Alarmins: chemotactic activators of immune responses Joost J Oppenheim and De Yang The recruitment and activation of antigen-presenting cells are critical early steps in mounting an immune response. Many microbial components and endogenous mediators participate in this process. Recent studies have identified a group of structurally diverse multifunctional host proteins that are rapidly released following pathogen challenge and/or cell death and, most importantly, are able to both recruit and activate antigen-presenting cells. These potent immunostimulants, including defensins, cathelicidin, eosinophil-derived neurotoxin, and high-mobility group box protein 1, serve as early warning signals to activate innate and adaptive immune systems. We propose to highlight these proteins’ unique activities by grouping them under the novel term ‘alarmins’, in recognition of their role in mobilizing the immune system. Addresses Laboratory of Molecular Immunoregulation, Center for Cancer Research, Basic Research Program, Scientific Application and International Cooperation, Inc. (SAIC)-Frederick, National Cancer Institute at Frederick, Frederick, MD 21702, USA Corresponding author: Oppenheim, Joost J (Oppenhei@ncifcrf.gov) Current Opinion in Immunology 2005, 17:359–365 This review comes from a themed issue on Host–pathogen interactions Edited by Bali Pulendran and Robert A Seder Available online 13th June 2005 0952-7915/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2005.06.002 Introduction ‘Danger signals’ include exogenous invasive microorgan- isms, endogenous tissue injury, and the intercellular inflammatory mediators generated to defend the host [1]. Since these mediators are released and/or secreted in response to danger, in reality they act as ‘warning’ signals that alert innate and adaptive immune host defense mechanisms. These warning signals interact with receptors including those that activate antigen-presenting cells (APCs) [1]. The most effective APCs, dendritic cells (DCs), are located in blood and peripheral tissues as resting, imma- ture DCs (iDCs) and have a high capacity for antigen uptake. These iDCs are chemoattracted to sites of tissue damage and infection, take up antigens and are activated to become mature DCs (mDCs) [2]. The maturation process is characterized by loss of phagocytic capacity, increased expression of MHC molecules and antigen- presenting capacity, expression of co-stimulatory mole- cules including CD40, CD80 and CD86, the production of proinflammatory cytokines, particularly IL-12, and up- regulation of CCR7 and CXCR5 chemokine receptors. Consequently, mDCs develop the capacity to migrate to draining lymphoid tissues and to present antigens to T cells to initiate adaptive immune reactions. Recent studies have identified several structurally diverse endogenous mediators of innate immunity with certain features: firstly, they are rapidly released in response to infection or tissue injury; secondly, they have both che- motactic and activating effects on APCs; and thirdly, they exhibit particularly potent in vivo immunoenhancing activity. This subset of mediators alerts host defenses by augmenting innate and adaptive immune responses to tissue injury and/or infection. On the basis of their unique activities, we propose to name them ‘alarmins’. In this review, we discuss the structure, expression and functional characteristics of alarmins with a particular focus on the receptors responsible for attracting and activating APCs and augmenting the adaptive immune response. Antimicrobial peptides and proteins with alarmin activity Innate-immune mediators possessing alarmin activity include defensins, cathelicidin, eosinophil-derived neu- rotoxin (EDN), and high mobility group box protein 1 (HMGB1). These structurally diverse molecules have other well-established functions. Defensins consist of a family of small (3–6 kDa) anti- microbial peptides with a characteristic b-sheet-rich fold and six cysteines forming three intra-chain disulfide bonds, which, primarily on the basis of disulfide connec- tivity of cysteine residues, are classified into three (a, b, and u) subfamilies [3]. Cathelicidins belong to another family of antimicrobial proteins with a conserved N-terminal prosequence of approximately 100 residues known as the ‘cathelin’ domain, and a C-terminal anti- microbial domain that is highly heterogeneous in terms of size (12–80 amino acids) and structure, which can be either an a-helix, b-hairpin with one or two intra-chain disulfide bonds, or extended polyproline-type folding [4]. Both defensins and cathelicidins have antimicrobial activ- ity against bacteria, fungi, some viruses and parasites [3,4,5  ,6,7,8  ]. www.sciencedirect.com Current Opinion in Immunology 2005, 17:359–365