Targeting inerleukin-6 for renoprotection

Abstract

Sterile inflammation has been increasingly recognized as a hallmark of non-infectious kidney diseases. Induction of pro-inflammatory cytokines in injured kidney tissue promotes infiltration of immune cells serving to clear cell debris and facilitate tissue repair. However, excessive or prolonged inflammatory response has been associated with immune-mediated tissue damage, nephron loss, and development of renal fibrosis. Interleukin 6 (IL-6) is a cytokine with pleiotropic effects including a major role in inflammation. IL-6 signals either via membrane-bound (classic signaling) or soluble receptor forms (trans-signaling) thus affecting distinct cell types and eliciting various metabolic, cytoprotective, or pro-inflammatory reactions. Antibodies neutralizing IL-6 or its receptor have been developed for therapy of autoimmune and chronic non-renal inflammatory diseases. Small molecule inhibitors of Janus kinases acting downstream of the IL-6 receptor, as well as recombinant soluble glycoprotein 130 variants suppressing the IL-6 trans-signaling add to the available therapeutic options. Animal data and accumulating clinical experience strongly suggest that suppression of IL-6 signaling pathways bears therapeutic potential in acute and chronic kidney diseases. The present work analyses the renoprotective potential of clinically relevant IL-6 signaling inhibitors in acute kidney injury, chronic kidney disease, and kidney transplantation with focus on current achievements and future prospects.

Keywords: IL-6; acute kidney injury; anti-cytokine therapy; chronic kidney disease; inflammation; kidney transplantation; trans-signaling.

Figure 1

Interleukin-6 (IL-6) signaling modes and their renal targets. The classic signaling takes place in podocytes expressing the membrane-bound IL-6 receptor (IL-6R) and may help maintaining the integrity of the glomerular filtration barrier. The trans-signaling recruits the soluble IL-6R (sIL-6R) generated by proteolytic cleavage involving the proteases ADAM17 and ADAM10. This type of signaling affects any kidney cell expressing gp130 independently on the presence of mIL-6R. The trans-presentation (cluster) mode may involve renal dendritic cells in local interactions with proinflammatory Th17 cells, in analogy to the reported trans-presentation setting in the brain tissue (16). The autocrine IL-6 signaling may occur intracellularly in cell types expressing IL-6, IL-6R, and gp130 simultaneously and likely contributes to pro-inflammatory immune cell reactions; although its role in the kidney requires further elucidation (15). While effects of the classic and trans-signaling pathways in the kidney have been well documented, the relevance of the trans-presentation and autocrine signaling modes in the renal physiology and pathophysiology remains speculative.

Figure 2

Distinct types of interleukin 6 (IL-6) signaling inhibition in therapeutic approaches. The four panels depict mechanisms of IL-6 signaling suppression utilized by monoclonal antibodies to IL-6 (left upper panel), monoclonal antibodies to IL-6 receptor (IL-6R; right upper panel), modified soluble glycoprotein 130 (gp130) variant (olamkicept; left lower panel), and small molecule inhibitors of Janus Kinases (JAK) – Signal Transducer and Activator of Transcription 3 (STAT3). The representative clinically relevant drugs are mentioned at respective panels.

Figure 3

Local and systemic pathophysiologic effects of IL-6 signaling during kidney injury. Acute or chronic hypoxic and metabolic stress of renal tissue breaks intact energy and protein homeostasis in kidney epithelia causing endoplasmic reticulum stress with unfolded protein response. Injured cells signal via enhanced IL-6 secretion thus attracting local immune cells. Decompensation of cell protective adaptations lead to apoptosis of renal tubular cells and release of Damage-Associated Molecular Patterns (DAMP) further enhancing the local immune response. Both IL-6 and DAMP induce invasion of T-cells and monocytes followed by predominant acquisition of pro-inflammatory Th17 and M1 phenotypes. The infiltrating immune cells produce IL-6 and other pro-inflammatory cytokines thus adding to local sterile inflammation of renal tissue. Later migration of antigen-presenting cells exposed to DAMP to lymphatic nodes may trigger production of autoantibodies by B-cells. Finally, the inflamed kidney tissue delivers substantial amounts of IL-6 into the blood thus provoking systemic inflammation.