Abstract
The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.
Highlights
The immune system has evolved to protect the host from external pathogens and their microbe or pathogen-associated molecular patterns (MAMPs or PAMPs)
This study indicates the careful use of cyclic GMP–AMP synthase (cGAS)-STING modulators in tumor therapy, including adjuvants in tumor immunotherapies in clinics
Animal studies have shown that the angiotensin II (Ang II) infusion increases the plasma concentration of selfDNA that is recognized by the TLR9 expressed on immune cells, including macrophages, which secrete pro-inflammatory cytokines and other molecules promoting atherogenesis in the aortic arch [235]
Summary
The immune system has evolved to protect the host from external pathogens and their microbe or pathogen-associated molecular patterns (MAMPs or PAMPs). The cGAS [C6orf150 or MAB-21 domain containing protein 1 (MB21D1)]-STING signaling molecules have evolved to serve as intracellular PRRs for the cytosolic dsDNA recognition and comprise a crucial cytosolic innate immune signaling pathway (in different innate immune cells, including fibroblasts, macrophages, and DCs) to induce type 1 IFN production in response to dsDNA viruses, retroviruses (human immunodeficiency virus-1 or HIV-1 and HIV-2), and hostderived self dsDNA [15, 20,21,22,23,24,25,26]. Along with activating IRF3-dependent type 1 IFN production, STING activation is involved in the NF-kB, MAPK, and STAT6 (signal transducer and activator of transcription 6) activation, and stimulating autophagosome formation through activating LC3 puncta formation due to its co-localization with it and autophagy-related protein 9a (Atg9a, a multi-spanning membrane protein crucial for autophagy) upon recognizing cytosolic dsDNA (Figure 1) [49, 67,68,69]. MtDNA-STING signaling inhibition may serve as a novel therapeutic approach for sepsis
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