Immunology: Short-term memory
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Pathogen Stimulation Proinflammatory genes Restimulation LPS TLR4 OFF ON Antimicrobial genes Antimicrobial genes OFF ON Proinflammatory genes OFF OFF OFF ON Y X Figure 1 | Chromatin modifications and the response of macrophages to pathogens. In response to bacterial lipopolysaccharide (LPS), a TLR4-mediated signalling cascade is activated in macrophages, which induces the expression of both antimicrobial and proinflammatory genes. However, on restimulation with LPS — which is accompanied by desensitization of the downstream signalling pathways — antimicrobial genes are selectively activated. Foster et al. 1 show that this is in part mediated by chromatin modifications (green and orange balls), which selectively mark the antimicrobial genes, among others. Consequently, on restimulation — and with the help of an unknown activator (X) — the expression of antimicrobial genes is increased to the same or higher levels. By contrast, certain other genes, including proinflammatory genes, lose their histone marks after initial stimulation, preventing their expression on restimulation; this is also aided by an unknown repressor (Y). This process prevents excessive inflammation, which can be deadly. the nervous system to slow disease progres- sion. Although initial exposure to this vaccine caused fever, repeated daily exposures sup- pressed the induction of fever and led to a state of tolerance. Similarly, macrophages, which underpin many of the physiological responses to endotoxins, exhibit LPS tolerance on repeated stimulation 4 . Consequently, through limiting the production of proinflammatory molecules, tolerance is thought to provide a mechanism for restraining systemic inflam- mation and avoiding septic shock 4 . The induction of a ‘tolerized’ state in a macrophage on repeated stimulation with LPS involves desensitization of the downstream sig- nalling pathways. In naive macrophages, LPS stimulation activates signalling pathways medi- ated by the MAPK and IKK enzymes. These, in turn, trigger gene transcription factors AP-1 and NF-κB respectively to activate the expres- sion of both antimicrobial and proinflamma- tory genes 4 . On restimulation with LPS, the signalling response of tolerized macrophages is attenuated. Several proteins, including IRAK-M, SOCS-1 and SHIP, which are com- ponents of negative-feedback loops induced by these signalling pathways, constrain LPS signalling during the initial stimulation and play a role in establishing tolerance 5 . So, based on this conceptual framework, repeated LPS sensing by macrophages should impair the induction of both proinflammatory and anti- microbial genes, thereby compromising the innate immune response to various pathogens. This is not the case. Foster and colleagues 1 hypothesized that macrophages may have gene-specific control mechanisms to circumvent the problem posed by generalized desensitization to reiterative LPS signalling. Accordingly, genes encoding proinflammatory mediators should be tran- siently inactivated in tolerized macrophages, whereas those encoding antimicrobial pro- teins should remain inducible on repeated LPS stimulation. They performed genome-wide expression analysis of naive and tolerized macrophages, and, indeed, identified two classes of genes — tolerizeable and non-tolerizeable. On res- timulation with LPS, tolerizeable genes, largely proinflammatory genes such as IL-1 and IL-6, were not induced. Non-tolerizeable genes were expressed to the same, or even greater, level compared with the initial stimulation; this class largely contained antimicrobial genes. The authors also show that, on initial LPS stimulation, the histones associated with both tolerizeable and non-tolerizeable genes tran- siently undergo chemical modifications that promote the expression of their associated genes. As expected, RNA polymerase II — the enzyme that transcribes genes into messenger RNA — is also initially recruited to both classes of gene. However, on restimulation, tolerize- able genes selectively failed to undergo activat- ing histone modifications or to recruit RNA polymerase II (Fig. 1). This refractory state IMMUNOLOGY Short-term memory Benjamin N. Gantner and Harinder Singh Chemical modification of histone proteins can affect the expression of their associated genes. Some immune cells seem to exploit this process to avoid excessive inflammation while fighting invading pathogens. The innate immune system has several essen- tial roles: it must detect infectious pathogens, initiate antimicrobial mechanisms to remove them and trigger inflammation to activate additional immune responses such as fever. This last function is tricky because too lit- tle inflammation will lead to an ineffective response and too much can lead to septic shock and death. So how does the innate immune system prevent excessive responses while repeatedly encountering the same path- ogen during an infection? It has been appreciated for some time that particular innate immune cells — macrophages — can dampen their reactions; however, on page 972 of this issue, Foster et al. 1 suggest a more complex change in the sensitivity of these cells to pathogens. They find that macrophages selectively modify the histone proteins that package the genes activated in response to pathogens, to adapt to repeated exposure. More than a century ago, Richard Pfeiffer discovered 2 that components of dead bacteria, which he called endotoxins, could kill test animals; this is now known to be due to an excessive inflammatory response. Endotoxins are highly conserved components of patho- gens that are recognized by the innate immune system. Among the most potent endotoxins is lipopolysaccharide (LPS), which is a compo- nent of the outer membrane of bacterial cells. It is recognized by Toll-like receptor 4 (TLR4) on the surface of macrophages, where it initiates the molecular signalling pathways that lead to the activation of proinflammatory and antimicrobial genes. Paul Beeson’s seminal work 3 in the 1940s uncovered a fascinating twist to the endotoxin response in humans. The typhoid vaccine was used in patients with syphilitic infection of 916 NEWS & VIEWS NATURE|Vol 447|21 June 2007
Transcript of Immunology: Short-term memory
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Figure 1 | Chromatin modifications and the response of macrophages to pathogens. In response to bacterial lipopolysaccharide (LPS), a TLR4-mediated signalling cascade is activated in macrophages, which induces the expression of both antimicrobial and proinflammatory genes. However, on restimulation with LPS — which is accompanied by desensitization of the downstream signalling pathways — antimicrobial genes are selectively activated. Foster et al.1 show that this is in part mediated by chromatin modifications (green and orange balls), which selectively mark the antimicrobial genes, among others. Consequently, on restimulation — and with the help of an unknown activator (X) — the expression of antimicrobial genes is increased to the same or higher levels. By contrast, certain other genes, including proinflammatory genes, lose their histone marks after initial stimulation, preventing their expression on restimulation; this is also aided by an unknown repressor (Y). This process prevents excessive inflammation, which can be deadly.
the nervous system to slow disease progres-sion. Although initial exposure to this vaccine caused fever, repeated daily exposures sup-pressed the induction of fever and led to a state of tolerance. Similarly, macrophages, which underpin many of the physiological responses to endotoxins, exhibit LPS tolerance on repeated stimulation4. Consequently, through limiting the production of pro inflammatory molecules, tolerance is thought to provide a mechanism for restraining systemic inflam-mation and avoiding septic shock4.
The induction of a ‘tolerized’ state in a macro phage on repeated stimulation with LPS involves desensitization of the downstream sig-nalling pathways. In naive macrophages, LPS stimulation activates signalling pathways medi-ated by the MAPK and IKK enzymes. These, in turn, trigger gene transcription factors AP-1 and NF-κB respectively to activate the expres-sion of both antimicrobial and proinflamma-tory genes4. On restimulation with LPS, the signalling response of tolerized macrophages is attenuated. Several proteins, including IRAK-M, SOCS-1 and SHIP, which are com-ponents of negative-feedback loops induced by these signalling pathways, constrain LPS signalling during the initial stimulation and play a role in establishing tolerance5. So, based on this conceptual framework, repeated LPS sensing by macrophages should impair the induction of both proinflammatory and anti-microbial genes, thereby compromising the innate immune response to various pathogens. This is not the case.
Foster and colleagues1 hypothesized that macrophages may have gene-specific control mechanisms to circumvent the problem posed by generalized desensitization to reiterative LPS signalling. Accordingly, genes encoding proinflammatory mediators should be tran-siently inactivated in tolerized macrophages, whereas those encoding antimicrobial pro-teins should remain inducible on repeated LPS stimulation.
They performed genome-wide expression analysis of naive and tolerized macrophages, and, indeed, identified two classes of genes — tolerizeable and non-tolerizeable. On res-timulation with LPS, tolerizeable genes, largely proinflammatory genes such as IL-1 and IL-6, were not induced. Non-tolerizeable genes were expressed to the same, or even greater, level compared with the initial stimulation; this class largely contained antimicrobial genes.
The authors also show that, on initial LPS stimulation, the histones associated with both tolerizeable and non-tolerizeable genes tran-siently undergo chemical modifications that promote the expression of their associated genes. As expected, RNA polymerase II — the enzyme that transcribes genes into messenger RNA — is also initially recruited to both classes of gene. However, on restimulation, tolerize-able genes selectively failed to undergo activat-ing histone modifications or to recruit RNA polymerase II (Fig. 1). This refractory state
IMMUNOLOGY
Short-term memoryBenjamin N. Gantner and Harinder Singh
Chemical modification of histone proteins can affect the expression of their associated genes. Some immune cells seem to exploit this process to avoid excessive inflammation while fighting invading pathogens.
The innate immune system has several essen-tial roles: it must detect infectious pathogens, initiate antimicrobial mechanisms to remove them and trigger inflammation to activate additional immune responses such as fever. This last function is tricky because too lit-tle inflammation will lead to an ineffective response and too much can lead to septic shock and death. So how does the innate immune system prevent excessive responses while repeatedly encountering the same path-ogen during an infection?
It has been appreciated for some time that particular innate immune cells — macrophages — can dampen their reactions; however, on page 972 of this issue, Foster et al.1 suggest a more complex change in the sensitivity of these cells to pathogens. They find that macrophages selectively modify the histone proteins that package the genes activated in response to
pathogens, to adapt to repeated exposure.More than a century ago, Richard Pfeiffer
discovered2 that components of dead bacteria, which he called endotoxins, could kill test animals; this is now known to be due to an excessive inflammatory response. Endotoxins are highly conserved components of patho-gens that are recognized by the innate immune system. Among the most potent endotoxins is lipopoly saccharide (LPS), which is a compo-nent of the outer membrane of bacterial cells. It is recognized by Toll-like receptor 4 (TLR4) on the surface of macrophages, where it initiates the molecular signalling pathways that lead to the activation of proinflammatory and antimicrobial genes.
Paul Beeson’s seminal work3 in the 1940s uncovered a fascinating twist to the endotoxin response in humans. The typhoid vaccine was used in patients with syphilitic infection of
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lymphocyte differentiation programmes that permanently modify the adaptive immune response by generating memory B and T cells. The findings of Foster et al.1 indicate that, after their receptor-mediated triggering, cells of the innate immune system are also capable of undergoing a differentiation programme with features of memory, albeit one that is short term. It is perhaps not surprising that many of the hallmarks of the adaptive immune system are manifest in the evolution-arily ancient innate immune system in a more primitive form. ■
Benjamin N. Gantner and Harinder Singh are in the Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637, USA.e-mail: [email protected]
1. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Nature 447, 972–978 (2007).
2. Beutler, B. & Rietschel, E. T. Nature Rev. Immunol. 3, 169–176 (2003).
3. Van Epps, H. L. J. Exp. Med. 203, 1137 (2006).4. Dobrovolskaia, M. A. & Vogel, S. N. Microbes Infect. 4,
903–914 (2002).5. Beutler, B. Immunity 21, 134–135 (2004). 6. Ma, L. & Pei, G. J. Cell Sci. 120, 213–218 (2007).7. Brickner, D. G. et al. PLoS Biol. 5, e81 (2007).
MATERIALS SCIENCE
Reflections on ionic liquidsRobin D. Rogers
Ionic liquids are generally regarded as solvents, but these modular, tunable compounds have far greater technological potential. With a coat of silver, they become ideal materials for the liquid mirror of a space telescope.
Ionic liquids seem to defy common sense. Most ionic compounds are crystalline solids with high melting points, but these fascinat-ing salts melt at temperatures below 100 oC; indeed, many are liquids at room temperature. Their melt forms are composed of discrete cations and anions1 that can be individually customized, allowing the synthesis of a wide range of liquid materials with tunable physical, chemical and biological properties.
There are thought to be about a million possible pure ionic liquids, and 1018 ternary liquid mixtures, so anyone designing the
perfect liquid material for a given application has a lot of room for manoeuvre. A particu-larly striking example is described by Borra et al.2 on page 979 of this issue. They have coated an ionic liquid with colloidal silver par-ticles, yielding a material that could be used as a liquid mirror in a telescope.
Ionic liquids are not new3, but they have recently received intense worldwide scrutiny as possible environmentally friendly solvents4 because many are non-volatile. This has fuelled a technological revolution, powered by the sheer number of unstudied liquids that might
Figure 1 | Liquid-mirror telescopes. The Large Zenith Telescope is sited in the Malcolm Knapp Research Forest, 70 kilometres east of Vancouver, Canada. It uses the world’s largest liquid mirror — a smoothly spinning pan of mercury, 6 metres in diameter. Borra et al.2 describe the preparation of a reflective ionic liquid that could also be used as a liquid mirror.
was reversed by inhibitors of the enzymes that remove activating histone modifications, indi-cating a role for these enzymes in turning off tolerizeable genes.
It remains possible that these inhibitors have additional effects unrelated to histone modi-fication. Therefore more definitive evidence will be required, such as the identification of the molecules required for gene ‘silencing’. Moreover, as loss of negative regulators of TLR4 signalling can also result in reactivation of proinflammatory genes5, it is likely that mac-rophages acquire tolerance by self-reinforcing mechanisms of attenuated TLR4 signalling, as well as repressive histone modifications.
Foster et al.1 found that, in contrast to tolerizeable genes, the chromatin of non-tolerizeable genes maintained some activat-ing histone modifications after the initial LPS stimulation. This is likely to prime the non-tolerizeable genes for even more robust activation on subsequent LPS stimulations. This possibility is supported by the more rapid and vigorous induction of non-tolerized genes on LPS restimulation, despite the attenuated TLR4-mediated signalling.
The establishment of primed and silenced chromatin states of non-tolerizeable and tol-erizeable genes respectively seems to depend on de novo synthesis of one or more factors as a consequence of the initial LPS signal (X and Y; Fig. 1). The nature and mechanisms of action of these essential secondary regula-tors are unknown. The β-arrestin proteins are potential candidate regulators of non-tolerizeable gene expression; they not only attenuate TLR-induced signalling but also bind to transcriptional complexes and promote activating histone modifications6. This raises the exciting possibility that, in macrophages, β-arrestins could both restrain TLR signalling and maintain the robust expression of the non- tolerizeable antimicrobial genes.
Another mechanism for sustaining and aug-menting the expression of non- tolerizeable genes on repeated LPS stimulation is sug-gested by a study in yeast7. The sugar galactose induces the expression of yeast GAL genes, which encode enzymes required for its usage. An initial exposure to galactose primes these genes for stronger activation on a secondary exposure — a phenomenon termed transcrip-tional memory. This is essentially dependent on the replacement of the canonical histone protein, H2A, which is associated with the GAL gene promoters, with a variant histone called H2A.Z. It will be interesting to determine whether, in LPS-stimulated macrophages, the priming of non-tolerized genes also involves histone replacement.
The discovery of Toll-like receptors greatly enhanced our understanding of immunology by establishing that the innate immune system also uses recognition systems with specificity for molecules displayed by pathogens — simi-lar to the antigen receptors of T and B cells. Stimulation of antigen receptors activates
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