TY - ABST

T1 - Interleukin (IL)-13 and IL-4 promote proliferation and mRNA expression of MUC2 and MUC5AC in primary human conjunctival goblet cells

AU - Tollenaere, M. A. X.

AU - Raevdal, P.

AU - Hedengran, A.

AU - Heegaard, S.

AU - Roepke, M.

AU - Schneider, S.

AU - Norsgaard, H.

AU - Thyssen, J. P.

AU - Kolko, M.

PY - 2022

Y1 - 2022

N2 - Interleukin (IL)-13 and IL-4 are key cytokines involved in the pathogenesis of atopic dermatitis (AD). Monoclonal antibodies that inhibit signalling of these type 2 cytokines have demonstrated clinical efficacy in patients with AD who have moderate-to-severe disease. Examples of these include dupilumab, which targets IL-4Rα thereby inhibiting IL-13 and IL-4 signalling, in addition to tralokinumab and lebrikizumab, which specifically neutralize IL-13. However, these treatments have also been associated with an increased incidence of conjunctivitis. Conjunctival goblet cell scarcity and mucin deficiency have been reported in patients with AD who were treated with dupilumab, which may partly explain the conjunctivitis observed. Importantly, the impact of IL-13 vs. IL-4 on human conjunctival goblet cells is not fully understood. Inhibition of IL-4 may induce T helper 1 polarization with increased production of interferon (IFN)-γ, which has been shown to lead to secretory dysfunction of mucins and to trigger conjunctival goblet cell apoptosis. In this mechanistic study, we explored the impact of the type 2 cytokines IL-13 and IL-4, in addition to the impact of the type 1 cytokine IFN-γ on primary human conjunctival goblet cells in vitro. IL-13 and IL-4 both promoted proliferation of primary human conjunctival goblet cells in a dose- and time-dependent manner, whereas IFN-γ had a strong negative impact on conjunctival goblet cell growth and viability. In addition, IL-13 and IL-4 both led to increased gene expression of two key mucins, MUC2 and MUC5AC, in primary human conjunctival goblet cells. In summary, IL-13 and IL-4 can both act as regulators of human conjunctival goblet cell proliferation and mucin expression. As conjunctival goblet cells are essential for maintaining homeostasis of the conjunctival mucosal surface, our findings may at least in part provide a mechanistic explanation behind the ophthalmological adverse events observed after treatment with biologics inhibiting IL-4 and IL-13 signalling. Owing to the functional redundancy of IL-13 and IL-4 on conjunctival goblet cell biology, targeted treatment with monoclonal antibodies that specifically neutralize IL-13 might be associated with a lower incidence of conjunctivitis in patients with AD compared with inhibiting both IL-13 and IL-4 with dupilumab.

AB - Interleukin (IL)-13 and IL-4 are key cytokines involved in the pathogenesis of atopic dermatitis (AD). Monoclonal antibodies that inhibit signalling of these type 2 cytokines have demonstrated clinical efficacy in patients with AD who have moderate-to-severe disease. Examples of these include dupilumab, which targets IL-4Rα thereby inhibiting IL-13 and IL-4 signalling, in addition to tralokinumab and lebrikizumab, which specifically neutralize IL-13. However, these treatments have also been associated with an increased incidence of conjunctivitis. Conjunctival goblet cell scarcity and mucin deficiency have been reported in patients with AD who were treated with dupilumab, which may partly explain the conjunctivitis observed. Importantly, the impact of IL-13 vs. IL-4 on human conjunctival goblet cells is not fully understood. Inhibition of IL-4 may induce T helper 1 polarization with increased production of interferon (IFN)-γ, which has been shown to lead to secretory dysfunction of mucins and to trigger conjunctival goblet cell apoptosis. In this mechanistic study, we explored the impact of the type 2 cytokines IL-13 and IL-4, in addition to the impact of the type 1 cytokine IFN-γ on primary human conjunctival goblet cells in vitro. IL-13 and IL-4 both promoted proliferation of primary human conjunctival goblet cells in a dose- and time-dependent manner, whereas IFN-γ had a strong negative impact on conjunctival goblet cell growth and viability. In addition, IL-13 and IL-4 both led to increased gene expression of two key mucins, MUC2 and MUC5AC, in primary human conjunctival goblet cells. In summary, IL-13 and IL-4 can both act as regulators of human conjunctival goblet cell proliferation and mucin expression. As conjunctival goblet cells are essential for maintaining homeostasis of the conjunctival mucosal surface, our findings may at least in part provide a mechanistic explanation behind the ophthalmological adverse events observed after treatment with biologics inhibiting IL-4 and IL-13 signalling. Owing to the functional redundancy of IL-13 and IL-4 on conjunctival goblet cell biology, targeted treatment with monoclonal antibodies that specifically neutralize IL-13 might be associated with a lower incidence of conjunctivitis in patients with AD compared with inhibiting both IL-13 and IL-4 with dupilumab.

U2 - 10.1111/bjd.21028

DO - 10.1111/bjd.21028

M3 - Conference abstract in journal

C2 - 35377955

VL - 186

SP - E146-E146

JO - British Journal of Dermatology, Supplement

JF - British Journal of Dermatology, Supplement

SN - 0366-077X

IS - 4

M1 - 620

T2 - Revolutionizing Atopic Dermatitis 2021

Y2 - 11 December 2021 through 13 December 2021

ER -