Interleukin-1 and Related Cytokines in the Regulation of Inflammation and Immunity

Abstract

Forty years after its naming, interleukin-1 (IL-1) is experiencing a renaissance brought on by the growing understanding of its context-dependent roles and advances in the clinic. Recent studies have identified important roles for members of the IL-1 family-IL-18, IL-33, IL-36, IL-37, and IL-38-in inflammation and immunity. Here, we review the complex functions of IL-1 family members in the orchestration of innate and adaptive immune responses and their diversity and plasticity. We discuss the varied roles of IL-1 family members in immune homeostasis and their contribution to pathologies, including autoimmunity and auto-inflammation, dysmetabolism, cardiovascular disorders, and cancer. The trans-disease therapeutic activity of anti-IL-1 strategies argues for immunity and inflammation as a metanarrative of modern medicine.

Figure 1. Structural organization of IL-1 family member and their receptors.

A) Subfamilies of IL-1 ligands, grouped by structural similarity. The consensus sequence (AXD), located 9 amino-acids after the cleavage site is shown. B) IL-1 receptors and their cognate agonists and antagonists. The ILR subfamily is composed by receptors and accessory proteins (AcPs) for the cytokines of the IL-1 family. A novel nomenclature of ILRs has been recently proposed and it is as follows: IL-1R1 (IL-1RI), IL-1R2 (IL-1RII), IL-1R3 (IL-1RAcP), IL-1R4 (ST2), IL-1R5 (IL-18Rα), IL-1R6 (IL-1Rrp2, IL-36R), IL-1R7 (IL-18Rβ), IL-1R8 (also known as TIR8 or SIGIRR), IL-1R9 (TIGIRR- 2), IL-1R10 (TIGIRR-1).

Figure 2. IL-1α as an alarmin in tissue damage.

For instance, ischemia is shown as a prototypic cause of tissue damage. 1. Subjected to low oxygen and increased acidity, cells in the ischemic or damaged tissues lose membrane integrity and the constitutively present IL-1α precursor leaves the cell. 2. IL-1α binds to the IL-1R1 on resident macrophages. 3. IL-1β is released via NLRP3 inflammasome activation with ATP derived from hypoxic cell. Also released is G-CSF. At this point, anakinra, anti-IL-1α and anti-IL-1R1 reduce inflammation. 4. IL-1β and G-CSF enter the venous circulation and into the right ventricle. From the heart, arterial blood reaches the bone-marrow and IL-1β and G-CSF induce the release of neutrophils and monocytes into the venous drainage. 5. The IL-1α precursor accumulates in the extracellular space of the ischemic tissue. 6. IL-1α binds to IL-1R1 on tissue fibroblasts, epithelial cells, astrocytes in the respective tissue type. Anti-IL-1α, anakinra or anti-IL-1R1 reduce the inflammatory process at this point. 7. Production of chemokines such as CCL1. 8. Arterial circulation reaches the ischemic tissue with neutrophils and monocytes from the bone marrow. 9. Neutrophils bind to ICAM-1 and cross the endothelial barrier with the assistance of chemokines. 10. Neutrophils accumulate in the tissue. 11. Neutrophil-mediated damage to the penumbral cells. 12. In addition to IL-1α, infiltrating monocytes produce IL-1β and the ischemic site becomes dominated by IL-1β, which contributes to steps 6-11 sustaining the inflammatory cascade.

Figure 3. Role of IL-1 family members in the differentiation and function of myelomonocytic cells and in the orchestration of innate and adaptive immune responses.

A) IL-1β regulates emergency hematopoiesis and trained innate immunity acting on bone marrow hematopoietic progenitors, and mature myeloid cell functional activity and survival. B-D) Schematic representation of type 1 (B), type 2 (C) and type 3 immunity (D) activated by IL-18, IL-33 and IL-1, respectively.

Figure 4. Mechanisms of tumor promotion and control by IL-1 family members.

A) Upstream conditions and downstream cell types and mediators involved in the networks of IL-1 and IL-33-driven tumor promotion and immune suppression. B) Representation of IL-1R8-dependent modulation of IL-18 activity on NK cells, and its role as co-receptor for IL-37.