- Email: [email protected]
Innate resistance and inflammation
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Innate resistance and inflammation Editorial overview Siamon Gordon and Giorgio Trinchieri Current Opinion in Immunology 2009, 21:1–2 Available online 14th February 2009 0952-7915/$ – see front matter # 2009 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2009.02.001
Siamon Gordon Sir William Dunn School of Pathology, University of Oxford, Oxford, UK e-mail: [email protected]
Siamon Gordon studied medicine at the University of Cape Town, South Africa, and completed his doctorate at Rockefeller University, New York in 1971, in the laboratory of Zanvil A Cohn, where he started his long standing interest in macrophages. He has been at the Sir William Dunn School of Pathology, University of Oxford since 1976, where he is now an emeritus professor of cellular pathology. He will be visiting the NIH, Bethesda, as a senior scholar for a year from April 2009. Giorgio Trinchieri Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Frederick, MD, USA e-mail: [email protected]
Giorgio Trinchieri is Director, Cancer and Inflammation Program, National Cancer Institute in Frederick, MD, and his main scientific interest is the interface between innate resistance and adaptive immunity in cancer, infectious diseases, autoimmunity and other inflammatory diseases.
It is apt to mark the centenary of the Nobel Prize of 1908 to Elie Metchnikoff and Paul Ehrlich by publishing this issue of Current Opinion in Immunology. Since Metchnikoff established many of the principles of natural immunity and Ehrlich the previously countervailing discoveries of acquired humoral immunity, these apparently different arms of the host response to infection have been reconciled and integrated. The past decade has seen a flowering of research into the scope and mechanisms of naturally occurring, innate immunity, still gathering momentum, as witnessed by the selection of review articles presented in this issue. The outline of sensing, signaling and responses to foreign and altered host components by myeloid cells has become clear, thanks to delineation of surface, vacuolar and cytosolic receptors, dissection of signal transduction pathways and analysis of gene expression, synthetic, secretory and metabolic responses. These underlie antimicrobial functions of macrophages, dendritic and other cells. Such cellular changes mediate protective inflammatory responses, recruitment and activation of lymphoid cells and direct humoral and cellular adaptive immunity. These normally tightly regulated processes can go awry, inducing tissue injury, auto-inflammation, autoimmunity and indeed death of the host. It is therefore of paramount interest to understand the molecular mechanisms and regulation of innate immunity, in order to develop effective treatments of deficient or excessive host responses. We are pleased to present state of the art discussions of recent research by selected investigators and provide a brief summary of their contributions. The Imler group has built on the pioneering studies of Jules Hoffmann and co-workers in Strasbourg that amply demonstrate the value of Drosophila melanogaster as model organism for genetic analysis of innate antimicrobial responses. The parallels and differences between such widely divergent species as Insects, Mouse and Man are a remarkable testament to conservation and evolution of anti-bacterial and anti-fungal immunity. Kemp and Imler discuss recent findings on the previously neglected aspects of antiviral immunity in Drosophila. Unlike in mammals, markedly dependent on interferon-induced responses, RNA interference plays a major role. Inducible responses do contribute and similarities in the sensing and signaling after viral infection are apparent between Drosophila and mammals. In particular, DExD/H box helicases play a crucial role in the sensing of RNA virus infection in flies and mammals. The sensing of pathogens and danger signals by the inflammasome is reviewed by Sutterwala and co-workers. Since the ground breaking work by the groups of Tschopp, Nunez, Kastner, Ting and others, the dissection of cytosolic, multiprotein complexes that activate caspase-1, in response to a wide range of microbial and self-derived stimuli, leading to processing and secretion of the pro-inflammatory cytokines IL-1b and IL18, has exploded.
www.sciencedirect.com
Current Opinion in Immunology 2009, 21:1–2
2 Innate immunity
Particularly striking has been implicating dysregulation of the inflammasome in pathogenesis of a number of autoinflammatory and auto-immune disorders, with dramatic benefits of anti-cytokine treatments, in some conditions. Both pathogen-derived or self-derived DNA stimulate innate immunity and the recognition of DNA sequences remains a controversial issue with several groups having partially characterized different sets of receptors. Yanai and others review here the present understanding of the cytosolic DNA receptors that, in addition to the membrane bound TLR9, can evoke innate responses. In particular, they discuss the role of DAI (DLM-1/ ZBP1), Trex1 and other regulators of the cytosolic DNA-sensing system that have recently been identified and characterized. Activation of inflammatory responses by DNA plays an important role in the response to viruses and other infections but the response to self-derived DNA clearly has a major impact in chronic inflammatory disorders and a better knowledge of the receptors involved and of the mechanisms of recognition will be very helpful for the understanding of the etio-pathogenesis of inflammatory diseases. Lambrecht and co-workers summarize recent findings of several groups that deal with the mechanisms of action of aluminum-containing adjuvants, widely used in humans. Alum-adjuvants apparently trigger an ancient pathway of innate recognition of crystals in monocytes, promoting their differentiation to immunogenic dendritic cells. This occurs via stimulation of the NALP3 inflammasome or indirectly, via uric acid. They describe evidence that adjuvants also activate stromal cells at local sites of injection. The discovery of Dectin-1 as a major b-glucan recognition surface receptor by Brown and co-workers has brought rapid progress in understanding of fungal recognition and signaling by a TLR unrelated, but interdependent mechanism. Components of signaling pathways such as Syk kinase, CARD9 and Raf-1 have been implicated in the ITAM dependent immunomodulation of macrophages and dendritic cells. A role has been described for Dectin-1 in the induction of Th17 responses. Dectin-1 contributes to anti-fungal immunity in mice and humans, and possibly to the control of mycobacterial infections. Evidence suggesting that triggering receptors expressed on myeloid cells (TREM) and TREM-like receptors regulate inflammation has rapidly accumulated. Cell types as diverse as monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, neutrophils, microglia, osteoclasts and platelets express at least one member of the TREM family. Ford and McVicar review here the most recent findings on the physiological import-
Current Opinion in Immunology 2009, 21:1–2
ance of this receptor family including the characterization of a new TREM-family receptor expressed on plasmacytoid dendritic cells; identification of B7-H3 as a ligand for TREM-like Transcript (TLT)-2 and the first well characterized TREM ligand; and the role of TREM and soluble form of TREM proteins in several diseases. The most recent progress in the characterization of TREM signaling and the complex functional interaction between TREM and TLR are also discussed. Barclay and co-workers have provided important structural data on the molecular analysis of paired immunoregulatory receptors such as CD200/CD200R. Here they summarize recent progress in the study of SIRP alpha/CD47, an intriguing inhibitory pair that modulates myeloid cell functions. In particular they compare the binding affinity to CD47 of SIRPa and SIRPb, a closely related receptor with low binding affinity. Autophagy is a process of cytoplasmic homeostasis by which cells digest their own cytosol removing toxic molecules and organelles not any longer needed. Recent data are showing that autophagy has a much broader physiological role than previously thought and it is very important in many mechanisms of resistance to infection and in the regulation of innate resistance and adaptive immunity. Deretic reviews here many of the molecular mechanisms regulating autophagy and the role of autophagy in delivering cytoplasmic antigens to the lumen of the MHC class II compartment and cytosolic pathogen-associated patterns to endosomal TLRs. Iron is an essential element for all living organisms and innate resistance uses a variety of mechanisms to restrict iron availability to microbial pathogens. Ganz reviews here the current knowledge of the specialized inflammation-regulated and infection-regulated proteins that chelate iron, transport it or modulate its transport or sequester siderophores and thus contribute to the response of the organism to microbial infections. In spite of the rapid growth in understanding of innate immune mechanisms and functions, major areas of ignorance remain. More attention needs to be devoted to the analysis of heterogeneity of innate immune responses in situ by diverse antigen presenting cells, of transcriptional and post-transcriptional regulation of the expression of effector molecules and of complex host-pathogen interactions that determine the outcome of infection. Further studies are needed of model stimuli, acute and chronic, in vivo. Genetic manipulation of mice and other organisms has been of great value already, but their relevance to human disease remains unclear, except in selected genetic syndromes. We anticipate that further progress will be made in the therapeutic modulation of innate immunity in Man.
www.sciencedirect.com
Innate resistance and inflammation Editorial overview Siamon Gordon and Giorgio Trinchieri Current Opinion in Immunology 2009, 21:1–2 Available online 14th February 2009 0952-7915/$ – see front matter # 2009 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coi.2009.02.001
Siamon Gordon Sir William Dunn School of Pathology, University of Oxford, Oxford, UK e-mail: [email protected]
Siamon Gordon studied medicine at the University of Cape Town, South Africa, and completed his doctorate at Rockefeller University, New York in 1971, in the laboratory of Zanvil A Cohn, where he started his long standing interest in macrophages. He has been at the Sir William Dunn School of Pathology, University of Oxford since 1976, where he is now an emeritus professor of cellular pathology. He will be visiting the NIH, Bethesda, as a senior scholar for a year from April 2009. Giorgio Trinchieri Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Frederick, MD, USA e-mail: [email protected]
Giorgio Trinchieri is Director, Cancer and Inflammation Program, National Cancer Institute in Frederick, MD, and his main scientific interest is the interface between innate resistance and adaptive immunity in cancer, infectious diseases, autoimmunity and other inflammatory diseases.
It is apt to mark the centenary of the Nobel Prize of 1908 to Elie Metchnikoff and Paul Ehrlich by publishing this issue of Current Opinion in Immunology. Since Metchnikoff established many of the principles of natural immunity and Ehrlich the previously countervailing discoveries of acquired humoral immunity, these apparently different arms of the host response to infection have been reconciled and integrated. The past decade has seen a flowering of research into the scope and mechanisms of naturally occurring, innate immunity, still gathering momentum, as witnessed by the selection of review articles presented in this issue. The outline of sensing, signaling and responses to foreign and altered host components by myeloid cells has become clear, thanks to delineation of surface, vacuolar and cytosolic receptors, dissection of signal transduction pathways and analysis of gene expression, synthetic, secretory and metabolic responses. These underlie antimicrobial functions of macrophages, dendritic and other cells. Such cellular changes mediate protective inflammatory responses, recruitment and activation of lymphoid cells and direct humoral and cellular adaptive immunity. These normally tightly regulated processes can go awry, inducing tissue injury, auto-inflammation, autoimmunity and indeed death of the host. It is therefore of paramount interest to understand the molecular mechanisms and regulation of innate immunity, in order to develop effective treatments of deficient or excessive host responses. We are pleased to present state of the art discussions of recent research by selected investigators and provide a brief summary of their contributions. The Imler group has built on the pioneering studies of Jules Hoffmann and co-workers in Strasbourg that amply demonstrate the value of Drosophila melanogaster as model organism for genetic analysis of innate antimicrobial responses. The parallels and differences between such widely divergent species as Insects, Mouse and Man are a remarkable testament to conservation and evolution of anti-bacterial and anti-fungal immunity. Kemp and Imler discuss recent findings on the previously neglected aspects of antiviral immunity in Drosophila. Unlike in mammals, markedly dependent on interferon-induced responses, RNA interference plays a major role. Inducible responses do contribute and similarities in the sensing and signaling after viral infection are apparent between Drosophila and mammals. In particular, DExD/H box helicases play a crucial role in the sensing of RNA virus infection in flies and mammals. The sensing of pathogens and danger signals by the inflammasome is reviewed by Sutterwala and co-workers. Since the ground breaking work by the groups of Tschopp, Nunez, Kastner, Ting and others, the dissection of cytosolic, multiprotein complexes that activate caspase-1, in response to a wide range of microbial and self-derived stimuli, leading to processing and secretion of the pro-inflammatory cytokines IL-1b and IL18, has exploded.
www.sciencedirect.com
Current Opinion in Immunology 2009, 21:1–2
2 Innate immunity
Particularly striking has been implicating dysregulation of the inflammasome in pathogenesis of a number of autoinflammatory and auto-immune disorders, with dramatic benefits of anti-cytokine treatments, in some conditions. Both pathogen-derived or self-derived DNA stimulate innate immunity and the recognition of DNA sequences remains a controversial issue with several groups having partially characterized different sets of receptors. Yanai and others review here the present understanding of the cytosolic DNA receptors that, in addition to the membrane bound TLR9, can evoke innate responses. In particular, they discuss the role of DAI (DLM-1/ ZBP1), Trex1 and other regulators of the cytosolic DNA-sensing system that have recently been identified and characterized. Activation of inflammatory responses by DNA plays an important role in the response to viruses and other infections but the response to self-derived DNA clearly has a major impact in chronic inflammatory disorders and a better knowledge of the receptors involved and of the mechanisms of recognition will be very helpful for the understanding of the etio-pathogenesis of inflammatory diseases. Lambrecht and co-workers summarize recent findings of several groups that deal with the mechanisms of action of aluminum-containing adjuvants, widely used in humans. Alum-adjuvants apparently trigger an ancient pathway of innate recognition of crystals in monocytes, promoting their differentiation to immunogenic dendritic cells. This occurs via stimulation of the NALP3 inflammasome or indirectly, via uric acid. They describe evidence that adjuvants also activate stromal cells at local sites of injection. The discovery of Dectin-1 as a major b-glucan recognition surface receptor by Brown and co-workers has brought rapid progress in understanding of fungal recognition and signaling by a TLR unrelated, but interdependent mechanism. Components of signaling pathways such as Syk kinase, CARD9 and Raf-1 have been implicated in the ITAM dependent immunomodulation of macrophages and dendritic cells. A role has been described for Dectin-1 in the induction of Th17 responses. Dectin-1 contributes to anti-fungal immunity in mice and humans, and possibly to the control of mycobacterial infections. Evidence suggesting that triggering receptors expressed on myeloid cells (TREM) and TREM-like receptors regulate inflammation has rapidly accumulated. Cell types as diverse as monocytes, macrophages, myeloid dendritic cells, plasmacytoid dendritic cells, neutrophils, microglia, osteoclasts and platelets express at least one member of the TREM family. Ford and McVicar review here the most recent findings on the physiological import-
Current Opinion in Immunology 2009, 21:1–2
ance of this receptor family including the characterization of a new TREM-family receptor expressed on plasmacytoid dendritic cells; identification of B7-H3 as a ligand for TREM-like Transcript (TLT)-2 and the first well characterized TREM ligand; and the role of TREM and soluble form of TREM proteins in several diseases. The most recent progress in the characterization of TREM signaling and the complex functional interaction between TREM and TLR are also discussed. Barclay and co-workers have provided important structural data on the molecular analysis of paired immunoregulatory receptors such as CD200/CD200R. Here they summarize recent progress in the study of SIRP alpha/CD47, an intriguing inhibitory pair that modulates myeloid cell functions. In particular they compare the binding affinity to CD47 of SIRPa and SIRPb, a closely related receptor with low binding affinity. Autophagy is a process of cytoplasmic homeostasis by which cells digest their own cytosol removing toxic molecules and organelles not any longer needed. Recent data are showing that autophagy has a much broader physiological role than previously thought and it is very important in many mechanisms of resistance to infection and in the regulation of innate resistance and adaptive immunity. Deretic reviews here many of the molecular mechanisms regulating autophagy and the role of autophagy in delivering cytoplasmic antigens to the lumen of the MHC class II compartment and cytosolic pathogen-associated patterns to endosomal TLRs. Iron is an essential element for all living organisms and innate resistance uses a variety of mechanisms to restrict iron availability to microbial pathogens. Ganz reviews here the current knowledge of the specialized inflammation-regulated and infection-regulated proteins that chelate iron, transport it or modulate its transport or sequester siderophores and thus contribute to the response of the organism to microbial infections. In spite of the rapid growth in understanding of innate immune mechanisms and functions, major areas of ignorance remain. More attention needs to be devoted to the analysis of heterogeneity of innate immune responses in situ by diverse antigen presenting cells, of transcriptional and post-transcriptional regulation of the expression of effector molecules and of complex host-pathogen interactions that determine the outcome of infection. Further studies are needed of model stimuli, acute and chronic, in vivo. Genetic manipulation of mice and other organisms has been of great value already, but their relevance to human disease remains unclear, except in selected genetic syndromes. We anticipate that further progress will be made in the therapeutic modulation of innate immunity in Man.
www.sciencedirect.com