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
inflammation^4,5:

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

Video

Role of Interleukin-1 in the Pathophysiology of Recurrent Pericarditis

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

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References:

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.
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.
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.
Dinarello CA, van der Meer JW. Treating inflammation by blocking interleukin-1 in humans. Semin Immunol. 2013;25(6):469-484.
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.
Dinarello CA. Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood. 2011;117(14):3720-3732.
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.