Deranged INFLAMMATION: Homeostasis of Systems Biology
February 16, 2009
Jacek Hawiger, M.D., Ph.D.
Functional Genomics and Proteomics: Applications to Immunobiology M&IM 351
Concepts:
1. Inflammation is Triggered by Microbial, Autoimmune, Chemical, and Physical Agents 2. Inflammation (Microbial, Autoimmune, Chemical, and Physical) Comprises the Most Prevailing Mechanism of Disease 3. Innate Immunity and Inflammation are Interwoven (Physiologic vs. Pathologic Response) 4. Intracellular Pathways, Intercellular Signals, Systems Response: From Blood Cells to Body on Fire 5. The Signaling Complexes (Signalosomes etc) 6. Nuclear Paradigm of Inflammation 7. Physiologic Regulators of Inflammation act via Feedback Inhibition
Inflammation: From Antiquity to Modernity
Celsus Signs Calor (Heat) Dolor (Pain) Rubor (Redness) Tumor (Swelling)
Aulus Cornelius Celsus 1st Century A.D.
Functio Laesa (Impaired Function)
Inflammation: Mechanism of disease caused by microbial, autoimmune, chemical, and physical agents. Inflammation is responsible for more acute and chronic diseases than cancer, inborn error of metabolism or degenerative diseases.
Picture obtained from: http://www.fh-augsburg.de/~harsch/Chronologia/Lspost01/Celsus/cel_intr.html
INFLAMMATION 2009
Implications for Immunobiology of Blood and Vascular Systems
Inflammation is the major mechanism of diseases caused by biologic, chemical, and physical agents. Inflammation underlies vascular system collapse in sepsis (septic shock) and the development of atherosclerosis. the inflammatory process that underlies 1 million heart attacks, 783,000 strokes, and an estimated 750,000 hospitalized sepsis patients in the United States. Atherosclerosis and sepsis converge prominently in the 60-85 year age group, with the mortality due to sepsis reaching 45% as compared to the overall mortality of 30% encompassing all age groups. The production of proinflammatory cytokines, which contribute to both disease processes, induces the acute phase protein response (APPR). APPR is manifested by the expression of a biomarker, C-reactive protein (CRP), along with the elevated levels of serum amyloid proteins, complement proteins, coagulation factors, and protease inhibitors that contribute to inflammatory injury of the cardiovascular system.
Inflammation
Degeneration
Mechanism of Disease
Inborn Errors in Metabolism
Cancer
Inflammation as the Major Mechanism of Disease
Acute Inflammatory Syndromes Systemic Inflammatory Response Syndrome (Sepsis Syndrome, Septic Shock and DIC) Acute Respiratory Distress Syndrome (ARDS, SARS) Anaphylactic Shock and Allergic Reactions Hepatitis /Colitis Chronic Inflammatory Syndromes Atherosclerosis Systemic Lupus Erythematosus Vasculitides, eg. Kawasaki Disease Type 1 Diabetes Rheumatoid Arthritis Multiple Sclerosis
Innate immunity: importance of cytokine/chemokine production
DiGiandomenico, 2007
Adapted from Kapetanovic and Cavaillon, 2007
Signaling Pathways in TLR-Generated Proinflammatory and Proapoptotic Nuclear Response Are Mediated By MyD88 Adaptors and Nuclear Import Adaptors
Cytokines IL-1, IL-18 Gram+ Bacteria Gram Bacteria
Lipid containing molecules CpG DNA HSP60
Fungi
dsRNA Poly (I:C)
Viruses
PGN
s s
LPS
LPS
TLR4 TLR9 TLR3
IL-1R IL-18R
s s s s
CD14
TLR2
CD14
TIR domain
MyD88 Adaptors control point
MyD88 IRAK
IKK complex B NF B
p p p
Trif Mal
JNK, P38 MAPKs) ( AP1
TRAM
TRAF6
Nuclear Import control point
Nuclear pore complex
Inflammatory genes: TNF, IL6, IL8, COX2, IFN- , etc. ,
Massive Cytokine Production
Endothelial Damage
Sepsis Syndrome Multi-organ And Failure
Septic Shock
Cytokine Production is Sequential in Response to Proinflammatory Stimuli
Adapted from Abas, A.K., Lichtman, A. H. Cellular and Molecular Immunology 5th Ed.
IL1- and LPS- Induced Signaling Pathways are divergent at the IL1-R and TLR-4 Proximal nodes and convergent at NF and AP1- Activating nodes.
Adapted from Luke A. J. O'Neill & Andrew G. Bowie, Nature Reviews Immunology 7, 353-364 (May 2007)
General overview of bacterial sensing in a mammalian host cell.
The detection of specific PAMPs by their cognate PRMs that are discussed in the main text is depicted. See text for further details.
Schematic representation of potential interconnections of the TLR and NLR pathways. Green lines represent transcriptional regulation, black lines physical interactions and red ones putative cross-talk. See text for details.
The Signaling Complexes (platforms): apoptosome, NODosome and inflammasome. Complex formation (oligomerization) to induce recruitment and the activation of downstream effector molecules (induced proximity signaling) is characteristic for NLR proteins and APAF-1. The signaling pathways used by different NLRs and APAF-1 are subject to extensive cross-talk which depends on the cellular context.
Changing Paradigms of Inflammation
Extracellular
Complement Kinins
Intracellular
Prostaglandins Cox 1 Cox 2 Leukotriens Lipoxygenase
Nuclear
Genes that Encode Mediators and Suppressors of Inflammation
Cytokines Cytokine Receptors
Microbial Agents Toll-like Receptors
NF-B
NKB NKB
NLS NLS
AP-1 AP-1 c-fos
NLS
c-jun
NLS
NF-ATc P
NLS
IB
Phosphorylation/ Proteolysis Proteosome 26S
p50
NLS
Protein Synthesis
p65
NLS
Dephosphorylation
NF-ATc
NLS
c-fos c-jun
NLS NLS
Nuclear Import System Inhibited by SN50 Peptide
IB
NLS
NLS
NLS
NLS
NLS
p50
p65
c-fos c-jun NF-ATc
DNA
Il-1
TNF
IL-6
IFN-
Proinflammatory Signaling to the Nucleus is Mediated by Stress Responsive Transcription Factors (SRTFs). Cell-penetrating SN50 peptide inhibits nuclear import of SRTFs.
Figure 2 | Overview of transcription-factor activation through TIR-domain-containing adaptors for the TLR/IL-1R super...