{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent evidence indicates that PI16—a secreted protein originally implicated in myocardial stress responses—plays a multifaceted role in cardiovascular pathology. In the heart, PI16 is produced by fibroblasts and appears to function as part of an autocrine/paracrine circuit: one study highlighted that, in the setting of cardiomyocyte hypertrophy and congestive heart failure, PI16 suppresses the proteolytic activation of the chemokine chemerin by inhibiting cathepsin K, thereby potentially mitigating maladaptive stress responses in the myocardium."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Further, enhanced expression of PI16 in cardiac fibroblasts has been shown to curb fibroblast proliferation and reduce the production of fibrosis‐associated proteins through modulation of HDAC1 levels and subsequent changes in histone acetylation, resulting in smaller cardiac cell size and less collagen deposition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its cardiac actions, PI16 has been implicated in the pathogenesis of neuropathic pain. Research using a spared nerve injury model demonstrated that increased PI16 levels in fibroblasts located in the dorsal root ganglia meninges and adjacent peripheral nerve structures promote transendothelial leukocyte migration by enhancing endothelial barrier permeability. Conversely, mice lacking PI16 exhibit reduced leukocyte infiltration and are protected from pain hypersensitivity, underscoring the importance of fibroblast–endothelial cross-talk mediated by PI16 in the development of neuropathic pain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, PI16 has emerged as a critical regulator of immune homeostasis in autoimmune conditions such as rheumatoid arthritis. Elevated levels of PI16 in the peripheral blood and synovial tissues have been linked to impaired regulatory T cell (Treg) function. Specifically, PI16 interacts with and stabilizes the repressive factor Bmi-1 in Tregs, thereby inhibiting the degradation of Bmi-1 and promoting repressive histone modifications on the Foxp3 promoter. This cascade results in reduced Foxp3 expression and Treg dysfunction, which may exacerbate autoimmune inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Robert J A Frost, Stefan Engelhardt "}, {"type": "b", "children": [{"type": "t", "text": "A secretion trap screen in yeast identifies protease inhibitor 16 as a novel antihypertrophic protein secreted from the heart."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.107.696468"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.107.696468"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17909105"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17909105"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Michael Regn, Bernhard Laggerbauer, Claudia Jentzsch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peptidase inhibitor 16 is a membrane-tethered regulator of chemerin processing in the myocardium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Mol Cell Cardiol (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yjmcc.2016.08.010"}], "href": "https://doi.org/10.1016/j.yjmcc.2016.08.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27539859"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27539859"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Mengqing Deng, Shuo Yang, Yue Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Mol Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/jcmm.15178"}], "href": "https://doi.org/10.1111/jcmm.15178"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32227584"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32227584"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Pooja Singhmar, Ronnie The Phong Trinh, Jiacheng Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The fibroblast-derived protein PI16 controls neuropathic pain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1913444117"}], "href": "https://doi.org/10.1073/pnas.1913444117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32079726"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32079726"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Fang Wang, Xin Gu, Shiyu Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Immunol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clim.2023.109883"}], "href": "https://doi.org/10.1016/j.clim.2023.109883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38147957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38147957"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yuankai Sun, Shiyu Lin, Hui Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulatory role of PI16 in autoimmune arthritis and intestinal inflammation: implications for Treg cell differentiation and function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Transl Med (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12967-024-05082-1"}], "href": "https://doi.org/10.1186/s12967-024-05082-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38566233"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38566233"}]}]}]}