Alarmins: chemotactic activators of immune responses
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)
- et al.
The instructive role of dendritic cells on T cell responses: lineages, plasticity and kinetics
Curr Opin Immunol
(2001) - et al.
IL-22 increases the innate immunity of tissues
Immunity
(2004) - et al.
Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion
EMBO J
(2003) - et al.
IFN-γ induces high mobility group box 1 protein release partly through a TNF-dependent mechanism
J Immunol
(2003) GM-CSF-based cancer vaccines
Immunol Rev
(2002)- et al.
Anaphylatoxin C5a induces monocyte recruitment and differentiation into dendritic cells by TNFα and prostaglandin E2-dependent mechanisms
J Immunol
(2003) The danger model: a renewed sense of self
Science
(2002)Defensins: antimicrobial peptides of innate immunity
Nat Rev Immunol
(2003)Cathelicidins, multifunctional peptides of the innate immunity
J Leukoc Biol
(2004)- et al.
Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense
Annu Rev Immunol
(2004)