Originally published online as doi:10.1189/jlb.0607356 on December 21, 2007
Published online before print December 21, 2007
(Journal of Leukocyte Biology. 2008;83:489-492.)
© 2008
by Society for Leukocyte Biology
Sensing danger—Hsp72 and HMGB1 as candidate signals
John H. H. Williams1 and
H. Elyse Ireland
Chester Centre for Stress Research, University of Chester, Cheshire, United Kingdom
1Correspondence: Chester Centre for Stress Research, University of Chester, Parkgate Road, Cheshire, CH1 4BJ, UK. E-mail: john.williams{at}chester.ac.uk
ABSTRACT
Molecules that behave as danger signals are produced when the body is perceived to be under attack, and they alert the immune system to the problem. The immune system can then mount an appropriate response. Two molecules that have received attention as potential danger signals are heat shock protein 72 (Hsp72) and high mobility group box 1 (HMGB1), which are intracellular proteins but are released when cells are under stress, in particular, when necrosis occurs. This review considers the similarities between these two molecules and then contrasts their mechanism of action and problems that can arise when they are overpresented in the extracellular environment. It is proposed that Hsp72 and HMGB1 are members of a suite of danger molecules that provide a fingerprint of the threat, or stressor, to tissue or organism integrity.
Key Words: PAMPs • LPS • inflammation • cellular stress • necrosis • apoptosis
INTRODUCTION
The immune system is able to identify and respond appropriately to a threat to cells or tissues. Molecules that act as danger signals provide the immune system with the information necessary to respond appropriately to threat, whether it be a pathogenic infection or cellular damage induced by physiological or environmental events [1
2
3
]. There are three components to the signal that are important for the appropriate response: the right message, the correct amplitude, and the right timing. These danger signals could be exogenous or endogenous, and they act locally or distant to the site of release when reaching the circulation. Examples of exogenous signals are the bacterial antigens—pattern-associated molecular patterns. The endogenous signals are typically, but not exclusively, intracellular molecules that are released into the extracellular millieu as a result of cell necrosis or tissue damage [1
, 2
, 4
]. We will initially use a simplistic definition of a danger signal, derived essentially from the "danger model" [1
, 2
], before explaining whether this definition is sufficient. The potential danger signal will need to be present in serum, be increased in serum during threatening events, be released from necrotic cells, and generate a response from the cells of the immune system.
Although several endogenous danger signals have been proposed [4
], this review will concentrate on two: heat shock protein 72 (Hsp72) and high mobility group box 1 (HMGB1). Both of these proteins have clear, intracellular roles but interact strongly with the immune system when found in the extracellular environment. These two molecules have been chosen, as although there are many similarities between these proteins, there are also striking contrasts. It is in discussing these two molecules that some interesting insights may be drawn.
Hsp72 AS A DANGER SIGNAL
Hsp72 is an inducible member of the HSP70 molecular chaperone family. It has been shown to bind to partially denatured proteins, facilitate refolding, and stabilize membranes at elevated temperatures [3
]. The Hsp72 protein is induced by cellular stress, whether it is elevated temperature, heavy metal stress, or oxidative stress [3
]. Hsp72 has been shown to be present in serum and is increased following exposure to elevated temperature [5
], infection [6
, 7
], cardiovascular disease [8
, 9
], strenuous exercise [10
, 11
], and psychological stress [12
]. Therefore, serum Hsp72 is increased by a number of threatening stressors.
It has been proposed that Hsp72 is only released from necrotic cells [13
, 14
], consistent with the proposed role as a danger signal. However, not all of the stressors listed above, which lead to an increase in serum Hsp72, are likely to do so via necrotic cell death. Therefore, Hsp72 is released from necrotic cells, but its release is also increased by cellular stress.
Hsp72 has effects on APCs and phagocytic cells. It has been shown to stimulate production of proinflammatory cytokines by monocytes and macrophages [13
, 15
] and maturation of dendritic cells (DC) [16
]. Surface-bound Hsp72 has been shown to act as chemotactic for NK cells and to induce cytolytic activity [17
]. Therefore, Hsp72 induces a number of defensive and proinflammatory responses from the immune system.
HMGB1 AS A DANGER SIGNAL
HMGB1 is a nuclear protein that acts as a DNA chaperone in normal cells and promotes DNA–protein interactions [18
]. It is present in serum, in particular, following infection or exposure to LPS [19
20
21
]. Patients with sepsis have been shown to have elevated HMGB1, and the highest levels are found in patients that died [20
]. Serum HMGB1 is also elevated in rheumatoid arthritis [22
, 23
] and Churg-Strauss syndrome [24
]. Therefore, serum HMGB1 must be increased by a number of stressors.
HMGB1 is released by necrotic cells [25
] as well as LPS-stimulated macrophages/monocytes [20
, 26
, 27
], which can also be stimulated to release HMBG1 by treatment with TNF-
, IL-1β, IFN-
, or oxidative stress [20
, 28
, 29
]. Therefore, HMGB1 is released from necrotic cells, but release is also stimulated by a number of cellular stressors.
The stimulatory activity of HMGB1 has been demonstrated by its addition to macrophages, resulting in increases in TNF-, IL-1β, and IL-6 [23
], and to monocytes, resulting in increases in TNF- and IL-1β [30
, 31
]. HMGB1 is chemotactic for DC, as well as smooth muscle cells [32
33
34
]. Therefore, HMGB1 induces a number of defensive and proinflammatory responses from the immune system.
ACTIVE SECRETION OF Hsp72 AND HMGB1
Clearly, Hsp72 and HMGB1 have good credentials as danger signals, consistent with the danger model; both are elevated in serum following a number of stressors, are released by necrotic cells, and stimulate proinflammatory responses. However, they also exhibit some variance from the original danger signal hypothesis. First, both molecules are released by non-necrotic cells [28
, 35
36
37
38
39
]. They do this despite lacking peptide leader sequence targeting secretion, so both proteins use a nonclassical route of protein secretion [37
38
39
]. The secretion route for both proteins involves the ABC transporter system based on inhibition with glyburide and 4,4'-diisothiocyanostylbene-2,2'-disulfonic acid [38
, 39
]. IL-1β, which is also secreted via an ABC transporter route, is released under similar treatments to those stimulating release of Hsp72 and HMGB1. However, the mechanisms involved in the secretion of Hsp72 [38
] and HMGB1 [28
, 39
] are not identical to that of IL-1β. Further, HMGB1 transport is not inhibited by another ABC transport inhibitor, sulfobromophthalein [39
]. Both proteins interact with lipid rafts [37
, 38
, 40
] and more specifically, with phosphatidyl serine [41
, 42
] and can be expressed on the cell surface [42
, 43
]. However, despite these similarities, the secretion of the two proteins occurs over different time courses: Hsp72 release increases within 1–3 h following stimulation, and HMGB1 is only released after a delay of >24 h [36
37
38
, 44
]. A proportion of secreted Hsp72 has been reported to be in exosomes [17
, 45
, 46
], but as yet, no such data exist for HMGB1.
The conditions under which Hsp72 and HMGB1 are released from non-necrotic cells do show some similarities. We, along with others, have reported that Hsp72 is secreted from viable cells [36
, 47
48
49
] and that this can be regulated by temperature [37
, 46
] or exposure to bacterial antigens [36
, 49
]. HMGB1 is not released from viable cells [25
, 35
, 50
], and the time course of LPS-stimulated HMGB1 release suggests that it might be mediated via cytokines [44
], which was confirmed when IFN-, TNF-, and TGF-β were shown to induce HMGB1 release from macrophages [44
]. Apoptotic cells are reported to not release HMGB1 [25
] or Hsp72 [13
, 14
], although later reports demonstrate the release of HMGB1 from apoptotic cells [35
, 50
]. The stimulation of Hsp72 release at temperatures between 40°C and 42°C [37
, 46
] suggests that apoptotic cells can release Hsp72.
So, Hsp72 and HMGB1 are actively secreted by cells via similar pathways, and it would appear that both are secreted by apoptotic cells. This suggests that the danger model should include the release of these danger signals during cellular stress, analogous to the approach proposed recently [4
].
CONTRASTS IN EXTRACELLULAR BEHAVIOR OF Hsp72 AND HMGB1
Despite the similarities in these molecules as danger signals in their stimulation of proinflammatory cytokines, there are some striking contrasts, particularly in relation to their effects on other cells and tissues.
Hsp72 is well-known to protect cells from a variety of stressors through its intracellular role. As an extracellular protein, it also acts to protect cells by binding to cell surfaces and through internalization [47
, 51
]. There has been no published data suggesting that HMGB1 has similar activity, although HMGB1 will protect cells and tissues to an extent via its bacteriocidal activity [52
]. These data suggest that Hsp72 has the capacity to protect cells from a number of cellular stresses, whereas HMGB1 will protect cells from bacterial infection.
Overproduction of or injection with HMGB1 induces fever in mice and is fatal at low doses [20
, 30
]. Necrotic cells from HMGB1 knockout mice are less effective at promoting inflammation [25
], and anti-HMGB1 treatment prevents LPS-induced fever or sepsis [20
, 50
]. HMBG1 may contribute to autoimmune reactions in lupus through its stimulation of IFN-
secretion from DC [53
]. There is no evidence that Hsp72 directly damages cells or tissues; however, the presence of anti-Hsp72 antibodies in serum in autoimmune conditions has been used to suggest that extracellular Hsp72 under certain circumstances leads to an autoimmune response [54
].
Hsp72 and HMGB1 act as molecular chaperones, although for very different molecules. In the case of Hsp72, it has been suggested that the peptides carried by the secreted protein determine some of the cytokine-stimulating activity [55
]. It is certainly possible that the same is true for HMGB1. An area not yet explored is the nature and potential importance of the interaction of both of these proteins and LPS, as well as the interaction between the two proteins themselves.
THE FUTURE
We have attempted to compare and contrast Hsp72 and HMGB1 as danger signals. Both proteins have the general characteristics of danger signals. The differences between their secretion and extracellular activities suggest that their release is carrying information about the nature of the danger.
We suggest that low threat events such as increased temperature, exercise, and minimal oxidative stress result in increased secretion of Hsp72, which can act as a cellular protector. Differences in the peptides carried by the secreted Hsp72 could potentially provide information about the nature of the stress and therefore, direct an appropriate response. An increase in the stressor will stimulate further Hsp72 secretion and initiate HMGB1 secretion. The result would be a promotion of the inflammatory response. Once tissue damage occurs, the immune system is in overdrive as a result of the concerted efforts of Hsp72 and HMGB1. Loss of control of the secretion will have serious consequences for initially, the tissue and ultimately, the organism. Although we have suggested that high Hsp72 levels can lead to autoimmune reactions, it is possible that the tissue damage sustained as a result of high levels of HMGB1 is actually the cause of these reactions to Hsp72.
The result is that the stressor and the tissue involved are directing the immune system response analogous to that described in a modification of the danger model [2
]. Threats to the cell or tissue result in the secretion of a unique fingerprint of danger signals, including Hsp72 and HMGB1. Understanding that fingerprint and how it regulates the immune response should provide insights to how our bodies respond to stress and disease.
Received June 8, 2007;
revised October 1, 2007;
accepted October 4, 2007.
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