BRIEF REVIEW www.jasn.org Of Inflammasomes and Alarmins: IL-1b and IL-1a in Kidney Disease Hans-Joachim Anders Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians Universität, Munich, Germany ABSTRACT Kidney injury implies danger signaling and a response by the immune system. The enigmatic importance for the regulation inflammasome is a central danger recognition platform that triggers local and of systemic and tissue inflammation, systemic inflammation. In immune cells, inflammasome activation causes the release pro- and anti-inflammatory factors bal- of mature IL-1b and of the alarmin IL-1a. Dying cells release IL-1a also, indepen- ance the system at all levels, i.e., the re- dently of the inflammasome. Both IL-1a and IL-1b ligatethesameIL-1receptor ceptor ligands, the transmembrane cell (IL-1R) that is present on nearly all cells inside and outside the kidney, further am- surface receptors, and the signaling plifying cytokine and chemokine release. Thus, the inflammasome-IL-1a/IL-b-IL-1R pathways (Figure 1).4,5 system is a central element of kidney inflammation and the systemic consequences. Seminal discoveries of recent years have expanded this central paradigm of inflam- IL-1a mation. This review gives an overview of arising concepts of inflammasome and IL-1a is constitutively present in kerati- IL-1a/b regulation in renal cells and in experimental kidney disease models. There nocytes and other epithelia including is a pipeline of compounds that can interfere with the inflammasome-IL-1a/IL-b-IL- tubular epithelial cells, whereas macro- 1R system, ranging from recently described small molecule inhibitors of NLRP3, a phages, granulocytes, endothelial cells, component of the inflammasome complex, to regulatory agency–approved IL-1– fibroblasts, and mesangial cells express neutralizing biologic drugs. Based on strong theoretic and experimental rationale, the IL-1a precursor only upon acti- the potential therapeutic benefits of using such compounds to block the inflamma- vation.5 The 31 kDa IL-1a precursor some-IL-1a/IL-b-IL-1R system in kidney disease should be further explored. lacks a signal peptide fragment and is already biologically as active as the pro- J Am Soc Nephrol 27: 2564–2575, 2016. doi: 10.1681/ASN.2016020177 cessed 18 kDa “mature” form.6 Therefore, cells constitutively expressing IL-1a were considered “aloadedgun” that can at any time release a proinflammatory alarmin The immune system has a central role in extends the discussion to the alarmin upon cell necrosis.6–8 This way necrotic a maintaining homeostasis and in regain- IL-1 . A comprehensive view on the ex- cells alert surrounding tissues and set up ing homeostasis after injury. Infectious pression and biologic effects of the in- local tissue inflammation. and noninfectious triggers of injury have flammasome-IL-1 axis in renal cells fl an identical capacity to initiate in am- and its functional contribution to experi- IL-1b mation, e.g., a gouty or bacterial arthritis mental and human kidney disease is IL-1b is not constitutively expressed and both present as clinically indistinguish- required to appreciate the potential of in- its secretion is largely restricted to circu- fl fl – able acute joint in ammation. In the last ammasome-IL-1 related drugs in this lating monocytes that are activated for 15 years the research community has un- evolving area of translational nephrology. raveled the molecular mechanisms of danger signaling but this area remains a UPDATE ON IL-1 BIOLOGY Published online ahead of print. Publication date source of unexpected discoveries. Nu- available at www.jasn.org. merous data have accumulated since the Journal of the American Society of Since its first cloning in 1984 the knowl- Correspondence: Dr. Hans-Joachim Anders, Medi- fi zinische Klinik und Poliklinik IV, Klinikum der Universität Nephrology published a rst overview edge on the biology of the IL-1 family of München, Ziemssenstr.1, 80336 Munich, Germany. about inflammasomes in kidney disease cytokines has expanded to considerable Email: [email protected] 1 in 2011. This brief review provides an complexity as reviewed elsewhere in de- Copyright © 2016 by the American Society of – update on inflammasome biology and tail (Figure 1).2 4 As the system is of Nephrology 2564 ISSN : 1046-6673/2709-2564 JAmSocNephrol27: 2564–2575, 2016 www.jasn.org BRIEF REVIEW Figure 1. The families of IL-1 cytokines and cytokine receptors activate innate and adaptive immunity. Activated or dying cells re- lease all sorts of cytokines of the IL-1 family that specifically interact with several transmembrane surface receptors present on most cell types of the body. Some induce cell activation (IL-1R, IL-18R, IL-36R), others inhibit cell activation (IL-33R, TIGIRR, SIGIRR). This way the family elicits numerous regulatory effects on renal cells, immune cells of the innate and adaptive immune system, either activating or inhibiting their respective cell type–specific functions. AG, antigen; G-CSF, granulocyte colony-stimulating factor; MФ,macrophage; NETs, neutrophil extracellular traps; NK cell, natural killer cell; TIR domain, Toll/interleukin-1 receptor (TIR) homology domain. enzymatic cleavage of the inactive 266 infiltrating macrophages and neutro- to activate calpain-driven pro–IL-1a amino acid precursor into the 153 amino phils can release large amounts of IL- processing.10 Necrotic cells release both acid mature form of IL-1b.5 Therefore, 1b, whereas parenchymal cells may the 31 and 18 kDa forms of IL-1a pas- IL-1b mainly contributes to systemic in- release only small amounts under cer- sively from intracellular stores to alarm flammation by initiating acute phase tain circumstances.4 surrounding cells.6 In those cells that response proteins in the liver such as coexpress IL-1a and IL-1b,IL-1a secretion C-reactive protein, by activating endo- Enzymatic Processing can also be inflammasome-dependent, thelial cells, by triggering fever, by caus- Pro–IL-1a is a substrate for the calcium- implying that IL-1a and IL-1b are re- ing neutrophil mobilization from the dependent, nonlysosomal cysteine pro- leased together.12 bone marrow (leukocytosis), and by tease calpain (Figure 2),5,10,11 but little is Pro–IL-1b is a true precursor that activating all classes of leukocytes and known about how external triggers reg- requires enzymatic processing for renal cells (Figure 1).9 Within tissues, ulate calpain activity. Calcium release activation. Extrinsic or intrinsic dan- mainly resident dendritic cells and from intracellular stores seems sufficient ger signals that initiate the canonical J Am Soc Nephrol 27: 2564–2575, 2016 Inflammasome-IL-1 Axis in Kidney Disease 2565 BRIEF REVIEW www.jasn.org specklike protein (ASC), and caspase-1 (Figure 2).15 Different inflammasomes are defined by the different NLRs that serve as sensors for intracellular danger signals.15 Whereas the NLRC4, NLRP6, -7, -12, or AIM2 inflammasomes recog- nize preferably pathogen-associated mo- lecular patterns (PAMPs), NLRP1 and NLRP3 are more promiscuous and have the capacity to translate a large variety of different cytosolic danger signals into the caspase-1–dependent secretion of IL-1b.15 Many of these may also occur during kid- ney injury, such as mitochondrial release of reactive oxygen species and pore form- ing toxins, ATP, or osmotic pressure that affect intracellular potassium and calcium concentrations.15–17 Other danger-associated molecular patterns (DAMPs) that contribute to NLRP3- driven renal inflammation include uromodulin particles,18 biglycan,19 extracellular histones,20 oxalate, or urate crystals that destabilize lysosomes for cathepsin leakage into the cytosol like other phagocytosed microparticles.21–23 Cytosolic LPS is a known trigger for noncanonical inflammasome signaling involving caspase-11 in mice and caspases- 4 and -5 in humans.24–27 Caspase-11/4/5 activation leads to cleavage of the cyto- Figure 2. Inflammasome activation in dendritic cells and macrophages involves nu- solic protein gasdermin,24,28 and gasder- merous elements. Dendritic cells first need to induce the expression of the inflammasome min’sN–terminally cleaved product p70 components and of pro–IL-1a and pro–IL-1b.Thiscanoccurvia cytokine receptors or Toll-like subsequently activates the NLRP3 in- receptors (TLRs). Activation of inflammasome assembly can occur upon numerous intracellular flammasome for caspase-1–dependent danger signals such as mitochondrial reactive oxygen species release, lysosomal protease pro–IL-1b processing.24 leakage, and potassium efflux or calcium influx. The multiprotein inflammasome complex – b Unlike macrophages, dendritic cells forms a wheel-like structure to trigger caspase-1 driven IL-1 (and IL-18) enzymatic activation. – b fl fi do not constitutively express pro IL-1 In ammasome brils grow in size to a single macromolecular complex called ASC speck. fl Calcium activates calpain, which cleaves pro–IL-1a to IL-1a, but in contrast to pro–IL-1b,IL-1a and the in ammasome components. fi is already biologically active, and hence an alarmin. IL-1a,IL-1b, and IL-18 together with other Dendritic cells rst require a priming NF-kB–dependent cytokines and chemokines activate cytokine and chemokine receptors in signal via Toll-like receptors or cytokine an autocrine, paracrine, or systemic manner. Noncanonical inflammasome signaling, e.g., receptors that induce NF-ĸB–dependent triggered by cytosolic LPS, involves caspase-11 (mice) and caspase 4/5 (humans), which cleave transcription of NLRP3, ASC, caspase-1, gasdermin D. The cleaving product activates NLRP3. Noncanonical inflammasome signaling pro–IL-1a, and IL-1b.15 It is of note that is a recognized trigger for pyroptosis, an immunogenic form of cell death that leads to the also other enzymes have been found to release of numerous intracellular components that have the capacity to activate a plethora of cleave pro–IL-1b, such as serine prote- fl pattern recognition receptors and close the vicious cycle of necroin ammation.