The crosstalk between PTEN-induced kinase 1-mediated mitophagy and the inflammasome in the pathogenesis of alopecia areata
Jung-Min Shin
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorKyung Min Kim
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorMi Soo Choi
Department of Dermatology, Dankook University Hospital, Cheonan, Korea
Search for more papers by this authorSanghyun Park
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorDongkyun Hong
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorKyung-Eun Jung
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorYoung-Joon Seo
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorChang Deok Kim
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorHanseul Yang
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
Search for more papers by this authorCorresponding Author
Young Lee
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Correspondence
Young Lee, Department of Dermatology, School of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-Gu, Daejeon, Korea.
Email: [email protected]
Search for more papers by this authorJung-Min Shin
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorKyung Min Kim
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorMi Soo Choi
Department of Dermatology, Dankook University Hospital, Cheonan, Korea
Search for more papers by this authorSanghyun Park
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorDongkyun Hong
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorKyung-Eun Jung
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorYoung-Joon Seo
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorChang Deok Kim
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Search for more papers by this authorHanseul Yang
Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
Search for more papers by this authorCorresponding Author
Young Lee
Department of Dermatology, School of Medicine, Chungnam National University, Daejeon, Korea
Correspondence
Young Lee, Department of Dermatology, School of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-Gu, Daejeon, Korea.
Email: [email protected]
Search for more papers by this authorAbstract
Alopecia areata (AA) is a T-cell-mediated autoimmune disease that causes chronic, relapsing hair loss; however, its precise pathogenesis remains to be elucidated. Recent studies have provided compelling evidence of crosstalk between inflammasomes and mitophagy—a process that contributes to the removal of damaged mitochondria. Our previous studies showed that the NLR family pyrin domain containing 3 (NLRP3) inflammasome is important for eliciting and progressing inflammation in AA. In this study, we detected mitochondrial DNA damage in AA-affected scalp tissues and IFNγ and poly(I:C) treated outer root sheath (ORS) cells. In addition, IFNγ and poly(I:C) treatment increased mitochondrial reactive oxygen species (ROS) levels in ORS cells. Moreover, we showed that mitophagy induction alleviates IFNγ and poly(I:C)-induced NLRP3 inflammasome activation in ORS cells. Lastly, PTEN-induced kinase 1 (PINK1) knockdown increased NLRP3 inflammasome activation, indicating that PINK1-mediated mitophagy plays a critical role in NLRP3 inflammasome activation in ORS cells. This study supports previous studies showing that oxidative stress disrupts immune privilege status and promotes autoimmunity in AA. The results emphasize the significance of crosstalk between mitophagy and inflammasomes in the pathogenesis of AA. Finally, mitophagy factors regulating mitochondrial dysfunction and inhibiting inflammasome activation could be novel therapeutic targets for AA.
CONFLICT OF INTEREST STATEMENT
None declared.
Open Research
DATA AVAILABILITY STATEMENT
The data used during this study are available from corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| exd14844-sup-0001-FigureS1.pdfPDF document, 350.1 KB |
Figure S1 Effect of mitophagy on MHC class I expression. Figure S2 Effect of mitophagy on AA-related chemokine expression. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Shin JM, Ko JW, Kwon IS, et al. Clinical relevance for serum cold-inducible RNA binding protein level in alopecia areata. Ann Dermatol. 2019; 31(4): 387-392.
- 2Peterle L, Sanfilippo S, Borgia F, Cicero N, Gangemi S. Alopecia areata: a review of the role of oxidative stress, possible biomarkers, and potential novel therapeutic approaches. Antioxidants (Basel). 2023; 12(1): 135.
- 3Acharya P, Mathur MC. Oxidative stress in alopecia areata: a systematic review and meta-analysis. Int J Dermatol. 2020; 59(4): 434-440.
- 4Mustafa AI, Khashaba RA, Fawzy E, Baghdady SMAER, Rezk SM. Cross talk between oxidative stress and inflammation in alopecia areata. J Cosmet Dermatol. 2021; 20(7): 2305-2310.
- 5Prie BE, Voiculescu VM, Ionescu-Bozdog OB, et al. Oxidative stress and alopecia areata. J Med Life. 2015; 8: 43-46.
- 6Gkikas I, Palikaras K, Tavernarakis N. The role of mitophagy in innate immunity. Front Immunol. 2018; 9: 1283.
- 7Wei H, Liu L, Chen Q. Selective removal of mitochondria via mitophagy: distinct pathways for different mitochondrial stresses. Biochim Biophys Acta. 2015; 1853: 2784-2790.
- 8Xian H, Yang Q, Xiao L, Shen HM, Liou YC. STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism. Nat Commun. 2019; 10(1): 2059.
- 9Bhujabal Z, Birgisdottir ÅB, Sjøttem E, et al. FKBP8 recruits LC3A to mediate parkin-independent mitophagy. EMBO Rep. 2017; 18(6): 947-961.
- 10Szargel R, Shani V, Abd Elghani F, et al. The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Hum Mol Genet. 2016; 25(16): 3476-3490.
- 11Ambivero CT, Cilenti L, Main S, Zervos AS. Mulan E3 ubiquitin ligase interacts with multiple E2 conjugating enzymes and participates in mitophagy by recruiting GABARAP. Cell Signal. 2014; 26(12): 2921-2929.
- 12Sun Q, Fan J, Billiar TR, Scott MJ. Inflammasome and autophagy regulation – a two-way street. Mol Med. 2017; 23: 188-195.
- 13Marcuzzi A, Piscianz E, Loganes C, et al. Innovative target therapies are able to block the inflammation associated with dysfunction of the cholesterol biosynthesis pathway. Int J Mol Sci. 2015; 17(1): 47.
- 14Zhou R, Yazdi AS, Menu P, Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. 2011; 469(7329): 221-225.
- 15Yuk JM, Silwal P, Jo EK. Inflammasome and mitophagy connection in health and disease. Int J Mol Sci. 2020; 21(13): 4714.
- 16Petukhova L, Patel AV, Rigo RK, et al. Integrative analysis of rare copy number variants and gene expression data in alopecia areata implicates an etiological role for autophagy. Exp Dermatol. 2020; 29(3): 243-253.
- 17Hardman JA, Nicu C, Tai C, et al. Does dysfunctional autophagy contribute to immune privilege collapse and alopecia areata pathogenesis? J Dermatol Sci. 2020; 100(1): 75-78.
- 18Shin JM, Choi DK, Sohn KC, et al. Double-stranded RNA induces inflammation via the NF-kappaB pathway and inflammasome activation in the outer root sheath cells of hair follicles. Sci Rep. 2017; 7:44127.
- 19Shin JM, Choi DK, Sohn KC, et al. Induction of alopecia areata in C3H/HeJ mice using polyinosinic-polycytidylic acid (poly[I:C]) and interferon-gamma. Sci Rep. 2018; 8:12518.
- 20Sohn KC, Shi G, Jang S, et al. Pitx2, a beta-catenin-regulated transcription factor, regulates the differentiation of outer root sheath cells cultured in vitro. J Dermatol Sci. 2009; 54(1): 6-11.
- 21Shi G, Sohn KC, Kim SY, et al. Sox9 increases the proliferation and colony-forming activity of outer root sheath cells cultured in vitro. Ann Dermatol. 2011; 23(2): 138-143.
- 22Lazarou M. Keeping the immune system in check: a role for mitophagy. Immunol Cell Biol. 2015; 93(1): 3-10.
- 23Hall CJ, Boyle RH, Astin JW, et al. Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. Cell Metab. 2013; 18(2): 265-278.
- 24Khan S, Basu S, Raj D, Lahiri A. Role of mitochondria in regulating immune response during bacterial infection. Int Rev Cell Mol Biol. 2023; 374: 159-200.
- 25Kubli DA, Gustafsson AB. Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res. 2012; 111(9): 1208-1221.
- 26Petukhova L, Duvic M, Hordinsky M, et al. Genome-wide association study in alopecia areata implicates both innate and adaptive immunity. Nature. 2010; 466(7302): 113-117.
- 27Tafazzoli A, Forstner AJ, Broadley D, et al. Genome-wide MicroRNA analysis implicates miR-30b/d in the etiology of alopecia areata. J Invest Dermatol. 2018; 138(3): 549-556.
- 28Jo EK, Kim JK, Shin DM, Sasakawa C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol Immunol. 2016; 13(2): 148-159.
- 29Pontillo A, Girardelli M, Kamada AJ, et al. Polimorphisms in inflammasome genes are involved in the predisposition to systemic lupus erythematosus. Autoimmunity. 2012; 45(4): 271-278.
- 30Sui J, Li H, Fang Y, et al. NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis Rheum. 2012; 64(3): 647-654.
- 31Masters SL. Specific inflammasomes in complex diseases. Clin Immunol. 2013; 147(3): 223-228.
- 32Hashimoto K, Yamada Y, Sekiguchi K, Mori S, Matsumoto T. NLRP3 inflammasome activation contributes to development of alopecia areata in C3H/HeJ mice. Exp Dermatol. 2021; 31(2): 133-142.
- 33Yu X, Hao M, Liu Y, et al. Liraglutide ameliorates non-alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol. 2019; 864:172715.
- 34Bhansali S, Bhansali A, Dutta P, Walia R, Dhawan V. Metformin upregulates mitophagy in patients with T2DM: a randomized placebo-controlled study. J Cell Mol Med. 2020; 24(5): 2832-2846.
