{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRNase 7 is an abundant, 14.5‐kDa antimicrobial ribonuclease originally isolated from human skin, where it exhibits potent ribonuclease activity and broad-spectrum killing of bacteria—including drug‐resistant strains—and other pathogens. It is secreted primarily by keratinocytes and is also expressed in other epithelial tissues such as the urinary tract, where intercalated cells release RNase 7 at levels sufficient to maintain sterility during infection. Basal expression levels of RNase 7 and related antimicrobial peptides may even influence an individual’s susceptibility to pathogens such as Staphylococcus aureus."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, studies in epidermal keratinocytes have shown that RNase 7’s antimicrobial function is finely regulated. Endogenous ribonuclease inhibitors expressed by keratinocytes can bind RNase 7 and suppress both its ribonucleolytic and antimicrobial activities; however, proteolytic processes within the stratum corneum degrade these inhibitors, releasing RNase 7 to act on microbial membranes. In biophysical models, RNase 7 is shown to induce leakage of microbial membranes rapidly—prior to aggregate formation—thereby distinguishing its mechanism of action from related RNase family members."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRNase 7 expression is highly sensitive to immunomodulatory signals. Cytokines such as interleukin‑17A and interferon‑γ synergistically induce its transcription in keratinocytes, while factors present in tear fluid modulate its expression via microRNA regulation. Moreover, RNase 7 can act as an alarmin by facilitating the recognition of self‐DNA by plasmacytoid dendritic cells, thereby triggering robust type I interferon responses that enhance antiviral defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegional expression studies have revealed that RNase 7 levels vary with anatomical site, reflecting the localized nature of epithelial defense. In the urinary tract, epithelial and intercalated cells upregulate RNase 7 in response to infection—with concomitant modulation by endogenous inhibitors—while reviews on cutaneous immunity underscore its central role in providing a rapid, first-line barrier against invading pathogens."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMetabolic and pathogen‐challenge studies further delineate the regulation of RNase 7. In the urinary tract, insulin acts via the PI3K/AKT signaling pathway to stimulate RNase 7 production—a mechanism that may underlie the increased infection risk observed in diabetic individuals. In parallel, keratinocytes challenged by pathogens such as the dermatophyte Trichophyton rubrum show a synergistic induction of RNase 7 (especially when combined with proinflammatory cytokines), and functional studies in urinary models confirm its broad-spectrum bactericidal activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct antimicrobial actions, RNase 7 also exerts important immunomodulatory functions. It influences activated T cells—hinting at roles in shaping adaptive immunity—and, in keratinocytes, its ability to complex with self–DNA converts normally inert genetic material into a potent danger signal that provokes antiviral cytokine production. In related studies on intracellular innate immune regulation, distinct pathways such as those governing endoplasmic reticulum calcium handling have been characterized, although these are not directly linked to RNase 7."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nReceptor-mediated signaling is also central to RNase 7 regulation. Pseudomonas aeruginosa, for example, induces RNase 7 expression in keratinocytes through an epidermal growth factor receptor–dependent mechanism. Furthermore, genetic variations in the RNASE7 gene—such as single nucleotide polymorphisms that diminish its bactericidal potency—have been associated with increased susceptibility to urinary tract infections."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDevelopmental and neoplastic studies further expand the functional spectrum of RNase 7. Antimicrobial peptides, including RNase 7, exhibit differential expression during skin maturation, suggesting that their timely production is crucial for establishing a sterile environment in utero. Moreover, beyond its antimicrobial and immune‐regulatory roles, high RNase 7 expression in the oral epithelium has been linked to a suppression of malignant potential in oral squamous cell carcinoma, while its anti-inflammatory effects in bladder epithelium under high-glucose conditions hint at potential therapeutic applications in diabetic cystitis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these studies demonstrate that RNase 7 functions as a multifunctional effector in epithelial innate immunity. It not only directly targets a broad range of pathogens through membrane-disrupting activity but also integrates signals from cytokines, metabolic pathways, and receptor-mediated events to modulate immune responses and maintain tissue homeostasis.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jurgen Harder, Jens-Michael Schroder "}, {"type": "b", "children": [{"type": "t", "text": "RNase 7, a novel innate immune defense antimicrobial protein of healthy human skin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M207587200"}], "href": "https://doi.org/10.1074/jbc.M207587200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12244054"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12244054"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "John David Spencer, Andrew L Schwaderer, Huanyu Wang, et al. 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