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Alarmins: Awaiting a Clinical Response Alarmins: awaiting a clinical response James K. Chan, … , Nicole Horwood, Jagdeep Nanchahal J Clin Invest. 2012;122(8):2711-2719. https://doi.org/10.1172/JCI62423. Science in Medicine Alarmins are endogenous molecules that are constitutively available and released upon tissue damage and activate the immune system. Current evidence indicates that uncontrolled and excessive release of alarmins contributes to the dysregulated processes seen in many inflammatory and autoimmune conditions, as well as tumorigenesis and cancer spread. Conversely, alarmins have also been found to play a major role in the orchestration of tissue homeostasis, including repair and remodeling in the heart, skin, and nervous system. Here, we provide an update and overview on alarmins, highlighting the areas that may benefit from this clinical translation. Find the latest version: https://jci.me/62423/pdf Science in medicine Alarmins: awaiting a clinical response James K. Chan,1 Johannes Roth,2 Joost J. Oppenheim,3 Kevin J. Tracey,4 Thomas Vogl,2 Marc Feldmann,1 Nicole Horwood,1 and Jagdeep Nanchahal1 1Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom. 2Institute of Immunology, University of Münster, Münster, Germany. 3National Cancer Institute, Frederick, Maryland, USA. 4Feinstein Institute of Medical Research, New York, New York, USA. Alarmins are endogenous molecules that are constitutively available and released upon tissue damage and activate the immune system. Current evidence indicates that uncontrolled and exces- sive release of alarmins contributes to the dysregulated processes seen in many inflammatory and autoimmune conditions, as well as tumorigenesis and cancer spread. Conversely, alarmins have also been found to play a major role in the orchestration of tissue homeostasis, including repair and remodeling in the heart, skin, and nervous system. Here, we provide an update and overview on alarmins, highlighting the areas that may benefit from this clinical translation. Alarmins in health and disease tification of proinflammatory cytokines, in particular TNF-α, as a The alarmin family comprises structurally diverse and evolution- therapeutic target in the 1990s heralded a paradigm shift that led arily unrelated multifunctional endogenous molecules that are pas- to impressive clinical benefits, most notably in patients suffering sively released from necrotic cells upon infection or tissue injury or from RA (8). Unfortunately, cytokine blockade is not effective in a are rapidly secreted by stimulated leukocytes and epithelia. In the significant proportion of patients (9) and has been disappointing absence of injury or infection, alarmins play important intracellular in the treatment of patients with acute inflammatory disorders, roles (Table 1). However, once released extracellularly, alarmins pro- such as trauma-induced systemic inflammatory response syn- mote activation of innate immune cells and recruitment and activa- drome (SIRS) or sepsis (10). The recent identification of alarmins tion of antigen-presenting cells engaged in host defense and tissue as crucial mediators of the inflammatory processes in these dis- repair through pattern recognition receptors such as the TLRs, many orders and the observation that their release is accompanied by of which have a key role in the detection of pathogens (refs. 1–3 and an upregulation of their receptor suggests the alarmin signaling Table 1). In health, inflammation is self-limiting and a vital part of pathway as an alternative target (Figure 1). the innate host defense. It occurs in response to sterile injury or infec- tion and involves the recruitment of phagocytes to remove cell debris Acute disorders and microbes. This is followed by resolution, with the recruitment of SIRS and sepsis. Severe trauma remains the most common cause of other cell types, including stem and endothelial cells, to restore tissue death under the age of 45 years. There is a biphasic distribution homeostasis. As potent mediators of inflammation, alarmins play of mortality, with the initial peak corresponding to the “first hit,” a fundamental role in the pathogenesis of a wide range of sterile or such as severe injury or hemorrhagic shock. This triggers the host infection-induced immune and inflammatory disorders (4–6). Cru- innate immune system to mount an immediate inflammatory cially, their ability to enhance the adaptive immune response through response, the magnitude of which depends on the severity of the their effects on antigen-presenting cells, including DCs, makes them injuries. If the patient survives, this systemic inflammation is fur- a critical link between the innate and adaptive arms of the immune ther augmented by a “second hit,” such as ischemia/reperfusion, response (7). Hence, the alarmin family represents an intriguing ther- surgical interventions, and opportunistic infections, accounting apeutic target, not only to dampen inflammation but also to uncou- for the subsequent peak in mortality (11). The resultant “cytokine ple the innate and adaptive immune responses in chronic pathologies, storm,” which describes the overwhelming and sustained release of including autoimmune disorders. Furthermore, alarmins may serve pro/anti-inflammatory mediators, including TNF-α, IL-1β, IL-6, as useful diagnostic and prognostic biomarkers in inflammatory dis- and IL-10, is responsible for organ dysfunction as well as increased orders. While there is now a rapidly growing list of alarmins in the lit- susceptibility to sepsis (12–14). Indeed, prognosis correlates with erature, the best characterized in health and disease are high-mobility circulating levels of biomarkers of systemic inflammation, such as group protein B1 (HMGB1), S100 proteins, and heat shock proteins IL-6 and C-reactive protein (CRP). (HSPs). In this Review, we will focus on these alarmins, as they have The prospect of treating polytrauma and sepsis as an inflamma- the clearest and most tangible clinical translational potential to date. tory and immunological disease by immunomodulation remains unfulfilled (10, 15). Strategies involving blockade of cytokines and Modulation of the alarmin response their receptors were promising in the preclinical setting, but disap- to suppress inflammation pointed in clinical trials (10, 16), perhaps in part due to the very Dysregulation of inflammation underlies the pathophysiological early release of TNF-α precluding timely intervention. Currently, process in many immune and inflammatory disorders. The iden- there is no FDA-approved agent for the treatment of SIRS or sepsis after activated droterecogin alfa, the recombinant form of human activated protein C, was recalled by the FDA in 2011. Conflict of interest: Marc Feldmann is a shareholder in Merck, Johnson & Johnson, In their role as proinflammatory mediators, alarmins provide Maimonidex, Xenexus, and BioAtrix. He is a consultant for Halozyme TetraLogic Pharmaceuticals and GlaxoSmithKline (GSK) and receives research support from valuable insights into the regulation of traumatic inflammation Novo Nordisk, Merck, Wyeth, and GSK. and the pathogenesis of SIRS and related conditions, including Citation for this article: J Clin Invest. 2012;122(8):2711–2719. doi:10.1172/JCI62423. sepsis (17), which lead to multiorgan failure and death in up to The Journal of Clinical Investigation http://www.jci.org Volume 122 Number 8 August 2012 2711 science in medicine 2712 Table 1 Alarmins: physiological and pathological functions Alarmin Origin Intracellular Extracellular actions Release pathways Receptors Implicated diseases Regenerative physiological role potential HMGB1 All cell types Regulation of Proinflammatory response (when (a) Passive release by necrotic cells; TLR2, TLR4, Acute trauma and related Cardiac regeneration including immune DNA transcription bound to other DAMPs, e.g., LPS, (b) During apoptosis, HMGB1 is RAGE (subject conditions (S5–S9): sepsis (S31–S34), cells (non-histone IL-β1, DNA, RNA) (S1); chemotaxis, oxidized on Cys106, rendering it to redox states; (S5, S10–S13); ischemic brain revascularization (S35), nuclear protein) proliferation, and differentiation tolerogenic rather than proinflammatory S3, S4) injury (S14–S16); ischemia/ skin wound healing of immune and precursor cells, (S2); (c) Active secretion via reperfusion injury of the heart (S36), bone repair The Journal of Clinical Investigation Journal The including neurites and myocardial alternative pathway (not via (S16, S17); organ transplantation (S37, S38), skeletal precursors; angiogenesis; induction Golgi route): HMGB1 undergoes (S18–S20) muscle (S39), nerve of adaptive immune response several forms of post-translational regeneration (S40) modifications, e.g., acetylation, Chronic conditions: arthritides phosphorylation, methylation (S21–S23), SLE (S24), MS (S25), T1DM (S26), epilepsy (S27) Cancer (S28–S30) S100A8/ Epithelial cells Calcium regulation, Pro-inflammatory response; (a) Active secretion by epithelial S100A8/A9: TLR4, Acute: sepsis (S41, S42), acute Skin wound healing S100A9, and phagocytes cell motility neutrophil adhesion, migration, cells and innate immune cells Carboxylated lung injury (S43, S44), asthma (S67–S69); liver S100A12 (40% of soluble release from bone marrow; via alternative pathway (i.e., N-glycans/RAGE; (S45) regeneration (S70); (humans cytosolic content cytokine release by target bypass classical Golgi route); S100A12: RAGE musculoskeletal only, absent in neutrophils) cells, e.g., monocytes, (b) Passive release by necrotic Chronic:
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