List of Publications (2011-Current)
2022
Sanjel, Babina; Kim, Bo‐Hyun; Song, Myung‐Hyun; Carstens, Earl; Shim, Won‐Sik
Glucosylsphingosine evokes pruritus via activation of 5‐HT2A receptor and TRPV4 in sensory neurons Journal Article
In: British J Pharmacology, vol. 179, no. 10, pp. 2193–2207, 2022, ISSN: 1476-5381.
Abstract | Links | BibTeX | Tags: 5-HT2R, Atopic dermatitis, Calcium imaging, Dorsal root ganglia, Glucosylsphingosine, TRPV4
@article{Sanjel2022b,
title = {Glucosylsphingosine evokes pruritus via activation of 5‐HT_{2A} receptor and TRPV4 in sensory neurons},
author = {Babina Sanjel and Bo‐Hyun Kim and Myung‐Hyun Song and Earl Carstens and Won‐Sik Shim},
doi = {10.1111/bph.15733},
issn = {1476-5381},
year = {2022},
date = {2022-05-00},
urldate = {2022-05-00},
journal = {British J Pharmacology},
volume = {179},
number = {10},
pages = {2193--2207},
publisher = {Wiley},
abstract = {Background and purpose
Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels.
Experimental approach
Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice.
Key results
GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice.
Conclusion and implications
Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.},
keywords = {5-HT2R, Atopic dermatitis, Calcium imaging, Dorsal root ganglia, Glucosylsphingosine, TRPV4},
pubstate = {published},
tppubtype = {article}
}
Background and purpose
Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels.
Experimental approach
Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice.
Key results
GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice.
Conclusion and implications
Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.
Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels.
Experimental approach
Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild-type and Trpv4 knockout mice.
Key results
GS activated DRG neurons in a manner involving both the 5-HT2A receptor and TRPV4. Furthermore, GS-induced responses were significantly suppressed by various inhibitors, including ketanserin (5-HT2A receptor antagonist), YM254890 (Gαq/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS-evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5-HT2A receptor or TRPV4. As expected, GS-evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice.
Conclusion and implications
Overall, the present study provides evidence for a novel molecular signalling pathway for GS-evoked pruritus, which utilizes both 5-HT2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.
2021
Lee, Wook-Joo; Shim, Won-Sik
Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus Journal Article
In: Front. Immunol., vol. 12, 2021, ISSN: 1664-3224.
Abstract | Links | BibTeX | Tags: Calcium imaging, Dorsal root ganglia, Dry skin, Itch, TSLP
@article{Lee2021,
title = {Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus},
author = {Wook-Joo Lee and Won-Sik Shim},
doi = {10.3389/fimmu.2021.772941},
issn = {1664-3224},
year = {2021},
date = {2021-12-02},
urldate = {2021-12-02},
journal = {Front. Immunol.},
volume = {12},
publisher = {Frontiers Media SA},
abstract = {Dry skin is a symptom of skin barrier dysfunction that evokes pruritus; however, the cutaneous neuroimmune interactions underlying dry skin-induced pruritus remain unclear. Therefore, we aimed to elucidate the mechanisms underlying dry skin-induced pruritus. To this end, an acetone/ethanol/water (AEW)-induced mouse model of dry skin was used in this study. We observed that the production of thymic stromal lymphopoietin (TSLP) significantly increased in the keratinocytes of AEW mice. Importantly, treatment with an antagonist of transient receptor potential cation channel subfamily V member 4 (TRPV4), HC067047, ameliorated dry skin conditions in AEW mice. The symptoms of dry skin were significantly reduced in Trpv4 knockout (KO) mice following treatment with AEW. The increase in the intracellular calcium levels by TSLP in the dorsal root ganglia (DRG) of Trpv4 KO mice was also significantly attenuated. The spontaneous scratching bouts were significantly decreased in both the HC067047-treated and Trpv4 KO AEW mice. Importantly, the TSLP-dependent release of tryptase from the mast cells was significantly reduced in both the HC067047-treated mice and Trpv4 KO AEW mice. Notably, inhibition of the TSLP-induced signaling pathway in DRG selectively reduced the spontaneous scratching bouts in AEW mice. Overall, the results demonstrated that the cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus. },
keywords = {Calcium imaging, Dorsal root ganglia, Dry skin, Itch, TSLP},
pubstate = {published},
tppubtype = {article}
}
<jats:p>Dry skin is a symptom of skin barrier dysfunction that evokes pruritus; however, the cutaneous neuroimmune interactions underlying dry skin-induced pruritus remain unclear. Therefore, we aimed to elucidate the mechanisms underlying dry skin-induced pruritus. To this end, an acetone/ethanol/water (AEW)-induced mouse model of dry skin was used in this study. We observed that the production of thymic stromal lymphopoietin (TSLP) significantly increased in the keratinocytes of AEW mice. Importantly, treatment with an antagonist of transient receptor potential cation channel subfamily V member 4 (TRPV4), HC067047, ameliorated dry skin conditions in AEW mice. The symptoms of dry skin were significantly reduced in <jats:italic>Trpv4</jats:italic> knockout (KO) mice following treatment with AEW. The increase in the intracellular calcium levels by TSLP in the dorsal root ganglia (DRG) of <jats:italic>Trpv4</jats:italic> KO mice was also significantly attenuated. The spontaneous scratching bouts were significantly decreased in both the HC067047-treated and <jats:italic>Trpv4</jats:italic> KO AEW mice. Importantly, the TSLP-dependent release of tryptase from the mast cells was significantly reduced in both the HC067047-treated mice and <jats:italic>Trpv4</jats:italic> KO AEW mice. Notably, inhibition of the TSLP-induced signaling pathway in DRG selectively reduced the spontaneous scratching bouts in AEW mice. Overall, the results demonstrated that the cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus.</jats:p>
2019
Sanjel, Babina; Maeng, Han-Joo; Shim, Won-Sik
BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus Journal Article
In: Sci Rep, vol. 9, no. 1, 2019, ISSN: 2045-2322.
Abstract | Links | BibTeX | Tags: Animal model, Calcium imaging, Cholestasis, Dorsal root ganglia, MrgprC11, MRGPRX1, Scratching behavior
@article{Sanjel2019,
title = {BAM8-22 and its receptor MRGPRX1 may attribute to cholestatic pruritus},
author = {Babina Sanjel and Han-Joo Maeng and Won-Sik Shim},
doi = {10.1038/s41598-019-47267-5},
issn = {2045-2322},
year = {2019},
date = {2019-12-00},
urldate = {2019-12-00},
journal = {Sci Rep},
volume = {9},
number = {1},
publisher = {Springer Science and Business Media LLC},
abstract = {Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.},
keywords = {Animal model, Calcium imaging, Cholestasis, Dorsal root ganglia, MrgprC11, MRGPRX1, Scratching behavior},
pubstate = {published},
tppubtype = {article}
}
Pruritus is an unexpected symptom observed in cholestasis and its mechanism is still unclear. Here, we show that bovine adrenal medulla (BAM) 8–22, an endogenous itch-inducing peptide, could be involved in cholestatic pruritus. It was found that bile duct ligation (BDL) mice, an obstructive cholestasis model, showed increased spontaneous scratching behaviour. Importantly, the mRNA level of proenkephalin, a precursor polypeptide of BAM8-22, was significantly increased in the skin of BDL mice. Furthermore, the mRNA level of Mrgprx1, which encodes a receptor for BAM8-22, was significantly increased in the dorsal root ganglia (DRG) of BDL mice. This was further confirmed by elevation of intracellular calcium levels upon BAM8-22 treatment in primarily-cultured DRG neurons. In addition, BDL mice showed augmented scratching behaviour by BAM8-22, indicating enhanced activity of MRGPRX1. Moreover, the skin homogenate of BDL mice induced elevation of intracellular calcium levels through MRGPRX1. Finally, among the various bile acids, chenodeoxycholic acid significantly increased proenkephalin transcription in a human keratinocyte cell line (HaCaT). In conclusion, cholestatic pruritus could be attributed in part to enhanced action of both BAM8-22 in the skin and its receptor MRGPRX1 in sensory neurons.
2018
Ji, Yeounjung; Jang, Yongwoo; Lee, Wook Joo; Yang, Young Duk; Shim, Won-Sik
Different perception levels of histamine-induced itch sensation in young adult mice Journal Article
In: Physiology & Behavior, vol. 188, pp. 188–193, 2018, ISSN: 0031-9384.
Abstract | Links | BibTeX | Tags: Dorsal root ganglia, H1R, Histamine, Itch, Scratching behavior, TLR4, TRPV1
@article{Ji2018,
title = {Different perception levels of histamine-induced itch sensation in young adult mice},
author = {Yeounjung Ji and Yongwoo Jang and Wook Joo Lee and Young Duk Yang and Won-Sik Shim},
doi = {10.1016/j.physbeh.2018.02.015},
issn = {0031-9384},
year = {2018},
date = {2018-05-00},
urldate = {2018-05-00},
journal = {Physiology & Behavior},
volume = {188},
pages = {188--193},
publisher = {Elsevier BV},
abstract = {Itch is an unpleasant sensation that evokes behavioral responses such as scratching the skin. Interestingly, it isconceived that the perception of itch sensation is influenced by age. Indeed, accumulating evidence supports theidea that even children or younger adults show distinctive itch sensation depending on age. This evidence implies the presence of a mechanism that regulates the perception of itch sensation in an age-dependent fashion. Therefore, the purpose of the present study was to investigate a putative mechanism for the age-dependent perception of itch sensation by comparing histamine-induced scratching behaviors in 45-day old (D45) and 75-day old male “young adult” mice. The results indicated that, following histamine administration, the D75 mice spent a longer time scratching than D45 mice. However, the intensity of the calcium influx induced by histamine in primary culture of dorsal root ganglia (DRG) neurons was not different between D45 and D75 mice. Moreover, no apparent difference was observed in mRNA levels of a characteristic His-related receptor and ion channel. Incontrast, the mRNA levels of Toll-Like Receptor 4 (TLR4) were increased approximately by two-fold in D75 DRG compared with D45 DRG. Additionally, D75-derived DRG neurons exhibited enhanced intracellular calcium increase by lipopolysaccharide (LPS, a TLR4 agonist) than those of D45 mice. Furthermore, intensities of calciuminflux induced by histamine were significantly potentiated when co-treated with LPS in D75 DRG neurons, butnot in those of D45 mice. Thus, it appears that D75 mice showed enhanced histamine-induced scratching behaviors not by increased expression levels of histamine-related genes, but probably due to augmented TLR4},
keywords = {Dorsal root ganglia, H1R, Histamine, Itch, Scratching behavior, TLR4, TRPV1},
pubstate = {published},
tppubtype = {article}
}
Itch is an unpleasant sensation that evokes behavioral responses such as scratching the skin. Interestingly, it isconceived that the perception of itch sensation is influenced by age. Indeed, accumulating evidence supports theidea that even children or younger adults show distinctive itch sensation depending on age. This evidence implies the presence of a mechanism that regulates the perception of itch sensation in an age-dependent fashion. Therefore, the purpose of the present study was to investigate a putative mechanism for the age-dependent perception of itch sensation by comparing histamine-induced scratching behaviors in 45-day old (D45) and 75-day old male “young adult” mice. The results indicated that, following histamine administration, the D75 mice spent a longer time scratching than D45 mice. However, the intensity of the calcium influx induced by histamine in primary culture of dorsal root ganglia (DRG) neurons was not different between D45 and D75 mice. Moreover, no apparent difference was observed in mRNA levels of a characteristic His-related receptor and ion channel. Incontrast, the mRNA levels of Toll-Like Receptor 4 (TLR4) were increased approximately by two-fold in D75 DRG compared with D45 DRG. Additionally, D75-derived DRG neurons exhibited enhanced intracellular calcium increase by lipopolysaccharide (LPS, a TLR4 agonist) than those of D45 mice. Furthermore, intensities of calciuminflux induced by histamine were significantly potentiated when co-treated with LPS in D75 DRG neurons, butnot in those of D45 mice. Thus, it appears that D75 mice showed enhanced histamine-induced scratching behaviors not by increased expression levels of histamine-related genes, but probably due to augmented TLR4