overcoming the vicious cycle of chronic inflammation. Pro-inflammatory therapy can cause a subsequent anti-inflammatory response, resulting in the resolution of chronic inflammation. For instance, this can be the case in hyperthermia therapy ( 8 ). Chronic inflammation, which can occur for various reasons (chronic contact with infection or irritants, chronic stress, and the presence of cells that continuously secrete inflammatory mediators), lacks a complete resolution phase—it never ends. Anti-inflammatory cytokines are released continuously—along with pro-inflammatory cytokines. So, when the inflammatory stimulus becomes permanent, immunosuppression begins. This property can be used to achieve immune tolerance. Chronic low-grade inflammation might be localized—either in immune-privileged organs or tumors. It can lead to immunological tolerance (unresponsiveness to antigens) in the areas of chronic inflammation.

There are various examples of the transition to immune suppression during chronic inflammation.

One such example is the capability of essential inducers of inflammation (specifically, prostaglandins) to function as pro-resolvers—they promote factors necessary for anti-inflammatory and immunosuppressive responses (e.g., specialized pro-resolving mediators) ( 4 ). Inflammation also induces growth and differentiation factor 15 (GDF15), which regulate tolerance to inflammatory damage ( 9 ).

Another example is that one of the primary inflammatory mediators—IL-6 is needed for regenerative and protective processes in the body. For instance, in mice, IL-6 was essential for liver regeneration, gut barrier repair, and the suppression of inflammation in the kidney and pancreas ( 2 ).

The transition of inflammation to immune suppression can also occur at the cellular level. As an illustration, macrophages shut down the generation of pro-inflammatory mediators and activate a transcriptional program resulting in the release of anti-inflammatory cytokines [e.g., IL-10 and transforming growth factor β (TGFβ)] ( 4 ).

Other recent studies have shown that long-term activated dendritic cells (DCs) significantly changed their profile toward a non-functional, tumor-promoting, and anti-inflammatory phenotype ( 10 ). Such DCs promote the generation of T cells with a regulatory phenotype. One of the mechanisms of DCs turning to tolerogenic cells is the action of immunoregulatory enzymes involved in amino acid metabolism (indoleamine-2,3-dioxygenase 1—IDO1, arginase, and inducible nitric oxide synthase—iNOS). They are induced by chronic inflammation, particularly by repeated stimulation of TLR (e.g., exposure to endotoxin) and are involved in the autoimmunity limitation and maintenance of immune tolerance ( 11 , 12 ). These enzymes catabolize amino acids causing their deprivation in the microenvironment (arginase and iNOS catalyze the degradation of L-arginine and IDO1 catalyzes the degradation of L-tryptophan) and produce immune regulatory compounds. For instance, IDO1 produces 3-hydroxyantranilic and L-kynurenine, which serve as an activating ligand for the aryl hydrocarbon receptor (AhR) favoring the expression of protective TGFβ, regulatory T cells (Treg cells) differentiation and inducing IDO1 expression in DCs ( 11 , 13 , 14 ).

These mechanisms are involved in endotoxin tolerance—attenuated production of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-6, and IFN-γ, and increased production of anti-inflammatory cytokines such as IL-10 and TGFβ in response to repeated exposure to LPS (lipopolysaccharide) or a gram-negative infection ( 12 , 15 ).

Above-mentioned enzymes are interconnected as arginase enzymatic activity might be mandatory for the subsequent IDO1 upregulation. Arginine is actively metabolized by arginase to produce urea and l-ornithine. Polyamine spermidine is generated downstream of the decarboxylation of l-ornithine. Spermidine can promote IDO1 phosphorylation and signaling events in DCs, possibly via direct activation of the Src kinase, which has IDO1-phosphorylating activity ( 16 ). Low-Grade Inflammation in Pregnancy

There is much evidence that low-grade inflammation is significant for maintaining immune tolerance in immune-privileged sites. A successful pregnancy requires fine-tuning the level of inflammation. Either the increase or the decrease in the level of inflammatory mediators leads to negative consequences ( 7 ). For instance, it was shown that both a decrease or increase in the IL-6 concentration enhances the risk of infertility and miscarriage ( 17 […]

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