Title: Emerging roles of innate lymphoid cells in inflammatory diseases: clinical implications Short title: Role of innate lymphoid cells in inflammatory diseases Authors: Inge Kortekaas Krohn 1, Medya Mara Shikhagaie 2, Korneliusz Golebski 2,3, Jochem HJ Bernink 2, Christine Breynaert 1,4, Brecht Creyns 1, Zuzana Diamant 5,6 Wytske J Fokkens 3, Philippe Gevaert 7, Peter Hellings 8,1,3, Rudi W Hendriks 9, Ludger Klimek 10, Jenny Mjösberg 11, Hideaki Morita 12,13 Graham Ogg 14, Liam O’Mahony 13, Jürgen Schwarze 15,16 Sven F Seys 1, Mohamed H Shamji 17,18, Suzanne M Bal 2 Affiliations: 1 Laboratory of Clinical Immunology, Dpt. Microbiology & Immunology, KU Leuven, Leuven, Belgium 2 Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands 3 Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The Netherlands 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 1 2
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€¦ · Web viewairways, gut, inflammatory diseases, innate lymphoid cells, lungs, mucosa, skin. Acknowledgements: We would like to thank the European Academy of Allergy and Clinical
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Title:
Emerging roles of innate lymphoid cells in inflammatory diseases: clinical implications
Short title:
Role of innate lymphoid cells in inflammatory diseases
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Figures and Table legends
Figure 1: Innate lymphoid cells in airway diseases
In homeostasis, all innate lymphoid cell (ILC) subsets are present in the human lungs. In non-
allergic inflammation, IL-1β secreted from (alveolar) macrophages can activate both ILC2s
and ILC3s. This leads to the secretion of type 2 cytokines by ILC2s, including IL-13 which is
implicated in fibrosis, and IL-17A from ILC3s which recruits monocytes and neutrophils. In
response to inhaled allergens, the epithelium produces cytokines, such as IL-33 and TSLP,
inducing a type 2 response. Cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2),
secreted by activated mast cells, are activators of ILC2s. Upon activation, ILC2s rapidly
expand and secrete large amounts of IL-5, IL-13. ILC2s contribute to the allergic airway
inflammation by direct interaction with myeloid and Th2 cells, promoting cytokine and
mucus production, eosinophilia and accumulation of mast cells.
Figure 2: Innate lymphoid cells in skin diseases
ILCs are abundant in the dermis and they are implicated in tissue homeostasis and wound
repair due to the secretion of amphiregulin and IL-22 by ILC2s and ILC3s, respectively. In
psoriasis, the numbers of IL-22 producing ILC3s are elevated. IL-17A, secreted from ILC3s,
recruits monocytes and neutrophils. In patients with atopic dermatitis, elevated levels of IL-4
and IL-13 are found in parallel with increased levels of IL-33, TSLP and PGD2. Keratinocytes
interact with ILC2s via the B7-H6 - NKp30 axis and the E-cadherin – killer-cell lectin like
receptor G1 (KLRG1) interaction, leading to activation or suppression of ILC2s, respectively.
Figure 3: Innate lymphoid cells in intestinal homeostasis and diseases
A: ILC3s are important regulators of the homeostasis as they rapidly respond to the local
environment by the secretion of IL-22 and granulocyte-macrophage colony-stimulating
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factor (GM-CSF). IL-22 contributes to the epithelial barrier function and mucus production,
while GM-CSF stimulates intestinal macrophages to secrete IL-10 and retinoic acid regulating
the expansion of regulatory T cells (Tregs) and the induction of tolerance. ILC3s are also
important for the development of lymphoid structures, such as Peyer’s patches and isolated
lymphoid follicles.
B: The altered cytokine profile in the intestines of patients with Crohn’s disease (CD) or
ulcerative colitis (UC) leads to elevated IL-17-producing ILC3s and IFN-y producing ILC1s in
the intestines of CD patients, while IL-17 and type 2 cytokines are elevated in UC patients. In
food allergy, the allergic inflammation is characterized by a type 2 response with enhanced
levels of IgE, IL-4 and IL-13 and increased numbers of basophils and mast cells.
Figure 4: Clinical and therapeutic implications of innate lymphoid cells in allergic and
inflammatory diseases
A: Summary of the clinical implications of the subtypes of ILCs in allergic and inflammatory
diseases of the airways, gut and skin.
B: Overview of potential therapeutic implications for targeting ILCs via effector cytokines or
mediators that implicate ILC function.
Supplementary Table 1: Innate lymphoid cells being implicated in disease