Hyaluronidase inhibits reactive adipogenesis and inflammation of colon and skin

Dokoshi, Tatsuya; Zhang, Ling-juan; Nakatsuji, Teruaki; Adase, Christopher A.; Sanford, James A.; Paladini, Rudolph D.; Tanaka, Hiroki; Fujiya, Mikihiro; Gallo, Richard L.

doi:10.1172/jci.insight.123072

Cited by 41 publications

(39 citation statements)

References 54 publications

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“…A persistence of highmolecular weight HA enables this adipogenic response and results in much greater expression of Camp in the dermis at the site of infection. We have previously shown that increased hyaluronidase-1 activity (in contrast with the loss of hyaluronidase activity seen here in Cemip À/À mice) will inhibit reactive adipogenesis and Camp expression (Dokoshi et al, 2018). Our findings described in Figures 2 and 3 show that loss of Cemip enables the skin to respond to S. aureus infection by increasing expression of Camp, expanding DWAT and enhancing gene expression associated with adipogenesis.…”

Section: Discussionmentioning

confidence: 49%

“…We have recently shown that a major source of cathelicidin expression in the skin comes from the local differentiation of preadipocyte fibroblasts into adipocytes, a process we refer to as reactive adipogenesis (Zhang et al, 2015). Degradation of HA inhibits the capacity of preadipocytes to differentiate into mature adipocytes (Dokoshi et al, 2018;Ji et al, 2014). Therefore, we hypothesized that the digestion of HA by Cemip may inhibit the local adipogenic response and thus suppress the expression of the antimicrobial peptide by these cells.…”

Section: Loss Of Cemip Enhances Reactive Adipogenesismentioning

confidence: 99%

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Hyaluronan Degradation by Cemip Regulates Host Defense against Staphylococcus aureus Skin Infection

Dokoshi

Zhang

et al. 2020

Cell Reports

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Section: Discussionmentioning

confidence: 49%

Section: Loss Of Cemip Enhances Reactive Adipogenesismentioning

confidence: 99%

Hyaluronan Degradation by Cemip Regulates Host Defense against Staphylococcus aureus Skin Infection

Dokoshi

Zhang

et al. 2020

Cell Reports

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“…Adipose tissue undergoes local expansion after cutaneous tissue injury, inflammation, and bacterial infection in a phenomenon that we have named reactive adipogenesis (Dokoshi et al, 2018;Zhang et al, 2015). This phenomenon has been observed in other species.…”

Section: Reactive Adipogenesis: How the Adipogenic Response Defends Amentioning

confidence: 79%

“…Oral dextran sulfate sodium can be administered to induce acute colitis in mice, which results from increased epithelial wall permeability, impaired mucus secretion, dysregulated defensin production, and increased bacterial burden (Kruis et al, 2013). Recently, Dokoshi et al (2018) showed that these mice concomitantly developed increased mesenteric fat, submucosal layer thickening, mature adipocyte accumulation, and up-regulation of adipogenic genes, including Pref1 and Zfp423. Histologic examination of tissue from patients with inflammatory bowel disease showed similarly increased Pref1 expression and staining, suggesting that reactive adipogenesis occurs in both mouse and human colitis (Dokoshi et al, 2018).…”

Section: Reactive Adipogenesis: How the Adipogenic Response Defends Amentioning

confidence: 99%

Dermal White Adipose Tissue: A Newly Recognized Layer of Skin Innate Defense

Chen

Zhang

Gallo

2019

Journal of Investigative Dermatology

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Dermal white adipose tissue is a unique layer of adipocytes within the reticular dermis of the skin. Recently, several nonmetabolic activities have been discovered for dWAT and its fibroblast precursors. These functions include antimicrobial defense and roles in hair cycling, wound healing, and thermogenesis. In this review, we discuss recent progress in understanding the role of dermal white adipose tissue in immunity, both as an innate antimicrobial cell type and as an indirect communicator with other cutaneous immunocytes to enhance defense and potentially contribute to inflammatory disease.

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“…The protective role of cathelicidin was also confirmed in survival analysis between Cnlp wild-type and knockout group. Consistently, human cathelicidin protects rats against sepsis after bacterial challenge [33] and the increased expression of cathelicidin in adipocytes surrounding the colon limits the release of bacteria from mice with experimental colitis [34]. Nevertheless, contradictory evidence also exists in the literature.…”

Section: Discussionmentioning

confidence: 99%

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

Chan

Liang

et al. 2020

Crit Care

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Objectives: The intestinal epithelium compartmentalizes the sterile bloodstream and the commensal bacteria in the gut. Accumulating evidence suggests that this barrier is impaired in sepsis, aggravating systemic inflammation. Previous studies reported that cathelicidin is differentially expressed in various tissues in sepsis. However, its role in sepsis-induced intestinal barrier dysfunction has not been investigated.Design: To examine the role of cathelicidin in polymicrobial sepsis, cathelicidin wild-(Cnlp +/+ ) and knockout (Cnlp −/− ) mice underwent cecal-ligation and puncture (CLP) followed by the assessment of septic mortality and morbidity as well as histological, biochemical, immunological, and transcriptomic analyses in the ileal tissues. We also evaluated the prophylactic and therapeutic efficacies of vitamin D3 (an inducer of endogenous cathelicidin) in the CLP-induced murine polymicrobial sepsis model. Results: The ileal expression of cathelicidin was increased by three-fold after CLP, peaking at 4 h. Knockout of Cnlp significantly increased 7-day mortality and was associated with a higher murine sepsis score. Alcian-blue staining revealed a reduced number of mucin-positive goblet cells, accompanied by reduced mucin expression. Increased number of apoptotic cells and cleavage of caspase-3 were observed. Cnlp deletion increased intestinal permeability to 4kD fluorescein-labeled dextran and reduced the expression of tight junction proteins claudin-1 and occludin. Notably, circulating bacterial DNA load increased more than two-fold. Transcriptome analysis revealed upregulation of cytokine/inflammatory pathway. Depletion of Cnlp induced more M1 macrophages and neutrophils compared with the wild-type mice after CLP. Mice pre-treated with cholecalciferol (an inactive form of vitamin D3) or treated with 1alpha, 25-dihydroxyvitamin D3 (an active form of VD3) had decreased 7-day mortality and significantly less severe symptoms. Intriguingly, the administration of cholecalciferol after CLP led to worsened 7-day mortality and the associated symptoms.Conclusions: Endogenous cathelicidin promotes intestinal barrier integrity accompanied by modulating the infiltration of neutrophils and macrophages in polymicrobial sepsis. Our data suggested that 1alpha, 25-dihydroxyvitamin D3 but not cholecalciferol is a potential therapeutic agent for treating sepsis.

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Hyaluronidase inhibits reactive adipogenesis and inflammation of colon and skin

Abstract: Conflict of interest: RDP is an employee of Halozyme Therapeutics Inc. RLG is a consultant for and has equity interest in Senté and MatriSys Bioscience.

Cited by 41 publications

References 54 publications

Hyaluronan Degradation by Cemip Regulates Host Defense against Staphylococcus aureus Skin Infection

Hyaluronan Degradation by Cemip Regulates Host Defense against Staphylococcus aureus Skin Infection

Dermal White Adipose Tissue: A Newly Recognized Layer of Skin Innate Defense

Cathelicidin preserves intestinal barrier function in polymicrobial sepsis

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