Targeting interleukin-1 signaling for renoprotection

Abstract

Sterile inflammation with ensuing immune-mediated kidney damage has been implicated in pathophysiology of acute and chronic kidney diseases. Disinhibition of interleukin 1 (IL-1) signaling triggers local inflammation of renal tissue and may initiate or aggravate systemic inflammatory response. The IL-1α isoform is released by many cell types during cell necrosis to attract immune cells, whereas the IL-1β isoform is secreted by immune cells to amplify local inflammatory responses. The unfolding of IL-1 signaling is restricted by an endogenous IL-1 receptor antagonist and a decoy IL-1 receptor variant. Pharmacological IL-1 inhibitors mimicking the natural IL-1 suppressors are instrumental in management of a broad spectrum of (auto)inflammatory disorders. Progression of several kidney diseases toward renal fibrosis has been associated with a disbalance between the pro-inflammatory and anti-inflammatory IL-1 signaling components. While IL-1 inhibitors have proven success in prevention and treatment of renal complications accompanying the autoimmune disorders, broader opportunities in kidney diseases have been expected. The present review work analyzes potential niches for IL-1 signaling in the field of nephrology.

Keywords: ADPKD (autosomal dominant polycystic kidney disease); acute kidney injury; chronic kidney disease; cytokines; interleukins; nephroprotection.

Figure 1

Schematic drawing of interleukin 1 (IL-1) signaling. The IL-1α isoform precursor (pro-IL-1α) is produced in epithelial, endothelial, or glial cells and released upon necrotic cell death to induce the pro-inflammatory response in neighboring immune cells via binding to the IL-1 receptor type 1 (IL-1R1) and downstream signal transduction through the myeloid differentiation primary response 88 adaptor protein (MyD88). The pro-IL-1α can be further presented at the cell surface to the neighboring IL-1R1-expressing cell (juxtacrine signaling). Finally, activation of calpains (Ca²⁺-dependent proteases) during necrotic cell death may lead to proteolytic cleavage and release of mature IL-1a with higher affinity to IL-1R1. In contrast to the active pro-IL-1α, the precursor of IL-1β isoform (pro-IL-1β) produced by immune cells is inactive. The proteolytic cleavage of pro-IL-1β in inflammasomes by caspase-1 converts it to the active IL-1β, which induces and amplifies the inflammatory response upon release and binding to IL-1R1. The pro-inflammatory action of IL-1α and IL-1β is balanced by endogenous inhibitors encompassing the IL-1 receptor antagonist (IL-1Ra) and the decoy type 2 IL-1 receptor existing in the membrane bound (mIL-1R2) and soluble forms (sIL-1R2).

Figure 2

Physiologic and pathophysiologic effects of IL-1 signaling in the kidney. The left panel summarizes available data on physiological effects of the IL-1 signaling in the kidney including the coordinated antimicrobial immune response, natriuretic and diuretic actions, as well as potential contribution to the podocyte survival upon stress. The right panel illustrates pathophysiological implications of the IL-1 in kidney disease such as renal salt retention, aggravated proteinuria, amplification of vasopressin signaling, as well as local and systemic pro-inflammatory effects.

Figure 3

Potential nephrological fields for therapeutic application of distinct IL-1 signaling inhibitors and mechanisms of actions. The left panel describes the large renal pathologies which may be responsive to IL-1 signaling inhibitors. The middle panel illustrates mechanisms of IL-1 signaling suppression utilized by distinct approved inhibitor drugs. The right panel provides the list of currently available and clinically approved IL-1 inhibiting drugs.