IL-33, an Alarmin of the IL-1 Family Involved in Allergic and Non Allergic Inflammation: Focus on the Mechanisms of Regulation of Its Activity

Abstract

Interleukin-33 (IL-33) is a member of the interleukin-1 (IL-1) family that is expressed in the nuclei of endothelial and epithelial cells of barrier tissues, among others. It functions as an alarm signal that is released upon tissue or cellular injury. IL-33 plays a central role in the initiation and amplification of type 2 innate immune responses and allergic inflammation by activating various target cells expressing its ST2 receptor, including mast cells and type 2 innate lymphoid cells. Depending on the tissue environment, IL-33 plays a wide variety of roles in parasitic and viral host defense, tissue repair and homeostasis. IL-33 has evolved a variety of sophisticated regulatory mechanisms to control its activity, including nuclear sequestration and proteolytic processing. It is involved in many diseases, including allergic, inflammatory and infectious diseases, and is a promising therapeutic target for the treatment of severe asthma. In this review, I will summarize the literature around this fascinating pleiotropic cytokine. In the first part, I will describe the basics of IL-33, from the discovery of interleukin-33 to its function, including its expression, release and signaling pathway. The second part will be devoted to the regulation of IL-33 protein leading to its activation or inactivation.

Keywords: IL-33; alarmin; allergy; asthma; inflammation; protease; type-1 immunity; type-2 immunity.

Figure 1

Mechanisms regulating IL-33 bioactivity. The figure shows IL-33 producing cells, inducers of IL-33 release, IL-33 bioactive forms, ST2⁺ target cells implicated in type 1 and type 2 immune responses (left panels) and the mechanisms regulating IL-33 activity (right panels).

Figure 2

Activation of protein IL-33 by cleavage in the protease sensor domain. The figure shows the three domains of human IL-33 protein. The N-terminal nuclear domain contains a short chromatin binding motif (CBM). The central protease sensor domain is a platform of cleavage for various endogenous and exogenous proteases. The C-terminal IL-1 cytokine domain mediates binding to ST2. The cleavage sites for endogenous inflammatory proteases and exogenous allergen proteases are indicated on the human IL-33 sequence.