Pathophysiology of Disease

Uncovering the Underlying cause of inflammation

Approximately 80% to 90% of pericarditis episodes are deemed
idiopathic and presumed to be postviral, but most clinicians may not
fully understand the underlying cause for the recurrences.1 Emerging
evidence indicates that recurrences of pericarditis have an underlying
pathophysiology driven by IL-1.1-3

Interleukin-1 (IL-1) is a master cytokine
of local and systemic inflammation.4,5

The Role Of Interleukin-1 (IL-1)

IL-1 Family
IL-1α
IL-1β
IL-1Ra
IL-18
IL-36Ra
IL-36α
IL-37
IL-36β
IL-36γ
IL-38
IL-33

IL-1 belongs to the IL-1 superfamily of cytokines
and cytokine receptors, comprising 11 distinct
family members with both pro- and anti-inflammatory functions.5-7

The master cytokine of inflammation

Multiple characteristics have led to IL-1 being
referred to as a master cytokine of local and systemic
inflammation4,5:

  • Highly proinflammatory
  • Drives multiple proinflammatory functions
  • Stimulates other proinflammatory cytokines
    (eg, IL-6 and TNF-α)
  • Mediates inflammation in virtually every tissue
    in the body
  • Stimulates its own production

The significance of IL-1α and IL-1β

IL-1α and IL-1β play an important role in the
autoinflammatory cycle of recurrent pericarditis.
The IL-1α precursor is present and active
inside healthy cells. During pericardial injury, cell
death occurs and IL-1α is released and able
to activate adjacent cells bearing the IL-1 receptor.
In contrast, IL-1β is inactive and a product of specific
immune cells. It needs to be cleaved by caspase-1,
which itself requires activation after assembly of
the inflammasome.2,5

This interaction between IL-1α and IL-1β triggers
and drives ongoing tissue injury in the pericardium.2,3

Why does pericarditis recur again and again?

The pathophysiology of recurrent pericarditis involves a multistage autoinflammatory process. It begins with pericardial damage that causes pericardial cells to die and release IL-1α, which is already present in the cells.2

The released IL-1α initiates a localized inflammatory reaction by attracting neutrophils through chemotaxis.2

Released IL-1α also binds and activates IL-1 receptors on the surface of tissue macrophages, which induces macrophages to produce immature inactive IL-1β.2

A structure inside macrophages called the inflammasome then cleaves and activates IL-1β.2

The inflammasome is also stimulated by other inflammatory signals called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)—also known as “danger signals.”2

These danger signals stimulate the inflammasome to produce even greater amounts of IL-1β and induce more pericardial damage and inflammation.2

Active IL-1β is then secreted by macrophages.2

Both active IL-1β and IL-1α activate IL-1 receptors on the surface of vascular endothelial cells, which results in multiple inflammatory effects, including2:
•   Stimulation of white blood cell adhesion
•   Increased monocyte and neutrophil infiltration
•   Increased capillary leak

Pericardial inflammation mediated by IL-1α and IL-1β causes additional tissue injury in the pericardium, which stimulates even more IL-1α and IL-1β to be produced.2,3

The ability of IL-1 to stimulate its own production
creates a continuous cycle of inflammation driven
by both IL-1α and IL-1β.2,3

Summary

Interleukin-1 (IL-1) is a master
cytokine of local and systemic
inflammation.4,5

This interaction between IL-1α and
IL-1β triggers and drives ongoing
tissue injury in the pericardium.2,3

The ability of IL-1 to stimulate its
own production creates a continuous
cycle of inflammation.2

Stay Connected

Sign Up

References:

  1. Cremer PC, Kumar A, Kontzias A, et al. Complicated pericarditis: understanding risk factors and pathophysiology to inform imaging and treatment. J Am Coll Cardiol. 2016;68(21):2311-2328.
  2. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov. 2012;11(8):633-652.
  3. Brucato A, Imazio M, Cremer PC, et al. Recurrent pericarditis: still idiopathic? The pros and cons of a well-honoured term. Intern Emerg Med. 2018;13(6):839-844.
  4. Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469-484.
  5. De Mooij CEM, Netea MG, van der Velden WJFM, Blijlevens NMA. Targeting the interleukin-1 pathway in patients with hematological disorders. Blood. 2017;129(24):3155-3164.
  6. Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720-3732.
  7. Akdis M, Aab A, Altunbulakli C, et al. Interleukins (from IL-1 to IL-38), interferons, transforming growth factor ß, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2016;138(4):984-1010.