Innate Immunity Host Defense and Immunopathology David M

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Innate Immunity, Host Defense, and Immunopathology David M. Mosser, Ph. D. dmosser@umd. edu

Innate Immunity, Host Defense, and Immunopathology David M. Mosser, Ph. D. dmosser@umd. edu

Innate Immunity It all started here…. Fig. 5. From Lemaitre et al. Cell 86:

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/S 0092867400801725

Innate immune responses via toll-like receptors Toll-Like Receptors *Genetically pre-determined *Pattern recognition receptors *Constitutively

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-1 Rmediated 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 i. NOS 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 0 s that spur autophagy and immunity Fig. 1. From

PAMPs and DAMPs: signal 0 s 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 -065 X. 2012. 01146. x/full

Many TLRs Fig. 3 -11, pt. 1. From Kindt, Goldsby, and Osborne. Kuby Immunology

Many TLRs Fig. 3 -11, pt. 1. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007, New York: Freeman.

TLR structure Fig. 3 -10. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th

TLR structure Fig. 3 -10. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007, New York: Freeman. TIR = Toll, IL-1 receptor domain

Nuclear translocation of NF-k. B following bacterial infection of macrophages Untreated (dark nuclei) R.

Nuclear translocation of NF-k. B following bacterial infection of macrophages Untreated (dark nuclei) R. equi – infected LPS-treated Macrophages counterstained red NF-k. B (p 65) stained in green

Macrophage cytokine production TNF, IL-1, IL-6, IL-8, IL-12…

Macrophage cytokine production TNF, IL-1, IL-6, IL-8, IL-12…

Dendritic cell maturation (following TLR ligation) MHC Class II CD 40 CD 86 (B

Dendritic cell maturation (following TLR ligation) MHC Class II CD 40 CD 86 (B 7. 2) Immature Mature Increased MHC Increased CD 40 Increased co-stim

TLR ligands as adjuvants… improving CMI !/? Fig. 5. From Duthie et al. Immunol

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. 1600065 X. 2010. 00978. x/abstract Fig. 3 B & 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. 3 A. From De Brito et al.

TLR ligands as adjuvants… preventing allergy Fig. 3 A. From De Brito et al. J Clin Immunol 30: 280291, 2010. Available at link. springer. com/article/10. 1007%2 Fs 10875009 -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/PMC 36623 18/pdf/emmm 0005 -0762. pdf Cp. G TH 1 response R-848 Ig. E lung inflammation

Delivery of antigen and TLR agonists to APCs using nanoparticles Nanoparticles Antigen + TLR

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. 2 A,

DC-targeted TLRLs enhance maturation and activation of human DCs in vitro Fig. 2 A, top. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l Fig. 2 A, bottom. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l Fig. 2 B. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l DC maturation Co-stim Cytokines

Binding, uptake, and Ag presentation of NPs by mouse DCs Fig. 4 A. From

Binding, uptake, and Ag presentation of NPs by mouse DCs Fig. 4 A. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l Particle uptake Fig. 4 B. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l T cell proliferation Fig. 4 C. From Tacken et al. Blood 118: 6836 -6844, 2011. Freely available at bloodjournal. hematologylibrary. org/content/118/26/6836. ful l IFN-γ production

“Preserving the sanctity of the cytosol” Cytosolic PRRs Fig. 1. From Chamaillard et al.

“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

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%2 Fs 12026012 -8317 -3 Bacterial Peptidoglycans (top 2 NLRC) NLRP 3 (middle NLRP)

NLRP 3 Inflammasome Assembly Fig. 3. From Schroder, K. and Tschopp, J. Cell 140:

NLRP 3 Inflammasome Assembly Fig. 3. From Schroder, K. and Tschopp, J. Cell 140: 821 -832, 2010. Available at www. cell. com/retrieve/pii/S 0092867410000759 IL-1 and IL-18 secretion

Proteolytic cleavage to secrete IL-1, IL-18, and IL-33 Fig. 1. From Lamkanfi, M. and

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. 1600065 X. 2008. 00730. x/abstract NLRP 3 NLRC 4 NLRP 1

Inflammasomes Anthrax lethal toxin ATP Pore-forming toxins Crystals Flagellin T 3 SS and T

Inflammasomes Anthrax lethal toxin ATP Pore-forming toxins Crystals Flagellin T 3 SS and T 4 SS 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. ds. DNA Francisella DNA: also RIGI and MAVS

NLRP 3 inflammasome Fig. 1. From Leemans et al. Immunol Rev 243: 152 -162,

NLRP 3 inflammasome Fig. 1. From Leemans et al. Immunol Rev 243: 152 -162, 2011. Available at http: //onlinelibrary. wiley. com/doi/10. 1111/j. 1600065 X. 2011. 01043. x/full

Cytosolic nucleic acid recognition by the host Fig. 1, a-c. From Monie, TP. Trends

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/S 09680004 13000029

Many ways to activate… Fig. 1. From Monie, TP. Trends Biochem Sci 38: 131

Many ways to activate… Fig. 1. From Monie, TP. Trends Biochem Sci 38: 131 -139, 2013. Available at www. sciencedirect. com/science/article/pii/S 09680004 13000029

Innate immune pathways Fig. 8. 1. From Witte et al. Adv Immunol 113: 135

Innate immune pathways Fig. 8. 1. From Witte et al. Adv Immunol 113: 135 -156, 2012. Available at www. sciencedirect. com/science/article/pii/B 978012394590 7000026

Inflammasomes and gut homeostasis Fig. 2. From Zambetti et al. Immunol Res 53: 78

Inflammasomes and gut homeostasis Fig. 2. From Zambetti et al. Immunol Res 53: 78 -90, 2012. Available at link. springer. com/article/10. 1007%2 Fs 12026012 -8272 -z

NLRP 6 inflammasome regulates colonic microbial ecology and risk for colitis Elinav E, Strowig

NLRP 6 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/PMC 3140910/ Fig. 4, G-I. From Elinav et al. Cell 145: 745 -757, 2011. Freely available at www. ncbi. nlm. nih. gov/pmc/articles/PMC 3140910/

The price of immunity Fig. 1. From Goldzmid, RS and Trinchieri, G. Nature Immunol

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/v 13/n 10/full/ni. 2422. html

Autophagy and host defense Fig. 2. From Kuballa et al. Annu. Rev. Immunol. 30:

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-immunol 020711 -074948

Granuloma formation – inflammation! Figure courtesy of Professor Wagner Tafuri, UFMG, Brazil.

Granuloma formation – inflammation! Figure courtesy of Professor Wagner Tafuri, UFMG, Brazil.

Chemotaxis (margination)

Chemotaxis (margination)

Molecules involved in margination Fig. 13 -8. From Kindt, Goldsby, and Osborne. Kuby Immunology

Molecules involved in margination Fig. 13 -8. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007. New York: Freeman.

Chemokine binding to its receptor Fig. 2. 32. From Janeway’s Immunobiology (5 th ed).

Chemokine binding to its receptor Fig. 2. 32. From Janeway’s Immunobiology (5 th ed). 2001. New York: Garland Sci. IL-8 Chemokine receptor (actually rhodopsin from bacteria)

From en. wikipedia. org/wiki /Chemotaxis

From en. wikipedia. org/wiki /Chemotaxis

CC Chemokines Fig. 3. 22. From Janeway’s Immunobiology (5 th ed). 2001. New York:

CC Chemokines Fig. 3. 22. From Janeway’s Immunobiology (5 th ed). 2001. New York: Garland Sci.

CXC Chemokines Fig. 3. 22. From Janeway’s Immunobiology (5 th ed). 2001. New York:

CXC Chemokines Fig. 3. 22. From Janeway’s Immunobiology (5 th ed). 2001. New York: Garland Sci.

Chemoattractants (3) 1. Formylated peptides f. Met-leu-phe 2. Complement anaphylotoxins C 5 a, C

Chemoattractants (3) 1. Formylated peptides f. Met-leu-phe 2. Complement anaphylotoxins C 5 a, C 3 a 3. Chemokines CC Chemokines - many CXC Chemokines - many

Simplified signal transduction G protein-coupled receptors Fig. 13 -2. From Kindt, Goldsby, and Osborne.

Simplified signal transduction G protein-coupled receptors Fig. 13 -2. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007. New York: Freeman.

Chemokine receptors as activation markers Fig. 13 -3. From Kindt, Goldsby, and Osborne. Kuby

Chemokine receptors as activation markers Fig. 13 -3. From Kindt, Goldsby, and Osborne. Kuby Immunology (6 th Ed. ). 2007, New York: Freeman.

CCR 5 and CXCR 4 chemokine receptors as coreceptors for HIV Fig 2. From

CCR 5 and CXCR 4 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/S 0166354209003945

Monocytes Fig. 1. From Strauss-Ayali et al. J. Leukocyte Biol. 82: 244 -252, 2007.

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

GR 1+ Monocytes Produce O 2 and Kill Leishmania major Fig. 5, E &

GR 1+ Monocytes Produce O 2 and 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. 3 A. 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

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/v 8/n 12/abs/nri 2448. html

IFN LPS 2˚ (Ag-Ab) IFN LPS Regulatory M (R-M ) Anti-inflammatory IL-4/13 High Class

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 O 2 - and NO production - microbicidal IL-12/23 – Th 1 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

Regulatory Macrophages Rescue Mice From Lethal Endotoxemia

Cold-induced metabolic adaptations require alternatively activated macrophages Fig. 2, a & d. From Nguyen

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/v 480/n 7375/full/nature 10653. html

Mosser Lab – University of Maryland Xia Zhang, MD/Ph. D. Ricardo Goncalves, DVM/Ph. D

Mosser Lab – University of Maryland Xia Zhang, MD/Ph. D. Ricardo Goncalves, DVM/Ph. D Justin Edwards Ziyan Yang Heather Cohen Rahul Suresh Bryan Flemming Bess Gerhart