Allergic contact dermatitis in mice with interleukin-6 deficiency in dendritic cells

Contact dermatitis is a disease characterized by skin inflammation caused by external agents, most commonly, allergens. Patients with contact dermatitis have impaired skin barrier function, causing permeability of the epidermis layer. Haptens, including oxazolone, are the small molecules that easily penetrate the epidermal barrier. When oxazolone binds to the tissue proteins, new antigenic conformations are formed, triggering an immune response and, subsequently, the development of allergic contact dermatitis. The pathogenic role of interleukin-6 in the development of contact dermatitis has been previously described in various murine models. Dendritic cells (DC), along with keratinocytes, are an important source of IL-6 in the skin. Moreover, DC as an antigen-presenting cells are involved in the development of allergic reaction. To establish the functional role of IL-6 from DC in development of allergic contact dermatitis, we induced dermatitis in the knockout mice with deficiency of IL-6 in dendritic cells (CD11c-IL-6 KO), and in wild-type control mice by applying oxazolone to the abdominal skin and then to the skin of the ears. Mice with deficiency of IL-6 from dendritic cells had more pronounced symptoms of skin inflammation than wild-type mice after sensitization with oxazolone. Thus, IL-6 produced by dendritic cells seems to have protective and regulatory functions in allergic contact dermatitis. Implementation of these functions may be mediated by TGF-β, whose expression was reduced in mice with tissue-specific IL-6 knockout in dendritic cells. TGF-β is an important regulatory cytokine that controls the balance of effector and regulatory T cell populations. Moreover, TGF-β is important for the resolution of inflammation and tissue healing. At the same time, the lack of difference in IL-4 and IL-17a expression between CD11c-IL-6 KO and wild type mice suggests that the Th2 and Th17 branches of the cellular response were not affected in highly susceptible mice with IL-6-deficiency in dendritic cells. The effects of systemic IL-6 deficiency shown in various models of dermatitis suggest a predominantly pathogenic role of this cytokine in the development of allergic contact dermatitis. Our data suggests that dendritic cells may serve as sources of “protective” IL-6 activity, participating not only in the development of the immune response but also in repair and maintenance of skin barrier functions.

1. Kruglov A.A., Nosenko M.A., Korneev K.V., Sviriaeva E.N., Drutskaya M.S., Hidalgo J., Nedospasov S.A. Generation and preliminary characterization of mice with geneticdeficiency of IL-6 in dendritic cells. Immunologiya = Immunologiya, 2016, Vol. 37, no. 6, pp. 316-319. (In Russ.)

2. Clausen B.E., Stoitzner P. Functional specialization of skin dendritic cell subsets in regulating t cell responses. Front. Immunol., 2015, Vol. 6, 534. doi: 10.3389/fimmu.2015.00534.

3. Dong H., Feng C., Cai X., Hao Y., Gu X., Cai L., Wu S., Chen J., Liu Z., Xie W., Lu X., Qian H., Liu Y., Cao Y., Zhu J., Xu J., Zhou Y., Ma S., Yang S., Shi Y., Yu H., Shi M., Wang Y., Gu H.F., Fan L., Wu L. 7-Methoxyisoflavone ameliorates atopic dermatitis symptoms by regulating multiple signaling pathways and reducing chemokine production. Sci. Rep., 2022, Vol. 12, no. 1, 8760. doi: 10.1038/s41598-022-12695-3.

4. Fan X., Shu P., Wang Y., Ji N., Zhang D. Interactions between neutrophils and T-helper 17 cells. Front. Immunol., 2023, Vol. 14, 1279837. doi: 10.3389/fimmu.2023.1279837.

5. Frempah B., Luckett-Chastain L.R., Calhoun K.N., Gallucci R.M. Keratinocyte-specific deletion of the IL-6RAlpha exacerbates the inflammatory response during irritant contact dermatitis. Toxicology, 2019, Vol. 423, pp. 123-131.

6. Grabbe S., Steinert M., Mahnke K., Schwartz A., Luger T.A., Schwarz T. Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but nonspecific proinflammatory effects of haptens determine the concentration-dependent elicitation of allergic contact dermatitis. J. Clin. Invest., 1996, Vol. 98, no. 5, pp 1158-1164.

7. Heink S., Yogev N., Garbers C., Herwerth M., Aly L., Gasperi C., Husterer V., Croxford A.L., MollerHackbarth K., Bartsch H.S., Sotlar K., Krebs S., Regen T., Blum H., Hemmer B., Misgeld T., Wunderlich T.F., Hidalgo J., Oukka M., Rose-John S., Schmidt-Supprian M., Waisman A., Korn T. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T(H)17 cells. Nat. Immunol., 2017, Vol. 18, no. 1, pp 74-85.

8. Honda T., Egawa G., Grabbe S., Kabashima K. Update of immune events in the murine contact hypersensitivity model: toward the understanding of allergic contact dermatitis. J. Invest. Dermatol., 2013, Vol. 133, no. 2, pp. 303-315.

9. Hope J.C., Campbell F., Hopkins S.J. Deficiency of IL-2 or IL-6 reduces lymphocyte proliferation, but only IL-6 deficiency decreases the contact hypersensitivity response. Eur. J. Immunol., 2000, Vol. 30, no. 1, pp 197-203.

10. Kaplan D.H., Igyarto B.Z., Gaspari A.A. Early immune events in the induction of allergic contact dermatitis. Nat. Rev. Immunol., 2012, Vol. 12, no. 2, pp. 114-124.

11. Kimber I., Basketter D.A., Gerberick G.F., Dearman R.J. Allergic contact dermatitis. Int. Immunopharmacol., 2002, Vol. 2, no. 2-3, pp. 201-211.

12. Lee E.G., Mickle-Kawar B.M., Gallucci R.M. IL-6 deficiency exacerbates skin inflammation in a murine model of irritant dermatitis. J. Immunotoxicol., 2013, Vol. 10, no. 2, pp. 192-200.

13. Lin Y.L., Chen S.H., Wang J.Y. Critical role of IL-6 in dendritic cell-induced allergic inflammation of asthma. J. Mol. Med. (Berl.), 2016, Vol. 94, no. 1, pp. 51-59.

14. Martin S.F., Dudda J.C., Bachtanian E., Lembo A., Liller S., Durr C., Heimesaat M.M., Bereswill S., Fejer G., Vassileva R., Jakob T., Freudenberg N., Termeer C.C., Johner C., Galanos C., Freudenberg M.A. Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity. J. Exp. Med., 2008, Vol. 205, no. 9, pp. 2151-2162. 15. McLoughlin R.M., Hurst S.M., Nowell M.A., Harris D.A., Horiuchi S., Morgan L.W., Wilkinson T.S., Yamamoto N., Topley N., Jones S.A. Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms. J. Immunol., 2004, Vol. 172, no. 9, pp 5676-5683.

15. McMinn P.C., Halliday G.M., Muller H.K. Effects of gliotoxin on Langerhans’ cell function: contact hypersensitivity responses and skin graft survival. Immunology, 1990, Vol. 71, no. 1, pp. 46-51.

16. Nurieva R., Yang X.O., Chung Y., Dong C. Cutting edge: in vitro generated Th17 cells maintain their cytokine expression program in normal but not lymphopenic hosts. J. Immunol., 2009, Vol. 182, no. 5, pp. 2565-2568.

17. Paquet P., Pierard G.E. Interleukin-6 and the skin. Int. Arch. Allergy Immunol., 1996, Vol. 109, no. 4, pp. 308-317.

18. Peng G., Mu Z., Cui L., Liu P., Wang Y., Wu W., Han X. Anti-IL-33 antibody has a therapeutic effect in an atopic dermatitis murine model induced by 2, 4-dinitrochlorobenzene. Inflammation, 2018, Vol. 41, no. 1, pp. 154-163.

19. Strzepa A., Gurski C.J., Dittel L.J., Szczepanik M., Pritchard K.A. Jr., Dittel B.N. Neutrophil-derived myeloperoxidase facilitates both the induction and elicitation phases of contact hypersensitivity. Front. Immunol., 2020, Vol. 11, pp 608871. doi: 10.3389/fimmu.2020.608871.

20. Tan C.H., Rasool S., Johnston G. A. Contact dermatitis: allergic and irritant. Clin. Dermatol., 2014, Vol. 32, no. 1, pp. 116-124.

21. Wang J., Zhao X., Wan Y.Y. Intricacies of TGF-beta signaling in Treg and Th17 cell biology. Cell. Mol. Immunol., 2023, Vol. 20, no. 9, pp. 1002-1022.

22. Weber F.C., Nemeth T., Csepregi J.Z., Dudeck A., Roers A., Ozsvari B., Oswald E., Puskas L.G., Jakob T., Mocsai A., Martin S.F. Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity. J. Exp. Med., 2015, Vol. 212, no. 1, pp. 15-22.

23. Xiao C., Zhu Z., Zhang C., Gao J., Luo Y., Fang H., Qiao H., Li W., Wang G., Fu M. A population of dermal Langerin(+) dendritic cells promote the inflammation in mouse model of atopic dermatitis. Front. Immunol., 2022, Vol. 13, 981819. doi: 10.3389/fimmu.2022.981819.

24. Xu L., Kitani A., Fuss I., Strober W. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J. Immunol., 2007, Vol. 178, no. 11, pp. 6725-6729.