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Letter to Dermatology

Free Access

The Magnitude of mTORC1 Signalling May Predict the Response to Isotretinoin Treatment in Patients with Hidradenitis Suppurativa

De Vita V.a · Melnik B.C.b

Author affiliations

aDermatology Unit, University of Naples Federico II, Naples, Italy; bDepartment of Dermatology, Environmental Medicine and Health Theory, University of Osnabrück, Osnabrück, Germany

Corresponding Author

Valerio De Vita

Dermatology Unit, Department of Clinical Medicine and Surgery

University of Naples Federico II, Via Sergio Pansini, 5

IT-80131 Naples (Italy)

E-Mail valeriodevita@yahoo.it

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We have read with great interest the paper by Huang and Kirchhof [1] and the commentary by Boer [2]. Boer pointed out that the use of isotretinoin is not recommended by the European Treatment Guidelines for hidradenitis suppurativa (HS) [3]. Nevertheless, he noted that HS patients responding well to isotretinoin are the ones with inflammatory, migratory, furunculoid lesions [2].

In accordance with this view, we would like to provide our interpretation. We think that mechanistic target of rapamycin complex 1 (mTORC1) activity may determine the outcome to isotretinoin in patients with HS.

mTOR is the core constituent of the phosphatidylinositol 3-kinase-related kinase protein family that forms at least 2 multiprotein complexes known as mTORC1 and mTORC2 [4]. mTORC1 is the major regulator of survival, growth, proliferation, and motility in response to mitogen, energy, and nutrient levels [4]. Another important sensor of the cells' nutritional status is the forkhead box class O transcription factor-1 (FoxO1) [5]. FoxO1, also known as the transcription factor of starvation, inhibits the activity of mTORC1, thus linking nutrient availability to mTORC1-mediated protein and lipid synthesis, cell proliferation, and differentiation [5]. Due to its central role in cellular functions, mTORC1 dysregulation is involved in a number of inflammatory or neoplastic conditions [6]. The mTORC1 pathway is of pivotal importance for metabolic regulation and functioning of innate and adaptive immune cells, as clearly verified by the immune-suppressive function of mTORC1 inhibitors such as rapamycin [7]. Notably, the differentiation of Th17 cells is controlled by mTORC1, which promotes Th17 differentiation [8,9]. Moran et al. [10] recently confirmed substantial infiltration of inflammatory Th17 cells with a striking Th17-skewed cytokine profile in HS skin. Upregulation of mTORC1 has been observed in common inflammatory IL-17-driven dermatoses such as psoriasis, acne vulgaris, and HS, respectively [11,12,13]. In particular, increased mTOR core protein expression has been found in lesional as well as non-lesional skin of HS patients [13], indicating exaggerated mTORC1 signalling in HS.

Substantial evidence has shown that isotretinoin increases nuclear levels of FoxO1 [14,15,16,17]. Recent evidence indicates that isotretinoin induces the expression of the transcription factor p53 [18,19]. p53 induces the expression of FoxO1 and PTEN, but inhibits the expression of IGF-1 and androgen receptors, resulting in impaired IGF-1/mTORC1 and androgen signalling [19].

In light of the above, at least 2 considerations come to mind. Firstly, researchers often ask themselves why isotretinoin is not always effective in HS treatment. A possible explanation for its limited therapeutic response may be the fact that isotretinoin's major mode of action is p53-driven apoptosis [19]. Isotretinoin adversely affects the hair cycle and increases catagen, an apoptosis-dominated phase of the hair cycle [20,21], which may further destabilize terminal hair follicles promoting HS, a dissecting terminal hair folliculitis [22].

On the other hand, we know from our experience with acne that isotretinoin reduces inflammation. From this perspective, isotretinoin-mediated downregulation of mTORC1 may attenuate the expression of mTORC1-induced production of IL-17, a proinflammatory signature cytokine overexpressed in HS lesions. Importantly, higher levels of mTOR expression can be detected in patients with inflammatory [13], especially migratory furunculoid, lesions [unpubl. data]. In the light of this evidence, it is arguable that patients exhibiting higher levels of mTORC1 activity may represent a subgroup in which isotretinoin-mediated suppression of mTORC1 exerts the most beneficial anti-inflammatory effects. On this subject matter, note that in HS mTOR gene expression statistically correlates with the severity of the disease and, like in acne vulgaris [23], with the body mass index (BMI) [13]. Recently, it has been suggested that patients with a low and high BMI could represent 2 clinically different subtypes, since eruption patterns and risk factors may change depending on the BMI value [24]. Consequently, isotretinoin might exert major anti-inflammatory effects in patients with a higher BMI.

To sum up, increased mTORC1 signalling in HS patients not only explains the association with other mTORC1-driven comorbidities including obesity [25], but also suggests a possible mechanism of action of isotretinoin in HS. In this regard, it should be mentioned that metformin, another inhibitor of mTORC1 [17,26], improved acne [27] and HS [28], likely sharing a common mode of action with isotretinoin. The different magnitude of mTORC1 signalling in clinically different subtypes may explain and predict the different response to isotretinoin in patients with HS. Further laboratory and clinical investigations are required to increase our understanding of the complex interplay of metabolic deviations, immune regulation, and therapeutic intervention in HS.

Key Message

HS patients who have higher levels of mTOR expression may represent an inflammation-prone subgroup who may exhibit a higher benefit from isotretinoin treatment.

Acknowledgement

We would like to thank Prof. Gerd Plewig, commendable Master, who encouraged us to write this letter.

Disclosure Statement

The authors declare no conflict of interest. No financial interest exists.


References

  1. Huang CM, Kirchhof MG: A new perspective on isotretinoin treatment of hidradenitis suppurativa: a retrospective chart review of patient outcomes. Dermatology 2017;233:120-125.
  2. Boer J: Are there indications for isotretinoin treatment of hidradenitis suppurativa? Dermatology 2017;233:111-112.
  3. Zouboulis CC, Desai N, Emtestam L, et al: European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015;29:619-644.
  4. Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell 2006;124:471-484.
  5. Hay N: Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta 2011;1813:1965-1970.
  6. Dazert E, Hall MN: mTOR signaling in disease. Curr Opin Cell Biol 2011;23:744-755.
  7. Linke M, Fritsch SD, Sukhbaatar N, et al: mTORC1 and mTORC2 as regulators of cell metabolism in immunity. FEBS Lett. 2017;591:3089-3103.
  8. Nagai S, Kurebayashi Y, Koyasu S: Role of PI3K/Akt and mTOR complexes in Th17 cell differentiation. Ann NY Acad Sci 2013;1280:30-34.
  9. Ren W, Yin J, Duan J, et al: mTORC1 signaling and IL-17 expression: defining pathways and possible therapeutic targets. Eur J Immunol 2016;46:291-299.
  10. Moran B, Sweeney CM, Hughes R, et al: Hidradenitis suppurativa is characterised by dysregulation of the Th17:Treg cell axis, which is corrected by anti-TNF therapy. J Invest Dermatol 2017;137:2389-2395.
  11. Balato A, Di Caprio R, Lembo S, et al: Mammalian target of rapamycin in inflammatory skin conditions. Eur J Inflamm 2014;12:341-350.
  12. Monfrecola G, Lembo S, Caiazzo G, et al: Mechanistic target of rapamycin (mTOR) expression is increased in acne patients' skin. Exp Dermatol 2016;25:153-155.
  13. Monfrecola G, Balato A, Caiazzo G, et al: Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop. J Eur Acad Dermatol Venereol 2016;30:1631-1633.
  14. Melnik BC: Is nuclear deficiency of FoxO1 due to increased growth factor/PI3K/Akt-signalling in acne vulgaris reversed by isotretinoin treatment? Br J Dermatol 2010;162:1398-1400.
  15. Melnik BC: The role of transcription factor FoxO1 in the pathogenesis of acne vulgaris and the mode of isotretinoin action. G Ital Dermatol Venereol 2010;145:559-571.
  16. Melnik BC: Isotretinoin and FoxO1: a scientific hypothesis. Dermatoendocrinol 2011;3:141-165.
  17. Melnik BC, Schmitz G: Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1? Exp Dermatol 2013;22:502-504.
  18. Melnik BC: Apoptosis may explain the pharmacological mode of action and adverse effects of isotretinoin, including teratogenicity. Acta Derm Venereol 2017;97:173-181.
  19. Melnik BC: p53: key conductor of all anti-acne therapies. J Transl Med 2017;15:195.
  20. Botchkareva NV, Ahluwalia G, Shander D: Apoptosis in the hair follicle. J Invest Dermatol 2006;126:258-264.
  21. Kmieć ML, Pajor A, Broniarczyk-Dyła G: Evaluation of biophysical skin parameters and assessment of hair growth in patients with acne treated with isotretinoin. Postepy Dermatol Alergol 2013;30:343-349.
  22. Chen W, Plewig G: Should hidradenitis suppurativa/acne inversa best be renamed as “dissecting terminal hair folliculitis?” Exp Dermatol 2017;26:544-547.
  23. Melnik BC, John SM, Plewig G: Acne: risk indicator for increased body mass index and insulin resistance. Acta Derma Venereol 2013;93:644-649.
  24. Theut Riis P, Marie Saunte D, Benhadou F, et al: Low and high body mass index in hidradenitis suppurativa patients - different subtypes? J Eur Acad Dermatol Venereol 2017; DOI: 10.1111/jdv.14599.
  25. Saxton RA, Sabatini DM: mTOR signaling in growth, metabolism, and disease. Cell 2017;168:960-976.
  26. Melnik BC, Schmitz G: Metformin: an inhibitor of mTORC1 signaling. J Endocrinol Diabetes Obes 2014;2:1029.
  27. Fabbrocini G, Izzo R, Faggiano A, et al: Low glycaemic diet and metformin therapy: a new approach in male subjects with acne resistant to common treatments. Clin Exp Dermatol 2016;41:38-42.
  28. Verdolini R, Clayton N, Smith A, et al: Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol 2013;27:1101-1108.

Author Contacts

Valerio De Vita

Dermatology Unit, Department of Clinical Medicine and Surgery

University of Naples Federico II, Via Sergio Pansini, 5

IT-80131 Naples (Italy)

E-Mail valeriodevita@yahoo.it


Article / Publication Details

Published online: December 20, 2017
Issue release date: Published online first

Number of Print Pages: 2
Number of Figures: 0
Number of Tables: 0

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

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References

  1. Huang CM, Kirchhof MG: A new perspective on isotretinoin treatment of hidradenitis suppurativa: a retrospective chart review of patient outcomes. Dermatology 2017;233:120-125.
  2. Boer J: Are there indications for isotretinoin treatment of hidradenitis suppurativa? Dermatology 2017;233:111-112.
  3. Zouboulis CC, Desai N, Emtestam L, et al: European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015;29:619-644.
  4. Wullschleger S, Loewith R, Hall MN: TOR signaling in growth and metabolism. Cell 2006;124:471-484.
  5. Hay N: Interplay between FOXO, TOR, and Akt. Biochim Biophys Acta 2011;1813:1965-1970.
  6. Dazert E, Hall MN: mTOR signaling in disease. Curr Opin Cell Biol 2011;23:744-755.
  7. Linke M, Fritsch SD, Sukhbaatar N, et al: mTORC1 and mTORC2 as regulators of cell metabolism in immunity. FEBS Lett. 2017;591:3089-3103.
  8. Nagai S, Kurebayashi Y, Koyasu S: Role of PI3K/Akt and mTOR complexes in Th17 cell differentiation. Ann NY Acad Sci 2013;1280:30-34.
  9. Ren W, Yin J, Duan J, et al: mTORC1 signaling and IL-17 expression: defining pathways and possible therapeutic targets. Eur J Immunol 2016;46:291-299.
  10. Moran B, Sweeney CM, Hughes R, et al: Hidradenitis suppurativa is characterised by dysregulation of the Th17:Treg cell axis, which is corrected by anti-TNF therapy. J Invest Dermatol 2017;137:2389-2395.
  11. Balato A, Di Caprio R, Lembo S, et al: Mammalian target of rapamycin in inflammatory skin conditions. Eur J Inflamm 2014;12:341-350.
  12. Monfrecola G, Lembo S, Caiazzo G, et al: Mechanistic target of rapamycin (mTOR) expression is increased in acne patients' skin. Exp Dermatol 2016;25:153-155.
  13. Monfrecola G, Balato A, Caiazzo G, et al: Mammalian target of rapamycin, insulin resistance and hidradenitis suppurativa: a possible metabolic loop. J Eur Acad Dermatol Venereol 2016;30:1631-1633.
  14. Melnik BC: Is nuclear deficiency of FoxO1 due to increased growth factor/PI3K/Akt-signalling in acne vulgaris reversed by isotretinoin treatment? Br J Dermatol 2010;162:1398-1400.
  15. Melnik BC: The role of transcription factor FoxO1 in the pathogenesis of acne vulgaris and the mode of isotretinoin action. G Ital Dermatol Venereol 2010;145:559-571.
  16. Melnik BC: Isotretinoin and FoxO1: a scientific hypothesis. Dermatoendocrinol 2011;3:141-165.
  17. Melnik BC, Schmitz G: Are therapeutic effects of antiacne agents mediated by activation of FoxO1 and inhibition of mTORC1? Exp Dermatol 2013;22:502-504.
  18. Melnik BC: Apoptosis may explain the pharmacological mode of action and adverse effects of isotretinoin, including teratogenicity. Acta Derm Venereol 2017;97:173-181.
  19. Melnik BC: p53: key conductor of all anti-acne therapies. J Transl Med 2017;15:195.
  20. Botchkareva NV, Ahluwalia G, Shander D: Apoptosis in the hair follicle. J Invest Dermatol 2006;126:258-264.
  21. Kmieć ML, Pajor A, Broniarczyk-Dyła G: Evaluation of biophysical skin parameters and assessment of hair growth in patients with acne treated with isotretinoin. Postepy Dermatol Alergol 2013;30:343-349.
  22. Chen W, Plewig G: Should hidradenitis suppurativa/acne inversa best be renamed as “dissecting terminal hair folliculitis?” Exp Dermatol 2017;26:544-547.
  23. Melnik BC, John SM, Plewig G: Acne: risk indicator for increased body mass index and insulin resistance. Acta Derma Venereol 2013;93:644-649.
  24. Theut Riis P, Marie Saunte D, Benhadou F, et al: Low and high body mass index in hidradenitis suppurativa patients - different subtypes? J Eur Acad Dermatol Venereol 2017; DOI: 10.1111/jdv.14599.
  25. Saxton RA, Sabatini DM: mTOR signaling in growth, metabolism, and disease. Cell 2017;168:960-976.
  26. Melnik BC, Schmitz G: Metformin: an inhibitor of mTORC1 signaling. J Endocrinol Diabetes Obes 2014;2:1029.
  27. Fabbrocini G, Izzo R, Faggiano A, et al: Low glycaemic diet and metformin therapy: a new approach in male subjects with acne resistant to common treatments. Clin Exp Dermatol 2016;41:38-42.
  28. Verdolini R, Clayton N, Smith A, et al: Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol 2013;27:1101-1108.
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