Cell-Free DNA in the Pathogenesis and Therapy of Non-Infectious Inflammations and Tumors

Abstract

The basic function of the immune system is the protection of the host against infections, along with the preservation of the individual antigenic identity. The process of self-tolerance covers the discrimination between self and foreign antigens, including proteins, nucleic acids, and larger molecules. Consequently, a broken immunological self-tolerance results in the development of autoimmune or autoinflammatory disorders. Immunocompetent cells express pattern-recognition receptors on their cell membrane and cytoplasm. The majority of endogenous DNA is located intracellularly within nuclei and mitochondria. However, extracellular, cell-free DNA (cfDNA) can also be detected in a variety of diseases, such as autoimmune disorders and malignancies, which has sparked interest in using cfDNA as a possible biomarker. In recent years, the widespread use of liquid biopsies and the increasing demand for screening, as well as monitoring disease activity and therapy response, have enabled the revival of cfDNA research. The majority of studies have mainly focused on the function of cfDNA as a biomarker. However, research regarding the immunological consequences of cfDNA, such as its potential immunomodulatory or therapeutic benefits, is still in its infancy. This article discusses the involvement of various DNA-sensing receptors (e.g., absent in melanoma-2; Toll-like receptor 9; cyclic GMP–AMP synthase/activator of interferon genes) in identifying host cfDNA as a potent danger-associated molecular pattern. Furthermore, we aim to summarize the results of the experimental studies that we recently performed and highlight the immunomodulatory capacity of cfDNA, and thus, the potential for possible therapeutic consideration.

Elucidating the Biological Effects of Cell-Free DNA (cfDNA) Extracted from Septic Mice: In Vitro and In Vivo Investigations and Mechanistic Insights

“…cfDNA can activate the innate immune system, the body's first line of defense against pathogens and foreign substances. Once released into the bloodstream, cfDNA can be recognized by immune cells, such as macrophages and dendritic cells, and trigger an inflammatory response [13]. This response can help fight infections or cancer, but if it is improperly regulated, it can lead to the development of autoimmune diseases or other inflammatory conditions.…”

Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy

“…Interestingly, even in the absence of TME, activation of the TLR9-mediated inflammatory pathway may lead to the appearance of the CSC phenotype. The biological effects of cfDNA depend on its structure and origin [ 95 ]. We studied the pathobiological effects of cfDNA administration in HT29 colon adenocarcinoma cells using an in vitro model lacking the TME or the host’s immune system.…”

The Diagnostic, Prognostic, and Therapeutic Potential of Cell-Free DNA with a Special Focus on COVID-19 and Other Viral Infections

“…Increased levels of cf-mtDNA was shown to be associated with mortality of patients in the ICUs [ 185 ] and ARDS [ 186 ], conditions common in severe COVID-19 cases. cfDNA can be detected in autoimmune disorders [ 5 ]. Autoimmunity is one of the hallmarks of patients with severe COVID-19 and symptoms of post-COVID syndrome [ 187 ].…”

“…An increasing number of studies demonstrate the potential use of cfDNA as a noninvasive biomarker to determine pathologic conditions in various diseases, in particular diabetes [ 3 ], autoimmune rheumatic diseases [ 4 ], non-infectious inflammations and tumors [ 5 ], as well as brain diseases [ 6 , 7 ]. In addition, placenta-derived—so-called cell free fetal DNA (cffDNA)—is aggressively marketed, irrespective of its known restrictions in the frame of the “non-invasive prenatal testing” (NIPT).…”