Both Sphingosine Kinase 1 and 2 Coordinately Regulate Cathelicidin Antimicrobial Peptide Production during Keratinocyte Differentiation

Shin, Kyong‐Oh; Kim, Kun Pyo; Cho, Yunhi; Kang, Min Kyung; Kang, Young Jong; Lee, Yong Moon; Ikushiro, Hiroko; Yokota, Mami; Yano, Takayuki; Choe, Sung Jay; Choi, Eung Ho; Lim, Chaehun; Park, Keedon; Holleran, Walter M.; Park, Kyungho; Uchida, Yoshikazu

doi:10.1016/j.jid.2018.08.015

Cited by 15 publications

(17 citation statements)

References 17 publications

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“…Possible mechanism of ER stress Proteasome insufficiency due to mutations in POMP (proteasome maturation protein) gene induces persistent elevated ER stress in keratinocytes [11] Abnormal terminal differentiation [11] Ichthyosis follicularis, alopecia and photophobia (IFAP) syndrome Mutated MBTPS2 (a membrane-embedded zinc metalloprotease)-induced impairment in the cleavage of ATF6 induces UPR in keratinocytes [34,35] Abnormal keratinization [34,35] Psoriasis Undefined Abnormal epidermal keratinocyte differentiation [2] Rosacea Various triggering factors of rosacea such as UV exposure, skin irritants, heat and some foods induce ER stress in keratinocytes [38,39] Upregulation of TLR2, which triggers TLR2-KLK5-LL-37 inflammatory cascade [37][38][39] Vitiligo Environmental factors that induce oxidative stress such as UV exposure and certain chemicals can induce UPR in melanocytes [5,40,41] Activation of innate inflammation that triggers autoimmunity targeting melanocytes [5,40,41] Melanoma Hypoxia, hypoglycemia, genome instability and cytotoxic compounds [7,42] Cellular adaptation to ER stress can be the survival strategies of melanoma cells [6] ER stress-induced autophagy can be a pro-survival mechanism of melanoma cells to overcome BRAF inhibitor resistance [45] (a) involvement of the intensity, type and duration of ER stress in epidermal barrier homeostasis, and (b) the underlying pathomechanism of skin disease associated with ER stress are still unknown.…”

Section: Diseasementioning

confidence: 99%

“…Finally, ceramide metabolites, sphingosine‐1‐phosphate and ceramide‐1‐phosphate, signal to stimulate the key antimicrobial peptide, cathelicidin antimicrobial peptide, and human β‐defensin 2 and 3, respectively, in KCs to enhance antimicrobial defense in response to physiological levels of ER stress induced by external perturbations such as UV irradiation and other types of oxidative stress . Moreover, sphingosine‐1‐phosphate‐dependent increases in cathelicidin antimicrobial peptide production are likely linked to an increase in physiological ER stress during KC differentiation .…”

Section: Physiological Er Stress Is Required For Normal Cellular Funcmentioning

confidence: 99%

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Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

et al. 2019

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Endoplasmic reticulum (ER) stress is a mechanism that allows to protect normal cellular functions in response to both internal perturbations, such as accumulation of unfolded proteins, and external perturbations, for example redox stress, UVB irradiation, and infection. A hallmark of ER stress is the accumulation of misfolded and unfolded proteins. Physiological levels of ER stress trigger the unfolded protein response (UPR) which is required to restore normal ER functions. However, the UPR can also initiate a cell death program/apoptosis pathway in response to excessive or persistent ER stress. Recently, it has become evident that chronic ER stress occurs in several diseases, including skin diseases like Darier’s disease, rosacea, vitiligo, and melanoma; furthermore, it is suggested that ER stress is directly involved in the pathogenesis of these disorders. Here, we review the role of ER stress in skin function, and discuss its significance in skin diseases.

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Section: Diseasementioning

confidence: 99%

Section: Physiological Er Stress Is Required For Normal Cellular Funcmentioning

confidence: 99%

Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

et al. 2019

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“…Ceramide's key metabolite (sphingosine-1-phosphate [S1P]) promotes cellular division as opposed to apoptosis [18]. In fact, ceramides are hydrolyzed by ceramidases to sphingosine, which is phosphorylated by sphingosine kinases into S1P [19].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, while ceramides have a prominent role in the regulation of apoptosis, one key metabolite, sphingosine-1-phosphate (S1P), is largely recognized as an anti-apoptotic lipid [18]. Thus, we further assessed whether DPE-mediated activation of NOXs alters cellular levels of S1P.…”

Section: Neutral Sphingomyelinase (Smase) Is Required For Dpe/nox Actmentioning

confidence: 99%

NADPH Oxidase-Mediated Activation of Neutral Sphingomyelinase Is Responsible for Diesel Particulate Extract-Induced Keratinocyte Apoptosis

Lee¹,

Park

Kwon³

et al. 2020

IJMS

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Human epidermis is positioned at the interface with the external environment, protecting our bodies against external challenges, including air pollutants. Emerging evidence suggests that diesel particulate extract (DPE), a major component of air pollution, leads to impairment of diverse cellular functions in keratinocytes (KC). In this study, we investigated the cellular mechanism underlying DPE-induced KC apoptosis. We first addressed cell death occurring in KC exposed to DPE, paralleled by increased activation of NADPH oxidases (NOXs) and subsequent ROS generation. Blockade of NOX activation with a specific inhibitor attenuated the expected DPE-induced KC apoptosis. In contrast, pre-treatment with a specific inhibitor of reactive oxygen species (ROS) generation did not reverse DPE/NOX-mediated increase in KC apoptosis. We next noted that NOX-mediated KC apoptosis is mainly attributable to neutral sphingomyelinase (SMase)-mediated stimulation of ceramides, which is a well-known pro-apoptotic lipid. Moreover, we found that inhibition of NOX activation significantly attenuated DPE-mediated increase in the ratio of ceramide to its key metabolite sphingosine-1-phosphate (S1P), an important determinant of cell fate. Together, these results suggest that activation of neutral SMase serves as a key downstream signal for the DPE/NOX activation-mediated alteration in ceramide and S1P productions, and subsequent KC apoptosis.

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“…According to our previous research27 and related reports, ApoM, as a physiological carrier of sphingosine-1-phosphate (S1P), together with the S1P receptor signaling pathway constitutes the ApoM-S1P axis, which is involved in diverse biological processes such as anti-atherosclerosis, lipoprotein metabolism, endoplasmic reticulum (ER) stress and tumorigenesis 28,29. Shin et al30 reported that S1P synthesized by the phosphorylation of sphingosine by sphingosine kinases (SphK) could activate nuclear factor-kB (NF-kB). In addition, Sun et al31 reported that VDR could play an inhibitory role on the regulation of NF-kB activation.…”

Section: Discussionmentioning

confidence: 99%

<p>Apolipoprotein M could inhibit growth and metastasis of SMMC7721 cells via vitamin D receptor signaling</p>

Yu¹,

Pan²,

Sang³

et al. 2019

CMAR

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Objective: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with high mortality-to-incidence ratios. Apolipoprotein M (ApoM), a member of the apolipoprotein family, is mainly synthesized in the liver, whereas its role in HCC has not been elucidated. Here, we examined the effect of ApoM on the biological behavior of HCC cells and the possible mechanisms. Methods: We used CRISPR/Cas9 technology to knock out ApoM in SMMC7721 cells. Differentially expressed genes before and after ApoM knockout (KO) were analyzed by GeneChip microarrays and confirmed by qRT-PCR. Cell assays of proliferation, apoptosis, migration and invasion were performed in SMMC7721 cells, and the expression of epithelialmesenchymal transition (EMT) markers was performed by western blot. And we performed functional recovery experiments by overexpressing vitamin D receptor (VDR) in SMMC7721. Results: The ApoM-KO SMMC7721 cell line was successfully constructed using the CRISPR/ Cas9 technology. Our results showed that silencing ApoM suppressed apoptosis and promoted proliferation, migration, invasion and EMT of SMMC7721 cells. The microarray data revealed that a total of 1,868 differentially expressed genes were identified, including VDR. The qRT-PCR and western blot verification results demonstrated that knocking out ApoM could significantly reduce the expression of VDR. The functional recovery experiments indicated that VDR overexpression could offset the inhibition of cell apoptosis and the promotion of cell proliferation, migration, invasion and EMT caused by knocking out ApoM in SMMC7721 cells. Conclusion: ApoM could function as a tumor suppressor to inhibit the growth and metastasis of SMMC7721 cells via VDR signaling in HCC.

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Both Sphingosine Kinase 1 and 2 Coordinately Regulate Cathelicidin Antimicrobial Peptide Production during Keratinocyte Differentiation

Cited by 15 publications

References 17 publications

Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

Insights into the role of endoplasmic reticulum stress in skin function and associated diseases

NADPH Oxidase-Mediated Activation of Neutral Sphingomyelinase Is Responsible for Diesel Particulate Extract-Induced Keratinocyte Apoptosis

<p>Apolipoprotein M could inhibit growth and metastasis of SMMC7721 cells via vitamin D receptor signaling</p>

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