STRATEGIES TO SENSE PATHOGENS AND DAMAGED TISSUES (Bottazzi, Garlanda, Doni, Mantovani Annu Rev Immunol 2010)
Decoy: Colotta et al Science 1993 MyD88 etc in TLR: J. Exp Med 1998
ILRs TLRs - IL-1F5 - IL-1F5 IL-1ras IL-1F6 - IL-1F7 IL-1 α IL-1F8 LPS, CpG, ? ? ? Flagellin, Poly I:C... IL-1 β IL-1 β IL-33 IL-1F9 IL-18 IL-18 IL-1RII IL-18BP IL-1RI ST-2 IL-1R TIGIRR-1 IL-1R IL-1R AcP IL-1R IL-18R IL-1Rrp2 SIGIRR TLR1-10 AcP AcP AcP IL-18R IL-1RAPL AcP TIR8/ decoy - - - Ig domain Leucine - rich repeat MyD88 TIR domain domain TIRAP/MAL Negative TRIF - regulation SARM TRAM ? Unknown ligand (Garlanda, Anders and Mantovani Trends Immunol 2009)
Human: Chromosome 11, 10 exons mRNA: 1695 bp TIR domain Protein: 410 aa Mouse: LPS IL-1 CpG Chromosome 7, 9 exons IL-18 nucleosomes mRNA: 1450 bp IL-1F5 IL-33 Death domain ?? Protein: 409 aa ??? Conserved aa (S447, T536) Replaced aa TIR8/ IL-1RI TLR4 (C222, L305) SIGIRR IL-18R TLR9 TLR7 ST2 ?? MyD88 Kidney transplantation Pulmonary TB IRAK Fungal infections Autoimmunity NFkB Asthma Arthritis Intestinal inflammation Colitis – associated cancer (Garlanda, Anders and Mantovani Trends Immunol 2009)
Regulation of inflammation by TIR8/SIGIRR LPS IL-1ra IL-1 Pro-inflammatory cytokines Epithelial mucosal Inflammatory chemokines cells , iDC, Endothelial cells Leukocyte infiltration TI TI TI TI TI TI TI TI IL-1RI R R R R R R R R D D D MyD88 MyD88 D - - Pulmonary TB- Fungal Inf- Intestinal inflammation and colitis – associated cancer (L.Romani) Autoimmunity TIR 8-/- 100 TIR8 +/+ Percent Survival Percent survival 75 50 25 0 0 10 20 30 40 50 60 70 Weeks days +/+ -/- (Garlanda et al PNAS 2005; Garlanda et al Cancer Res 2007; Garlanda et al JI 2007; Lech et al JEM 2008)
- IL-1ra - IL-1 α IL-1F7 IL-1 β IL-18 IL-33 IL-18BP T1/ST-2 SIGIRR SIGIRR SIGIRR IL-1RII IL-18R IL-18R IL-1RI TIR8/ TIR8/ TIR8/ IL-1R IL-1R AcP AcP AcP - - - - - Th17 Th2 Th1 (Garlanda, Anders and Mantovani Trends Immunol 2009)
Chemokine Receptor Main targets IL-8 CXCL8 GCP-2 CXCL6 CXCR1 Neutrophil NAP-2 CXCL7 ENA-78 CXCL5 CXCR2 GRO α CXCL1 GRO β CXCL2 GRO γ CXCL3 B cell IP-10 CXCL10 Mig CXCL9 CXCR3 I-TAC CXCL11 SDF-1 α/β CXCL12 CXCR4 BCA-1 CXCL13 Immature CXCR5 CXCL16 CXCR6 mDC BRAK CXCL14 Unknown Mature MCP-1 CCL2 MCP-4 CCL13 CCR2 MCP-3 CCL7 MCP-2 CCL8 Monocyte MIP-1 β CCL4 MIP-1 α S CCL3 CCR5 MIP-1 α P CCL3LI RANTES CCL5 Eosinophil MPIF-1 CCL23 HCC-1 CCL14 CCR1 Basophil HCC-2 CCL15 HCC-4 CCL16 Eotaxin CCL11 Naive Eotaxin-2 CCL24 CCR3 Memory Eotaxin-3 CCL26 Th1 T cell TARC CCL17 Th2 CCR4 MDC CCL22 Treg MIP-3 α CCL20 CCR6 ELC CCL19 CCR7 SLC CCL21 pDC CCR8 I-309 CCL1 TECK CCL25 CCR9 CTACK CCL27 CCR10 PARC CCL18 Unknown Lymphotactin XCL1 XCR1 NK cell SCM-1 β XCL2 CX3CR1 Fractalkine CX3CL1 (Mantovani, Bonecchi ,Locati Nature Rev Immunol 2006) Inflammatory (RED), homeostatic (GREEN), mixed (YELLOW)
The “darc side” of the chemokine system Atypical Signaling chemokine chemokine receptors receptors CXCR7 No conventional Signaling (CTX, Ca, MAPK, …) signaling (CTX, Ca, MAPK, …) (Mantovani, Bonecchi and Locati, Nature Rev Immunol 2006; CGFR 2009)
THE DECOY R D6: A SCAVENGER AND GATEKEEPER OF INFLAMMATORY CC CHEMOKINE TRANSFER TO LYMPH NODES Tissue Lymph node CCL2 HEV Blood D6 Lymph Endothelium CCL2 (-/- data: Martinez de la Torre et EJI, 2005; PNAS 2007; Jamieson et al Nature Immunol 2005; Liu et al J Immunol 2006. For review Mantovani, Bonecchi and Locati, Nature Rev Immunol 2006)
M. tuberculosis infection in D6 -/- CFUs M. tuberculosis (2 x 10 3 CFU) intranasal injection WT (n=10) D6 -/- (n=10) (Di Liberto & Locati et al, J Exp Med 2008)
D6 AS A DECOY AND SCAVENGER: IN VIVO VERITAS Fetal loss under inflammatory conditions Colitis and colon cancer Mycobacterium tubercolosis Martinez de la Torre Y et al, PNAS 2007 Vetrano et al 2010 Di Libero Locati et al J Exp Med 2008 Granulomatous reaction to CFA injection Allergic airway inflammation Skin Inflammation and carcinogenesis Martinez de la Torre Y et al, Eur J Immunol 2005 Whitehead Am J Res Crit C Med 2007 Otero K et al unpiblished Induction of EAE Induction of EAE (Liu et al JI 2006) (Liu et al JI 2006) Jameson Nature Immunol 2005 Nibbs RJ, J Clin Invest 2007
Negative regulators (D6; TIR8): 1. tune and balance resistance versus uncontrolled inflammation; 2. resolution TIR8 or D6 -/- Brakes: TIR8, D6…… TLR/ILR; chemokines Antimicrobial & Inflammation resistance Antimicrobial Inflammation resistance Equilibrium and Death long survival
DECOY RECEPTORS Receptor IL-1R TNF IL-10 IL-4/IL13 Chemokines EGF family Core MyD88 Caspase/TRAF JAK/STAT JAK/STAT G protein TK signaling Decoys Argos IL-13R 2 IL-18BP IL-18 FDR FASL IL-22BP D6 Decoy RII IL-1 DcR3 FASL, LIGHT Inflammatory IL-22 IL-13 CC chemokines DcR1, DcR2 TRAIL Osteoprotegerin RANK, TRAIL (updated from Mantovani et al Trends Immunol 2001 )
THE PROTOTYPIC LONG PENTRAXIN PTX3 Human Genomic clone 17 Kb Chr 3q25 Murine gene Chr 3 mRNA 1866 bp Protein 381 aa Protomer 43 kDa Signal Glycosylation 2 kDa X domain Pentraxin domain peptide Protein is mainly organized in covalently linked octamer Inforzato et al, JBC 2008 (Garlanda et al Annu Rev Immunol 2005, 2010; Bottazzi et al Curr Op Immunol, 2006, 2008)
Shape of the PTX3 protein Transmission Electron Microscopy (TEM)… Visualization of the rhPTX3 protein by TEM (Inforzato et al, in revision on J. Biol. Chem. )
Shape of the PTX3 protein …and Small Angle X -ray Scattering (SAXS). SAXS analysis of rhPTX3 and an ab initio model of the PTX3 protein (Inforzato et al, in revision on J. Biol. Chem. )
THE PENTRAXIN SUPERFAMILY (Garlanda, Bottazzi and Mantovani Annu Rev Immunol 2005)
"The serum obtained from human beings and monkeys during the acute phase of diverse infections contains a protein which is precipitable by the C polysaccharide of pneumococcus" Abernathy and Avery, J. Exp. Med., 1941 Tillet and Francis, J. Exp. Med, 1930
THE PENTRAXIN SUPERFAMILY (Garlanda, Bottazzi and Mantovani Annu Rev Immunol 2005)
SELECTIVE SUSCEPTIBILITY OF PTX3 -/- MICE TO A.FUMIGATUS A.FUMIGATUS CLP L. MONOCYTOGENES (Garlanda et al Nature 2002)
REGULATION OF PTX3 PRODUCTION IN MYELOMONOCYTIC CELLS TLR AGONISTS PRIMARY INFLAMMATORY (e.g. LPS) CYTOKINES (IL-1, TNF) IFNg - + IL-10 Mø myeloid DC HUMORAL INNATE IMMUNITY HA MATRIX TUNING DEPOSITION INFLAMMATION (C; OPSONIZATION VIA FcgR; NEUTRALIZATION) (Bottazzi et al Annu Rev Immunol 2010)
The yin-yang of macrophage polarization M1 M2-like - intracellular pathogens - tissue damage - tumor resistance - parasite encapsulation - tissue remodeling - tumor promotion - immunoregulation Modified from Biswas and Mantovani Nature Immunol 2010
Ligands recognized by PTX3 - Microbial ligands: OMPA, galactomannan and more - Apoptotic cells Complement: C1q, Factor H - - FcgR - ECM Outer Membrane Protein A (Bottazzi et al JBC; Jeannin et al Immunity 2005; Rovere et al Blood 2004; Garlanda et al Nature 2002; Lu et al Nature 2009)
Synergy between Ficolin-2 and PTX3 boosts innate immune recognition and complement deposition C4 deposition depends on Ficolin-2 and Ficolin-2/PTX3 collabo Ficolin-2/PTX3 cross-talk on A. fumigatus Ficolin-2 isolation from human plasma by immobilized PTX3 Ma Y J et al. J. Biol. Chem. 2009, L-ficolin; see also Gout et al J Immunol 2011, M-Ficolin
Figure 2 PENTRAXINS (CRP, SAP, PTX3) Classical pathway Lectin pathway Alternative pathway Antibodies, Pentraxins C3b-microorganisms MBL, Ficolins C1q, C3b C1r, C1s MASPs Factor B, Factor D, C4, C2 Properdin C3 and C5 convertases C3a, C5a C3b Factor H C5b-C9 C1q Amplification loop Ficolin MBL CRP Inflammation Membrane Opsonization attack complex, SAP lysis (Bottazzi, Garlanda, Doni, PTX3 Mantovani, Annu Rev Immunol 2010)
Localization of PTX3 in human Neutrophil granules (Jaillon et al, JEM 2007)
Localization of PTX3 in Neutrophil Extracellular Traps (NETs) (Jaillon et al, JEM 2007)
Box 2 | Neutrophil extracellular traps Neutrophils in the activation and regulation of innate and adaptive immunity Mantovani A, Cassatella MA, Costantini C, Jaillon S. Nat Rev Immunol. 2011 Jul 25;11(8):519-31. Review.
Figure 1 | Neutrophils crosstalk with immune and non-immune cells in inflamed tissues and lymph nodes. Neutrophils in the activation and regulation of innate and adaptive immunity Mantovani A, Cassatella MA, Costantini C, Jaillon S. Nat Rev Immunol. 2011 Jul 25;11(8):519-31. Review.
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