IL-33 DUALITY

IL-33 IS A CYTOKINE RELEASED AT THE TOP OF THE INFLAMMATORY CASCADE THAT CAN DRIVE COPD1-6

IL-33 can impact a variety of downstream cell types and pathways1,6-9

Illustration Showing IL-33 Release from the Airway Epithelium Drives the Inflammatory Cascade In COPD Illustration Showing IL-33 Release from the Airway Epithelium Drives the Inflammatory Cascade In COPD
Downward Arrow Icon Representing the Flow of the IL-33 COPD Pathway Diagram Downward Arrow Icon Representing the Flow of the IL-33 COPD Pathway Diagram
Illustration Showing IL-33 Release Following Epithelial Damage, Activating Multiple Downstream Cell Types Involved in COPD Inflammation Illustration Showing IL-33 Release Following Epithelial Damage, Activating Multiple Downstream Cell Types Involved in COPD Inflammation

UPON EPITHELIAL DAMAGE,

IL-33 is released, directly activating a variety of downstream cell types

  • IL-33 COPD Mast Cells Icon

    Mast cells

  • ILC2s Icon

    ILC2s

  • Eosinophils Icon

    Eosinophils

Downward Arrow Indicating IL-33 Signaling That Initiates Multiple Inflammatory Pathways In COPD Downward Arrow Indicating IL-33 Signaling That Initiates Multiple Inflammatory Pathways In COPD
  • Neutrophils Icon in IL-33

    Neutrophils

  • Macrophages Icon in IL-33

    Macrophages

  • T Cell Icon in IL-33 COPD

    T cells

AND INITIATING

multiple inflammatory pathways

Type 2 Inflammation

  • IL-4 Cytokine is Involved in Type 2 Inflammation

    IL-4

  • IL-5 Cytokine is Involved in Type 2 Inflammation

    IL-5

  • IL-13 Cytokine is Involved in Type 2 Inflammation

    IL-13

Type 1 & 3 Inflammation

  • IFN- γ Cytokine Associated with Type 1 and Type 3 Inflammation

    IFN-γ

  • TNF-α Cytokine Associated with Type 1 and Type 3 Inflammation

    TNF-α

Note: The IL-33 pathway shown here has been simplified for illustration purposes only and does not align with specific disease pathology or clinical manifestations, nor does it imply clinical benefit or relevance.

COPD is a highly heterogeneous disease, featuring inflammation that is multicellular, complex, and distinct from that of asthma.10 IL-33 plays a key role in COPD:

Icon Represents IL-33-Driven Inflammatory Responses In COPD, Including Eosinophilic and Neutrophilic Inflammation Icon Represents IL-33-Driven Inflammatory Responses In COPD, Including Eosinophilic and Neutrophilic Inflammation
  • IL-33 is a driver of eosinophilic and neutrophilic inflammation, impacting the majority of patients with COPD6,11-17
  • Neutrophils are the dominant inflammatory driver in COPD that can increase during exacerbations and can be associated with disease progression18-20
Icon Represents Mucus Dysfunction In COPD, Including Mucus Hypersecretion, Impaired Clearance, And Mucus Plug Formation Icon Represents Mucus Dysfunction In COPD, Including Mucus Hypersecretion, Impaired Clearance, And Mucus Plug Formation
  • IL-33 also perpetuates the cycle of mucus dysfunction, characterized by mucus hypersecretion, impaired clearance, and mucus plugs1,21-23
  • Mucus dysfunction can contribute to symptoms of COPD and increased exacerbation risk1,24-29

IL-33 HAS 2 KEY BIOACTIVE FORMS THAT ARE ADVANCING OUR UNDERSTANDING OF COPD PATHOPHYSIOLOGY1

Upon epithelial damage, IL-33 triggers dual pathways—reduced IL-33 and oxidized IL-33—that contribute to many symptom manifestations

Diagram Showing Epithelial Damage Triggering IL-33 Dual Pathways, Including Reduced IL-33 and Oxidized IL-33 Diagram Showing Epithelial Damage Triggering IL-33 Dual Pathways, Including Reduced IL-33 and Oxidized IL-33
 

IL-33 OX acts on the epithelium, promoting mucus production1

Reduced IL-33 (IL-33 RED) Activating the ST2 Pathway and Promoting Inflammatory Responses In COPD Reduced IL-33 (IL-33 RED) Activating the ST2 Pathway and Promoting Inflammatory Responses In COPD

Reduced IL-33 (IL-33 RED) activates the ST2 pathway

and leads to the initiation and amplification of inflammation through a variety of cells that impact the majority of patients with COPD6,7,11-17

Icon Representing Neutrophilic Inflammation In COPD. Icon Representing Neutrophilic Inflammation In COPD.

Up to 92% of patients with COPD have neutrophilic inflammation, which remains the dominant type of inflammation even in those with high eosinophils15-17,30

Arrow Illustrating the Rapid Oxidation Of IL-33 From Reduced to Oxidized Form Arrow Illustrating the Rapid Oxidation Of IL-33 From Reduced to Oxidized Form
Oxidized IL-33 (IL-33 OX) activating the RAGE/EGFR pathway in COPD Oxidized IL-33 (IL-33 OX) activating the RAGE/EGFR pathway in COPD

Oxidized IL-33 (IL-33 OX) activates the RAGE/EGFR pathway

and is associated with mucus dysfunction—characterized by mucus hypersecretion, impaired clearance, and mucus plugs1,21-23

Icon Representing Mucus Plug Formation in the Airways of Patients With COPD Icon Representing Mucus Plug Formation in the Airways of Patients With COPD

Up to 24% increased risk of death was seen in patients with increased mucus plugs compared with no mucus plugs*32

Interested in learning more? Download the Mechanism of Disease InfographicDownload icon

Note: The IL-33 pathway shown here has been simplified for illustration purposes only and does not align with specific disease pathology or clinical manifestations, nor does it imply clinical benefit or relevance.

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IL-33 IS ASSOCIATED WITH A TWOFOLD INCREASED RISK OF EXACERBATIONS OVER 1 YEAR2

NEED MORE INFORMATION?

ONE CYTOKINE. TWO DISTINCT FORMS.1

Watch a short video about IL-33 and its dual effects in COPD or download the IL-33 Infographic.Download Icon

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COULD IL-33 REVEAL NEW WAYS OF THINKING ABOUT COPD?

Learn more about the dual pathways of IL-33 and their roles in COPD.

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COPD=chronic obstructive pulmonary disease; EGFR=epidermal growth factor receptor; IFN=interferon; IL=interleukin; ILC2=type 2 innate lymphoid cell; MSL=medical science liaison; OX=oxidized; RAGE=receptor for advanced glycation end-products; RED=reduced; ST2=suppression of tumorigenicity 2 (also known as serum stimulation-2); TNF=tumor necrosis factor.

*Patients with mucus plugs in ≥3 lung segments. There was a significant increase in death even when controlling for smoking, lung function, and other comorbidities.32

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