Inflammation/Immunology

Background


Inflammation is a self-limiting, localized response to any tissue injury or trauma caused by wounding or infection, and is characterized by redness, heat, pain and swelling (rubor, calor, dolor, tumor). This acute response is aimed at healing the affected tissue by the induction of an extensive network of chemical signals which in turn triggers host innate and adaptive immune responses. A cascade of chemokine and cytokine signals induced by tissue resident cells, such as mast cells and macrophages, promote the recruitment and infiltration of a variety of leukocytes from the blood. Neutrophils are typically the first responders, followed by monocytes, which are activated and directed to the site of inflammation by specific chemokines. Monocytes differentiate into tissue macrophages and become the main source of inflammatory cytokines and growth factors. The inflammatory response to pathogens and injury results in the production and secretion of several canonical pro-inflammatory cytokines, primarily by macrophages. The initial production of tumor-necrosis factor α (TNFα) promotes the inflammatory response and results in some of the cardinal signs of inflammation. A major effect of TNFα is the amplification of the inflammatory response by inducing the production of ΙL-1β, to initiate a cytokine cascade leading to the production of a variety of reactive oxygen species (ROS), chemokines and cytokines, adhesion molecules and other inflammatory mediators. The pro-inflammatory cytokines, specifically IL-1β, are sufficient to induce an inflammatory response, highlighting the importance of IL-1β in promoting inflammation.

Epidemiological and experimental evidence supports the concept that chronic inflammation promotes the development and progression of cancers. Since inflammation is a complex process involving many effector cells and mediators, it is likely that inflammation facilitates tumor progression through multiple mechanisms. Immune suppression may be one of these mechanisms, and have been hypothesized that chronic inflammation causes immune suppression which inhibits immune surveillance and/or tumor immunity, thereby enhancing the proliferation of malignant cells. This hypothesis was based on findings that chronic inflammation, through the production of the pro-inflammatory cytokine IL-1β, facilitated tumor progression and simultaneously elevated a population of suppressor cells called myeloidderived suppressor cells (MDSC3). MDSC are a heterogeneous mixture of immature myeloid cells that are potent inhibitors of anti-tumor immunity. They mediate their effects by inhibiting CD4+ and CD8+ T cell proliferation, by blocking NK cell activation, by limiting dendritic cell maturation, and by polarizing immunity towards a type 2 phenotype. MDSC are found in many patients and experimental animals with cancer, and their induction, expansion, and retention are driven by factors produced by tumor cells and tumor stroma, including potent inflammatory mediators, such as prostaglandin E2 (PGE2 and IL-1β).

Although the acute inflammatory response proceeds through a series of tightly regulated checkpoints, and is self-limiting, the chronic persistence of inflammation is associated with malignancy. Inflammation is normally limited by anti-inflammatory cytokines, stress modulators, and negative feedback loops, which prevent cytokine synthesis and signaling. Dampening of the inflammatory response usually involves the elimination of the initiating stimulus, the decrease in production of inflammatory mediators, and the removal of infiltrating cells. Apoptosis of infiltrating cells, such as neutrophils, triggers the production of anti-inflammatory cytokines, predominantly by macrophages, and tissue repair mechanisms. These processes are necessary to clear cellular debris, and initiate repair mechanisms to return tissue to homeostasis. However, dysregulation of inflammatory checkpoints or inhibition of anti-inflammatory mechanisms leads to the chronic persistence of the inflammatory response, which is a hallmark in many chronic diseases, autoimmunity and malignancy.

Reference: Li Xiao. Development and Evaluation of Molecular Imaging Agent for Inflammation and Cancer.