Alarmins: chemotactic activators of immune responses

https://doi.org/10.1016/j.coi.2005.06.002Get rights and content

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.

Introduction

‘Danger signals’ include exogenous invasive microorganisms, 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, immature 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 molecules 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 chemotactic 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.

Section snippets

Antimicrobial peptides and proteins with alarmin activity

Innate-immune mediators possessing alarmin activity include defensins, cathelicidin, eosinophil-derived neurotoxin (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) antimicrobial peptides with a characteristic β-sheet-rich fold and six cysteines forming three intra-chain disulfide bonds, which, primarily on the basis of disulfide connectivity of cysteine residues, are

Alarmins are rapidly released in response to infection and tissue injury

Many alarmins are stored in distinct anatomical compartments (Table 1). Human α-defensins are stored in granules of either neutrophils or small-intestinal Paneth cells. Of the four human β-defensins, HBD1 is constitutively expressed by keratinocytes and epithelial lining cells. Cathelicidin is stored in the granules of neutrophils and mast cells [10] and also expressed by keratinocytes and various epithelial cells. EDN is stored in eosinophil granules. HMGB1 is ubiquitously present in the

Chemotactic receptors for alarmins

All alarmins are multifunctional and have antimicrobial activities. Defensins, cathelicidins, and HMGB1 also promote inflammatory innate immune reactions by induction of proinflammatory mediators such as histamine, prostaglandins, chemokines (e.g. CXCL2/MIP-2, CXCL8/IL-8, CXCL5/ENA-78, CCL2/MCP-1), and TNF-α, suppression of IL-10, and enhancement of phagocytosis as recently reviewed [3, 4, 5•, 9].

Defensins, cathelicidins, EDN, and HMGB1 at nanomolar concentrations are chemotactic for distinct

Immunostimulating and APC-activating activities of alarmins

Alarmins have direct activating effects on APCs and immunoenhancing adjuvant activities. Human neutrophil-derived α-defensins and β-defensin-1–2 promote humoral and cellular immune responses against soluble antigens [5]. Human α-defensins promote both Th1 and Th2 responses [5]. Of the mouse molecules, mBD2 is a potent inducer of DC maturation and promotes cell-mediated antitumor immunity [29, 37] whereas mBD3 activates DCs and promotes humoral immunity [29]. Cathelicidins, including human

Activating receptors of alarmins

The receptors used by alarmins to activate APCs are distinct from GiPCRs (Table 2). The receptor responsible for DC-activating effect of mBD2 was shown to be TLR4 [37]. Although FPRL1 mediates the chemotactic effect of cathelicidins on monocytes/macrophages [5•, 34•], interaction with P2X7 is reported to enhance IL-1β processing and release from monocytes by LL-37 [41]. However, LL-37 stimulates IL-8 production by lung epithelial cells by trans-activating EGFR through metalloproteinase-mediated

Alarmins are distinct from other endogenous warning signals

Although during infection or tissue injury, numerous endogenous soluble signals are generated and/or released, alarmins are unique because, on the basis of their simultaneous APC-attracting and activating capacities, they act as endogenous immunoenhancing adjuvants. Proinflammatory cytokines possess APC-activating effects, but have generally been disappointing in their efficacy as endogenous adjuvants due perhaps to the lack of APC-chemoattracting effect. Only GM-CSF, which exhibits limited

Concluding remarks

Probably numerous alarmins remain to be identified. Urokinase and ribosomal protein S19 have recently been shown to be chemotactic by interacting with GiPCRs on mononuclear cells including DCs; however, it is not known whether they can activate DCs and exhibit adjuvant activity (see [19]). Another candidate is the anaphylotoxin C5a, which chemoattracts leukocytes including DCs by interacting with C5aR, a GiPCR. C5a also stimulates DCs to mature in vivo through the induction of TNF-α [49].

Update

Several recent reports indicate that a number of chemokines, either by directly activating DCs or by inducing more prolonged interaction of APCs with T cells at the immunological synapse, have immunoactivating or co-stimulating effects. Molon et al. [51••] have demonstrated that CCL5/RANTES derived from APCs can enhance T cell activation during APC–T cell interaction by prolonging the recruitment of CCR5 into the immunological synapse. Marsland et al. [52••] have shown that CCL19/ELC and

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We are grateful to Scott Durum, Andy Hurwitz, Zack Howard and Joshua Farber for critical reading of this manuscript, and to Joshua Farber for suggesting the ‘alarmin’ term. This project has been funded in part by DHHS #NO1-CO-12400.

References (53)

  • V. Nizet et al.

    Innate antimicrobial peptide protects the skin from invasive bacterial infection

    Nature

    (2001)
  • C.L. Wilson et al.

    Regulation of intestinal α-defensin activation by the metalloproteinase matrilysin in innate host defense

    Science

    (1999)
  • N.H. Salzman et al.

    Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin

    Nature

    (2003)
  • U. Andersson et al.

    HMGB1 as a DNA-binding cytokine

    J Leukoc Biol

    (2002)
  • A. Di Nardo et al.

    Cutting Edge: mast cell antimicrobial activity is mediated by expression of cathelicidin antimicrobial peptide

    J Immunol

    (2003)
  • P. Scaffidi et al.

    Release of chromatin protein HMGB1 by necrotic cells triggers inflammation

    Nature

    (2002)
  • P. Rovere-Querini et al.

    HMGB1 is an endogenous immune adjuvant released by necrotic cells

    EMBO Rep

    (2004)
  • A.Y. Liu et al.

    Human β-defensin-2 production in keratinocytes is regulated by interleukin-1, bacteria, and the state of differentiation

    J Invest Dermatol

    (2002)
  • C.Y. Kao et al.

    IL-17 markedly up-regulates β-defensin-2 expression in human airway epithelium via JAK and NF-κB signaling pathways

    J Immunol

    (2004)
  • J.R. Garcia et al.

    Human β-defensin 4: a novel inducible peptide with a specific salt-sensitive spectrum of antimicrobial activity

    FASEB J

    (2001)
  • C.J. Hertz et al.

    Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human β defensin-2

    J Immunol

    (2003)
  • R.A. Dorschner et al.

    Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus

    J Invest Dermatol

    (2001)
  • D. Yang et al.

    Human ribonuclease A superfamily members, eosinophil-derived neurotoxin and pancreatic ribonuclease, induce dendritic cell maturation and activation

    J Immunol

    (2004)
  • G. Chen et al.

    Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms

    J Leukoc Biol

    (2004)
  • H. Wang et al.

    Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

    Nat Med

    (2004)
  • C.X. Zhou et al.

    An epididymis-specific β-defensin is important for the initiation of sperm maturation

    Nat Cell Biol

    (2004)
  • Cited by (0)

    View full text