Abstract
Detection of microbial nucleic acids by the innate immune system is mediated by numerous intracellular nucleic acids sensors. Upon the detection of nucleic acids these sensors induce the production of inflammatory cytokines, and thus play a crucial role in the activation of anti-microbial immunity. In addition to microbial genetic material, nucleic acid sensors can also recognize self-nucleic acids exposed extracellularly during turn-over of cells, inefficient efferocytosis, or intracellularly upon mislocalization. Safeguard mechanisms have evolved to dispose of such self-nucleic acids to impede the development of autoinflammatory and autoimmune responses. These safeguard mechanisms involve nucleases that are either specific to DNA (DNases) or RNA (RNases) as well as nucleic acid editing enzymes, whose biochemical properties, expression profiles, functions and mechanisms of action will be detailed in this review. Fully elucidating the role of these enzymes in degrading and/or processing of self-nucleic acids to thwart their immunostimulatory potential is of utmost importance to develop novel therapeutic strategies for patients affected by inflammatory and autoimmune diseases.
Highlights
The innate immune system is the first line of defense of an organism against microbial infections
PLD3 and PLD4 are novel nucleases working together in the endolysosomes of innate immune cells to prevent endogenous ssDNA sensing by TLR9 and the development of inflammatory syndromes (Figure 3), but further investigation is needed to address the relevance of PLD3/4 in humans and how they may contribute to specific autoimmune disorders [117,118,119]
Comprehensive studies performed in patients and validated in experimental mouse models certify the prominent role of nucleases and nucleic acids (NAs)-editing enzymes in the prevention of autoimmunity, autoinflammation, and malignancy
Summary
The innate immune system is the first line of defense of an organism against microbial infections. These enzymes, comprising both DNases and RNases, play a crucial role in the regulation of the abundance, the size, and the immunostimulatory potential of endogenous cfNAs as supported by in vivo studies and clinical observations indicating that their deficiencies and dysregulation contribute to the development of autoimmune syndromes.
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