Cytokines in Allergic Conjunctivitis: Unraveling Their Pathophysiological Roles

Abstract

Allergic conjunctivitis is one of the common immune hypersensitivity disorders that affect the ocular system. The clinical manifestations of this condition exhibit variability contingent upon environmental factors, seasonal dynamics, and genetic predisposition. While our comprehension of the pathophysiological engagement of immune and nonimmune cells in the conjunctiva has progressed, the same cannot be asserted for the cytokines mediating this inflammatory cascade. In this review, we proffer a comprehensive description of interleukins 4 (IL-4), IL-5, IL-6, IL-9, IL-13, IL-25, IL-31, and IL-33, as well as thymic stromal lymphopoietin (TSLP), elucidating their pathophysiological roles in mediating the allergic immune responses on the ocular surface. Delving into the nuanced functions of these cytokines holds promise for the exploration of innovative therapeutic modalities aimed at managing allergic conjunctivitis.

Keywords: IL-13; IL-25; IL-31; IL-4; IL-5; IL-6; IL-9; Th2 cells; mast cells; pathophysiology.

Figure 1

Priming of the conjunctival mast cells: Allergens on the conjunctiva are engulfed by dendritic cells and subsequently processed and presented to naïve CD4⁺T cells in the regional secondary lymphoid tissues. The allergen-specific CD4⁺T cell undergoes proliferation and differentiation into IL-4-secreting effector Follicular T helper cells. IL-4 drives the clonal expansion and differentiation of allergen-specific B cells into IgE-secreting plasma cells. The IgE released by the plasma cells binds to Fc$\epsilon$RI on mast cells to render the conjunctival mast cells primed. Created with biorender.com.

Figure 2

IL-4 binds to type I IL-4R to induce the JAK1/JAK3/STAT6 signaling cascade that results in the clinical manifestations of type 2 allergic immune response at the conjunctiva. Created with biorender.com.

Figure 3

IL-5 binds to IL-5R to initiate the JAK1/JAK2/STAT1/STAT3/STAT5 signaling cascade that results in the transcription of IL-5 responsive genes that facilitate activation and survival of eosinophils. Created with biorender.com.

Figure 4

Binding of IL-6/sIL-6R to gp130 results in the IL-6 trans-signaling. This initiates activation of the downstream intracellular signaling cascade via the JAK/STAT3 pathway leading to IL-6-mediated inflammatory responses. Created with biorender.com.

Figure 5

IL-9 binds to the IL-9R complex to initiate the JAK1/JAK3/STAT1/STAT3/STAT5 signal cascade that results in generating IL-9-mediated inflammatory response in the conjunctiva. Created with biorender.com.

Figure 6

The binding of IL-10 to IL-10R complex initiates the activation of JAK1/TYK2/STAT3 signaling cascade that leads to the development of STAT3-mediated anti-inflammatory responses. Created with biorender.com.

Figure 7

The binding of IL-13 to the receptor induces the JAK1/TYK2/STAT6 signaling cascade that results in generating IL-13-mediated allergic immune response in the conjunctiva. Created with biorender.com.

Figure 8

The binding of IL-25 to its receptor induces the transcription of IL-25 responsive genes via the TRAF6/NF$\mathsf{\kappa }$B-dependent signaling cascade and TRAF4/MAPK/AP-1-dependent signaling pathway. Created with biorender.com.

Figure 9

The interaction between IL-31 and its receptor results in the activation of JAK1/JAK2/STAT1/STAT3/STAT5 signal cascade that results in generating IL-31-mediated pathophysiological features of type 2 allergic immune responses. Created with biorender.com.

Figure 10

The binding of IL-33 to its receptor induces the MyD88/IRAK1/IRAK4/TRAF6/NF$\mathsf{\kappa }$B- dependent signaling pathway and the TRAF6/MAPK/AP-1-dependent signaling pathway. This initiates the transcription of IL-33-responsive genes that are responsible for the development of the pathophysiological changes observed in allergic conjunctivitis. Created with biorender.com.

Figure 11

TSLP Signaling Cascade: TSLP binds to the TSLPR complex to induce the JAK1/JAK2/STAT1/STAT3/STAT5 signaling cascade that results in the transcription of TSLP-responsive genes that exacerbates the inflammatory process associated with Th2-mediated immune responses. Created with biorender.com.