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Innate Immunity, Host Defense, and Immunopathology David M. Mosser, Ph.D. [email protected] Innate Immunity It all started here…. Fig. 5. From Lemaitre et al. Cell 86: 973–983, 1996. Freely available at www.cell.com/retrieve/pii/S0092867400801725 Innate immune responses via toll-like receptors Toll-Like Receptors *Genetically pre-determined *Pattern recognition receptors *Constitutively expressed on phagocytes *Signaling pathway similar to IL-1Rmediated NF-κB activation Pathogen-associated molecular patterns (PAMPs) *Associated with pathogen, not host *Indispensable to pathogen survival *Highly conserved among pathogens NF-κB *Nuclear transcription factor *Contributes to IL-12, TNFα, and iNOS transcription activation Fig. 2. From Medzhitov, R. and Janeway, C, Jr. N Engl J Med 343(5): 338-344, 2000. Available at www.ncbi.nlm.nih.gov /pubmed/10922424 PAMPs and DAMPs: signal 0s that spur autophagy and immunity Fig. 1. From Tang et al. Immunol Rev 249(1): 158175, 2012. Available at onlinelibrary.wiley.com.proxygw.wrlc.org/d oi/10.1111/j.1600-065X.2012.01146.x/full Many TLRs Fig. 3-11, pt. 1. From Kindt, Goldsby, and Osborne. Kuby Immunology (6th Ed.). 2007, New York: Freeman. TLR structure Fig. 3-10. From Kindt, Goldsby, and Osborne. Kuby Immunology (6th Ed.). 2007, New York: Freeman. TIR = Toll, IL-1 receptor domain Nuclear translocation of NF-kB following bacterial infection of macrophages Untreated (dark nuclei) R. equi – infected LPS-treated Macrophages counterstained red NF-kB (p65) stained in green Macrophage cytokine production TNF, IL-1, IL-6, IL-8, IL-12… Dendritic cell maturation (following TLR ligation) MHC Class II CD40 CD86 (B7.2) Immature Mature Increased MHC Increased CD40 Increased co-stim TLR ligands as adjuvants… improving CMI !/? Fig. 5. From Duthie et al. Immunol Rev 239: 178-196, 2011. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1600065X.2010.00978.x/abstract Fig. 3B & C. From Baldwin et al J Immunol 188: 2189-2197, 2012 Available at Fig. 6. From Baldwin et al J Immunol 188: 2189-2197, 2012 Available at TLR ligands as adjuvants… preventing allergy Fig. 3A. From De Brito et al. J Clin Immunol 30: 280291, 2010. Available at link.springer.com/article/10.1007%2Fs10875009-9358-9 Fig. 1, A&B, and H&L. From Xirakia et al. Am J Respir Crit Care Med 181: 1207-1216, 2010. Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC36623 18/pdf/emmm0005-0762.pdf CpG TH 1 response IgE R-848 lung inflammation Delivery of antigen and TLR agonists to APCs using nanoparticles Nanoparticles Antigen + TLR ligand Targeting molecule DC-targeted TLRLs enhance maturation and activation of human DCs in vitro Fig. 2A, top. From Tacken et al. Blood 118: 6836-6844, 2011. Freely available at bloodjournal.hematologylibrary.org/content/118/26/6836.full DC maturation Fig. 2A, bottom. From Tacken et al. Blood 118: 6836-6844, 2011. Freely available at bloodjournal.hematologylibrary.org/content/118/26/6836.full Co-stim Fig. 2B. From Tacken et al. Blood 118: 6836-6844, 2011. Freely available at bloodjournal.hematologylibrary.org/content/118/26/6836.full Cytokines Binding, uptake, and Ag presentation of NPs by mouse DCs Fig. 4A. From Tacken et al. Blood 118: 6836-6844, 2011. Freely available at bloodjournal.hematologylibrary.org/content/118/26/6836.full Particle uptake Fig. 4B. From Tacken et al. Blood 118: 6836-6844, 2011. Freely available at bloodjournal.hematologylibrary.org/content/118/26/6836.full T cell proliferation Fig. 4C. From Tacken et al. Blood 118: 6836-6844, 2011. Freely available at bloodjournal.hematologylibrary.org/content/118/26/6836.full IFN-γ production “Preserving the sanctity of the cytosol” Cytosolic PRRs Fig. 1. From Chamaillard et al. Cell Microbiol 5: 481-592, 2003. Freely available at http://onlinelibrary.wiley.com/doi/10.1046/j.14625822.2003.00304.x/full CARD domain containing proteins (Note: outdated nomenclature) The NLR family (Nucleotide-binding and oligomerization domain-like receptors) Fig. 1. From Yeretssian, G. Immunol Res 54: 25-36, 2012. Available at http://link.springer.com/article/10.1007%2Fs12026012-8317-3 Bacterial Peptidoglycans (top 2 NLRC) NLRP3 (middle NLRP) NLRP3 Inflammasome Assembly Fig. 3. From Schroder, K. and Tschopp, J. Cell 140: 821-832, 2010. Available at www.cell.com/retrieve/pii/S0092867410000759 IL-1 and IL-18 secretion Proteolytic cleavage to secrete IL-1, IL-18, and IL-33 Fig. 1. From Lamkanfi, M. and Dixit, VM. Immunol Rev 227: 95-105, 2009. Available at onlinelibrary.wiley.com/doi/10.1111/j.1600065X.2008.00730.x/abstract NLRP3 NLRC4 NLRP1 Inflammasomes Anthrax lethal toxin ATP Pore-forming toxins Crystals Flagellin T3SS and T4SS Pseudomonas Fig. From Ulland, TK and Sutterwala, FS. The inflammasomes: Activation of the inflammasome by bacterial pathogens. In: Progress in Inflammation Research. 2011. Springer: Basel, p. 37-50. dsDNA Francisella DNA: also RIGI and MAVS NLRP3 inflammasome Fig. 1. From Leemans et al. Immunol Rev 243: 152-162, 2011. Available at http://onlinelibrary.wiley.com/doi/10.1111/j.1600065X.2011.01043.x/full Cytosolic nucleic acid recognition by the host Fig. 1, a-c. From Monie, TP. Trends Biochem Sci 38: 131-139, 2013. Available at www.sciencedirect.com/science/article/pii/S09680004 13000029 Many ways to activate… Fig. 1. From Monie, TP. Trends Biochem Sci 38: 131-139, 2013. Available at www.sciencedirect.com/science/article/pii/S09680004 13000029 Innate immune pathways Fig. 8.1. From Witte et al. Adv Immunol 113: 135-156, 2012. Available at www.sciencedirect.com/science/article/pii/B978012394590 7000026 Inflammasomes and gut homeostasis Fig. 2. From Zambetti et al. Immunol Res 53: 78-90, 2012. Available at link.springer.com/article/10.1007%2Fs12026012-8272-z NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA. Fig. 3, E-F. From Elinav et al. Cell 145: 745-757, 2011. Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3140910/ Fig. 4, G-I. From Elinav et al. Cell 145: 745-757, 2011. Freely available at www.ncbi.nlm.nih.gov/pmc/articles/PMC3140910/ The price of immunity Fig. 1. From Goldzmid, RS and Trinchieri, G. Nature Immunol 13: 932-938, 2012. Freely available at www.nature.com/ni/journal/v13/n10/full/ni.2422.html Autophagy and host defense Fig. 2. From Kuballa et al. Annu. Rev. Immunol. 30: 611646, 2012. Available at www.annualreviews.org/doi/abs/10.1146/annurev-immunol020711-074948 Granuloma formation – inflammation! Figure courtesy of Professor Wagner Tafuri, UFMG, Brazil. Chemotaxis (margination) Molecules involved in margination Fig. 13-8. From Kindt, Goldsby, and Osborne. Kuby Immunology (6th Ed.). 2007. New York: Freeman. Chemokine Chemokine binding to its receptor Fig. 2.32. From Janeway’s Immunobiology (5th ed). 2001. New York: Garland Sci. IL-8 Chemokine receptor (actually rhodopsin from bacteria) From en.wikipedia.org/wiki /Chemotaxis CC Chemokines Fig. 3.22. From Janeway’s Immunobiology (5th ed). 2001. New York: Garland Sci. CXC Chemokines Fig. 3.22. From Janeway’s Immunobiology (5th ed). 2001. New York: Garland Sci. Chemoattractants (3) 1. Formylated peptides fMet-leu-phe 2. Complement anaphylotoxins C5a, C3a 3. Chemokines CC Chemokines - many CXC Chemokines - many Simplified signal transduction G protein-coupled receptors Fig. 13-2. From Kindt, Goldsby, and Osborne. Kuby Immunology (6th Ed.). 2007. New York: Freeman. Chemokine receptors as activation markers Fig. 13-3. From Kindt, Goldsby, and Osborne. Kuby Immunology (6th Ed.). 2007, New York: Freeman. CCR5 and CXCR4 chemokine receptors as coreceptors for HIV Fig 2. From Tilton JC and Doms RW. Antiviral Res 85:95-100, 2010. Available at www.sciencedirect.com/science/article/pii/S0166354209003945 Monocytes Fig. 1. From Strauss-Ayali et al. J. Leukocyte Biol. 82: 244-252, 2007. Freely available at http://www.jleukbio.org/content/82/2/244.long GR1+ Monocytes Produce O2and Kill Leishmania major Fig. 5, E & F. From Goncalves et al. J Exp Med 208: 1253-1265, 2011. Freely available at http://jem.rupress.org/content/208/6/1253.full Fig. 3A. From Goncalves et al. J Exp Med 208: 1253-1265, 2011. Freely available at http://jem.rupress.org/content/208/6/1253.full Exploring the full spectrum of macrophage activation Fig. 1. From Mosser, D.M. and Edwards, J.P. Nature Rev Immunol 8: 958-969, 2008. Available at www.nature.com/nri/journal/v8/n12/abs/nri2448.html IFN LPS 2˚ (Ag-Ab) IFN LPS Regulatory M (R-M) Anti-inflammatory IL-4/13 High Class II and APC function Low TNF, IL-12/23 High IL-10 Classically activated (Ca-M) Alternatively activated (AA-M) MHC Class II – Antigen presentation High O2- and NO production - microbicidal IL-12/23 – Th1 response TNF, IL-1, IL-6 – inflammation Relatively low IL-10 production Low MHC Class II – Poor APC Low or absent NO production – Arginase Lectin-like receptors and chitinases Low to absent IL-12/23 production Host Defense Immune regulation Wound healing Regulatory Macrophages Rescue Mice From Lethal Endotoxemia Cold-induced metabolic adaptations require alternatively activated macrophages Fig. 2, a & d. From Nguyen et al. Nature 480: 104-108, 2011. Available at www.nature.com/nature/journal/v480/n7375/full/nature10653.html Mosser Lab – University of Maryland Xia Zhang, MD/Ph.D. Ricardo Goncalves, DVM/PhD Justin Edwards Ziyan Yang Heather Cohen Rahul Suresh Bryan Flemming Bess Gerhart