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Differential Influence of IL-9 and IL-17 on Actin Cytoskeleton Regulates the Migration Potential of Human Keratinocytes

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Differential Influence of IL-9 and IL-17 on Actin Cytoskeleton Regulates the Migration Potential of Human Keratinocytes Differential Influence of IL-9 and IL-17 on Actin Cytoskeleton Regulates the Migration Potential of Human Keratinocytes This information is current as Sreya Das, Srisathya Srinivasan, Ankita Srivastava, Sushant of September 27, 2021. Kumar, Gargi Das, Suman Das, Alka Dwivedi, Atharva Karulkar, Khushi Makkad, Richa Bilala, Ankit Gupta, Abhijeet Sawant, Chitra Nayak, Prakriti Tayalia and Rahul Purwar J Immunol published online 13 February 2019 Downloaded from http://www.jimmunol.org/content/early/2019/02/12/jimmun ol.1800823 Supplementary http://www.jimmunol.org/content/suppl/2019/02/12/jimmunol.180082 http://www.jimmunol.org/ Material 3.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 27, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 13, 2019, doi:10.4049/jimmunol.1800823 The Journal of Immunology Differential Influence of IL-9 and IL-17 on Actin Cytoskeleton Regulates the Migration Potential of Human Keratinocytes Sreya Das,*,1 Srisathya Srinivasan,*,1 Ankita Srivastava,*,1 Sushant Kumar,* Gargi Das,* Suman Das,* Alka Dwivedi,* Atharva Karulkar,* Khushi Makkad,* Richa Bilala,† Ankit Gupta,† Abhijeet Sawant,‡ Chitra Nayak,† Prakriti Tayalia,* and Rahul Purwar* T cells mediate skin immune surveillance by secreting specific cytokines and regulate numerous functions of keratinocytes, including migration during homeostasis and disease pathogenesis. Keratinocyte migration is mediated mainly by proteolytic cleavage of the extracellular matrix and/or by cytoskeleton reorganization. However, the cross-talk between T cell cytokines and actomyosin ma- chinery of human primary keratinocytes (HPKs), which is required for cytoskeleton reorganization and subsequent migration, Downloaded from remains poorly examined. In this study, we describe that IL-9 profoundly reduced the actin stress fibers, inhibited contractility, and reduced the cortical stiffness of HPKs, which resulted in inhibition of the migration potential of HPKs in an adhesion- and MMP-independent manner. Similarly, IL-9 inhibited the IFN-g–induced migration of HPKs by inhibiting the actomyosin ma- chinery (actin stress fibers, contractility, and stiffness). IL-17A increased the actin stress fibers, promoted cellular contractility, and increased proteolytic collagen degradation, resulting in increased migration potential of HPKs. However, IL-9 inhibited the IL-17A–mediated HPKs migration. Mechanistically, IL-9 inhibited the IFN-g– and IL-17A–induced phosphorylation of myosin http://www.jimmunol.org/ L chain in HPKs, which is a major regulator of the actomyosin cytoskeleton. Finally, in addition to HPKs, IL-9 inhibited the migration of A-431 cells (epidermoid carcinoma cells) induced either by IFN-g or IL-17A. In conclusion, our data demonstrate the influence of T cell cytokines in differentially regulating the actomyosin cytoskeleton and migration potential of human keratino- cytes, which may have critical roles in skin homeostasis and pathogenesis of inflammatory diseases as well as skin malignancies. The Journal of Immunology, 2019, 202: 000–000. ealthy human adult skin contains twice as many effector Very recently, IL-9–secreting Th cells (Th9 cells) were dis- memory T cells compared with blood (1, 2). Skin resi- covered and reported to be present in healthy and lesional skin of by guest on September 27, 2021 dent effector memory T cells are the major mediators of skin inflammatory disorders, such as psoriasis and atopic derma- H + immune surveillance (1, 2). These CD4 T cells mediate effector titis (AD) (8). The effector functions of IL-9 are mediated by functions by secreting specific cytokines that are categorized as IL-9R, composed of a-chain and g-chain (9). IL-9R is expressed Th1 (IFN-g), Th2 (IL-4/IL13), Th17 (IL-17), and Th9 (IL-9), on numerous cell types, including mast cells, CD4+ T cells, based on their cytokine profile (3, 4). Although numerous stud- B cells, airway epithelial cells, and keratinocytes (10–13). Re- ies report the presence and functions of various Th cell subsets in cently, we and others have demonstrated that treatment with IL-9 multiple skin inflammatory diseases (5, 6) and malignancies (7), and Th9 cells leads to tumor regression in murine models of the roles of Th9 cells on human primary keratinocyte (HPK) melanoma (2, 14). Increased levels of IL-9 in serum and in skin functions have not been reported yet. More importantly, no study lesions are reported to have a positive correlation with the disease so far has probed the cross-talk between T cell cytokines (IL-9, progression of AD (15). In psoriatic lesional skin, higher numbers IFN-g, and IL-17) as well as actomyosin machinery of HPKs of IL-9 producing T cells were found compared with AD and and their subsequent impact on keratinocyte functions, including healthy skin (8). Recently, IL-9 has been reported to increase migration potential and proliferation. CXCL8 secretion in keratinocytes isolated from adult foreskin (13). *Department of Biosciences and Bioengineering, Indian Institute of Technology zymography experiments, and the analysis. A.D. and A.K. contributed in FACS Bombay, Mumbai, Maharashtra 400076, India; †Department of Skin and Venereal experiments. K.M. and P.T. contributed in optimizing the three-dimensional migra- Diseases, Topiwala National Medical College and BYL Nair Charitable Hospital, tion assay and editing the manuscript. A.G., R.B., and A. Sawant contributed in the Mumbai, Maharashtra 400008, India; and ‡Department of Plastic Surgery, Topiwala skin sample procurement. C.N. contributed to the design of the study and skin sample National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra procurement. R.P. contributed to the design of the study, interpretation of the results, 400008, India and writing of the manuscript. All authors read and approved the final manuscript. 1Sreya Das, S.S., and A. Srivastava contributed equally to this work. Address correspondence and reprint requests to Dr. Rahul Purwar, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, ORCIDs: 0000-0003-1933-7749 (Suman Das); 0000-0002-4056-2628 (P.T.). Maharashtra 400076, India. E-mail address: [email protected] Received for publication June 13, 2018. Accepted for publication January 18, 2019. The online version of this article contains supplemental material. This work was supported by funds from an intramural seed grant from the Indian Abbreviations used in this article: AD, atopic dermatitis; AFM, atomic force micros- Institute of Technology Bombay, the Council for Scientific and Industrial Research, copy; 3D, three-dimensional; DPBS, Dulbecco’s PBS; ECM, extracellular matrix; the Tata Education and Development Trust, Bristol-Myers Squibb, and the Wadhwani FA, focal adhesion; HPK, human primary keratinocyte; Mlc, myosin L chain; MMP, Foundation (to R.P.). matrix metalloproteinase; NMMIIA, nonmuscle myosin IIA; t, de-adhesion time Sreya Das, S.S., and A. Srivastava contributed in the design of the study, performed constant; ttotal, total de-adhesion time. the experiments, analyzed the data, and drafted the manuscript. S.K. contributed in the establishment of keratinocyte isolation and culture methods, and performed the Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 ELISA. G.D. and Suman Das contributed in performing the proliferation assay, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800823 2 ROLES OF IL-9 AND IL-17 IN KERATINOCYTE MIGRATION However, the role of IL-9 in the cellular responses of human ker- with 1% BSA for 15 min and washed thrice with 13 Dulbecco’s PBS atinocytes, such as proliferation and migration, remains unexplored. (DPBS). Cells were seeded on the collagen-coated coverslips for various Apart from IL-9 producing Th9 cells, the presence of Th17 cells experiments. have been reported in lesional skin and blood of patients with skin Pan cytokeratin staining for assessment of culture purity inflammatory diseases and malignancies as well (16, 17). Specific Isolated HPKs were stained for cytokeratin to ensure the purity of the cells. targeting of IL-17A with humanized mAbs, such as ixekizumab, has HPKs were seeded on collagen-coated 18-mm glass coverslips. The cells were been seen to improve clinical symptoms of psoriasis (18). IL-17 has washed thrice with warm 13 DPBS, fixed with 4% paraformaldehyde, and been observed to play a critical role in psoriatic inflammation (19), permeabilized using 0.1% Triton X-100. The cells were blocked with 1% proliferation (20), and tumor progression (21). Interestingly, the role BSA and incubated overnight with pan cytokeratin primary Ab (Invitrogen Carlsbad, CA) at 4˚C followed by Alexa Fluor 488 Goat anti-mouse secondary of IL-17A in promoting matrix
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