Immune Responses by Regulation of Leukocyte Trafficking in Vivo

Springer Semin Immunopathol(2000) 22:321-328 Springer Seminars in knmunopathology © Springer-Verlag2000

Introduction

Kouji Matsushima

Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo 7-3-1, Hongo, Bunkyo-ku,Tokyo 113-0033, Japan

Chemokine is the generic term for chemotactic cytokines. The chemokine family now comprises more than 40 members, subdivided into four groups based on the lo- cation of the very conserved first two cysteine residues as shown in Fig. 1. Interleukin-8 (IL-8), which, in collaboration with Teizo Yoshimura in 1987 at the National Cancer Institute, Md., USA, we identified, biochemically purified (based on in vitro neutrophil chemotactic activity) and molecularly cloned, is a prototype of the CXC chemokines [14, 22]. Monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), which was purified (based on in vitro monocyte chemotactic activity) and molecularly cloned independently by our group and that of Teizo Yoshimura in 1989, is a prototype of CC chemokines [15, 23]. These pioneer studies provided clues to the molecular basis of chemotactic activities which, since the early 1970s, had been further researched by numerous cellular immunologists. Before the discovery of chemokines, several endogenously produced chemotactic factors such as C5a, platelet-activating factor (PAF) and LTB4 had been identified, but none of them was shown to be involved in inflammation or immune responses by regulation of leukocyte trafficking in vivo. In addition, few people believed in the existence of an in vivo chemotactic gradient for the recruitment of leukocytes. Therefore, it was generally considered that the chemotactic activity of chemotactic factors against leukocytes observed in vitro was an artefact. In the early 1990s, we and several other groups initiated studies to determine the pathophysiological roles of chemokines in various animal inflammation models, us- ing specific blocking antibodies against chemokines. We used rabbits to study IL-8 because the IL-8 homologue does not exist in rodents and our monoclonal antibody prepared against human IL-8 completely cross-reacted with rabbit IL-8 and blocked the activity. We reported the essential involvement of IL-8 in the recruitment of neutrophils (called heterophils in rabbits) in acute inflammation models such as LPS/IL-1- induced dermatitis, immune complex-induced acute glomerulonephritis, lung repel'- fusion injury, acute respiratory distress syndrome and brain infarct, and also that the intervention of IL-8 led to the prevention of neutrophil infiltration-associated tissue injury [18]. Furthermore, we revealed the pivotal role of MCAF/MCP-1 in the recruitment of monocytes/macrophages in chronic inflammatory diseases through our pala~.t131-ouog gu!z,{l~U~ ,~q pOAO.ICl,{IFmJog s~ '/[[aA[.laodso.t 'SOl,~3ouou.I pu~ sl!qd -o~lnau jo luatul!n~aa~ art1 u! I-dDINMVDIAI pue 8-qI .Io OlO~ Iea!l.ua oql 'aoleq "[[[] s~ u! ppotu uo!suauod,{q/[aeuotulnd poanpu.[-ou!Flo.~aouotu aql pue '[L] s!soaalaSo~oql~ jo ppotu e s~ X~n.fu.[ /[aaUe p.~lOaea ~alJe mn.qatllopua jo gu.mo~a!ql '[]Tg] XpoqBue au~zqtUOLU 1UOtUOS~q ~[n~atuoI~!lu~ /[q pasn~a s!lgqdauoln~atUOlg a.moatta uo sa!pms

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M Introduction 323 mice for the IL-8 receptor homologue [4], and JE (murine homologue of MCAF/MCP-1) and its receptor CCR2. Notably, mating CCR2-/- mice with ApoE-/- mice dramatically reduced atherogenesis in these animals, establishing that the MCAF/MCP-1-CCR2 system is really involved in vascular atherogenesis [2]. On the other hand, mice with a defective lipooxygenase gene [5] or C5aR [9] showed no failure of leukocyte infiltration during inflammation or Arthus reaction in C5aR-/- mice [10], demonstrating that there is no essential involvement of these classic chemoattractants in regulating leukocyte infiltration in inflammation. These findings are totally unexpected and point to the necessity of rewriting the textbook of inflammation and immunology. Identification of receptors for chemokines selectively expressed on each type of leukocyte deepened our knowledge of the molecular basis of the action of chemokines. In 1991, the groups of W.E. Holmes and EM. Murphy succeeded in cloning of cDNA encoding the human IL-8 receptors CXCR1 [8] and CXCR2 [16], respective- ly. Since then, a total of 17 chemokine receptors (CXCR1-CXCR5, CCRI-CCR10, XCR1, CX3CR1) have been identified (Fig. 2). CXCR1 and CXCR2 are simulta- neously expressed on normal neutrophils, and IL-8 acts on both CXCR1 and CXCR2, but other neutrophil-chemoattractive chemokines act on CXCR2. Normal resting monocytes express CCR2, which is acted upon by MCAF/MCP-1. Mono- cytes also express CCR1 and CCR5, but the biological significance of the expression of these receptors in the regulation of monocyte infiltration during inflammation has not been established. In atopic reactions, the selective infiltration of eosinophils has long been recognized, but now the molecular basis has been revealed. Eosinophils selectively express CCR3, which is specific for both eotaxin and RANTES, whose production is highly inducible by stimulating fibroblasts and epithelial cells with TNF and IL-4. The recent discovery (via the signal trap method and expressed seqnence tag, EST, data base) of numerous novel chemokines, most of which are chemoattractants for immune cells such as subsets of T lymphocytes, B lymphocytes and dendritic cells (DC), has changed our understanding of the role of chemokines in host defense responses (see the contributions of H. Yoneyama and O. Yoshie et al. in this issue). CD4+CD45RA + naive T lymphocytes express CXCR3 and CCR7. CD4+CD45RO + memory T lymphocytes express CCR6, but also CXCR3 and CCR5 on the Thl subset and CCR4 on the Th2 subset. About 20% of CD4 + memory T lymphocytes express CCR4, and these cells proved to already be committed to preferentially produce Th2 cytokines; the percentage of this population is much increased in atopic diseases such as atopic dermatitis and asthma. Even in lymphocyte homing, chemokines seem to be pivotal. CCR7 naive CD4 + T lymphocytes are recruited from the blood circulation across high endothelial venules in the peripheral lymphoid tissue. The chemokine responsible for the recruitment of B lymphocytes to peripheral lymphoid tissue has not yet been identified. CCR1 or CCR6 ÷ immature DC, Langerhans cells in the epidermis, are recruited by secondary lymphoid tissue chemokine (SLC) into the paracortical "T cell" area of the regional lymph node through afferent lymphatics after antigen capture and maturation into CCR7 + mature DC. Antigen-processed, mature recruited DC (now called interdigitating DC) present antigen to naive T tymphocytes, which subsequently activate B lymphocytes. Activated B and some T lymphocytes start to express CXCR5 and are recruited into follicle by B lymphocyte chemoattractant (BLC) produced by follicular DC. B lymphocytes proliferate and form germinal cen- ters. Memory T lymphocytes leave the lymph node through efferent lymphatics and t~ Gro Eotaxin MIP-1 ,~ MCP-1/ MIP-1 ~ SLC ENA-78 MCP-2,3,4 MIP-1 p MCAF RANTES LARC/ ELC/ BLC/ IL-8 NAP-2 RANTES RANTES MCP-2,3,4 MCP-2,3 MIP-3a MIP-3 p BCA-1 Lymphotactin

XCR1 G neutrophil eosinophil monocyte immature DC mature DC B NK? basophil (activated)

SLC IP-10 MIP-1 a SDF-1/ ELC/ LARC/ Mig MIP-1 p TARC ILC/ PBSF MIP-3p MIP-3~ I-TAC RANTES MDC 1-309 TECK CTACK Fractalkine

CCR7 CCR6 CXCR3 CCR5 CCR4 CCR8 CCR9 CCFll0 CX3CR1 CXCR4

naive T memory T Thl Th2 activated a 4/9 7 ÷ T CLA* T NK, CD8 Th2 ? neuron Introduction 325 the thoracic duct, and enter into the systemic circulation (see chapter by C. Caux et al. in this issue). Among memory T lymphocytes, CCR7- T lymphocytes home to peripheral tissue, e.g., ot4~37+ cells into intestinal mucosa and CLA + cells into the skin; on the other hand, CCR7 + lymphocytes home to the paracortical area of secondary lymphoid tissue. The chemokines responsible for the homing into mucosa and dermis have been reported, but are the subject of some controversy.

Chemokines in angiogenesis

Chemokines have additional regulatory roles in pathophysiology. Glutamic acid- leucine-arginine (ELR) motif+ CXC chemokines, such as IL-8, are angiogenic, but ELR motif- CXC chemokines, such as PF4 and IP10, are anti-angiogenic [20]. This property of chemokines may be important for understanding the angiogenesis associated with inflammation and neoplasia. Chemokines are also involved in reproduc- tion. Pregnancy and the menstruation cycle, during which a specific type of leukocyte infiltration at particular time points has been documented, are episodes of pro- grammed inflammation controlled by hormones. In mice, an IL-8 functional homologue MIPII regulates postovulatory neutrophil infiltration into the vagina [19]. IL-8 also seems to be involved in cervical ripening.

Chemokines in hematopoiesis and development

Chemokines not only regulate the migration of mature leukocytes, but also regulate the function and migration of hematopoietic progenitor cells (HPC). MIPla inhibits the growth of early HPC through CCR1 [3], and IL-8 and M1Pla have been shown to induce HPC mobilization from bone marrow (BM) into the circulation [12, 21]. In addition, gene targeting of PBSF/SDF-1 and its receptor by T. Nagasawa et al. revealed that PBSF/SDF-I is involved in B lymphocyte poiesis in fetal liver and myelopoiesis in BM [13, 17]. These findings suggest that PBSF/SDF-1 regulates B lymphocyte growth but also migration of HPC from fetal liver to BM during development. They also observed that PBSF/SDF-1 is involved in the formation of the membrane part of septum of the heart and the vessels of the gastrointestinal tract. Extensive description of the phenotypes of gene targeting of chemokines and their receptors is provided in the chapter by D.M. Slattery et al.

Chemokines in infection

The breakthrough discovery in the field of chemokines during the last few years has been the identification (by E. Berger) of CXCR4 as a co-receptor for T lymphocyte- tropic HIV infection to T lymphocytes [6]. In the same context, CCR5 was identified as a co-receptor for monocyte-tropic HIV [1 ]. The mystery which has prevailed con- cerning an additional receptor, other than CD4, for HIV infection, as well as the molecular basis of cell tropism of HIV, can now be explained by the use of chemokine receptors by HIV. Furthermore, the molecular mechanism of resistance to HIV infection can also be partially explained by the mutation of the genes for chemokines and macrophage,neutrophil, T cell (CD4, CD8), DC

Wound healing Hematopoietic sl Growth / Mobilization HI______V Coreceptor J'~SV viral escape Neuronal s Infection bacteria fungi, virus Vessel inflammation can Acute; Neutrophil immune s~ Chronic; Mo, T, B Primary ii~iThymus~i Clonal Selection ystemic leukocytosis leukopenia

Se co n da ry ~:.::~ :.~i LN:. '~~~- -- H o m i n g immune responses Peyer~spatch!~ naive T-~, Thl / Th2 ~Cryptopatch : B, DC :: :!EL I~ NK, NKT

Physiological/Ernbryoiogicai-~< ,,Pathological Introduction 327 their receptors. Some of the open reading frames of herpes viruses encode chemokine antagonists as well as chemokines and receptors. This issue is potentially very important but still relatively unexplored (see the chapter by D.H. McDermott and R Murphy in this issue).

The chemokine world (Fig. 3)

In conclusion, chemokines were first studied as mediators of inflammation. Howev- er, it is now very clear that chemokines also regulate immune responses and the establishment of the immune system. The scope of chemokine biology has widened considerably, and chemokines are also thought to regulate angiogenesis associated with inflammation and neoplasia, the reproductive and hematopoietic systems, and organ development. Very excitingly, viruses such as HIV and herpes viruses have a close connection with the chemokine system. Although in this issue of Seminars in Immunopathology we have not discussed the development of novel therapeutic agents for inflammatory, immune and infec- tious diseases targeting the chemokine system, this will definitely be another very exciting product of the chemokine world in the near future.

References

1. Alkhatib G, Combadiere C, Broder CC, Feng Y, Kennedy PE, Murphy PM, Berger EA (1996) CC-CKR5; A RANTES, MIP-lc~, MIP+I 3 receptors as a fusion cofactor for macrophage tropic HIV-1. Science 272:1955 2. Boring L, Gosling J, Cleary M, Charo IF (1998) Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 394:894 3. Broxmeyer HE, Cooper S, Hangoc G, Gao JL, Murphy PM (1999) Dominant myelopoietic effector functions mediated by chemokine receptor CCR1. J Exp Med 189:1987 4. Cacalano G, Lee J, Kikly K, Ryan AM, Pins-Meek S, Hultgren B, Wood WI, Moore MW (1994) Neu- trophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science 265:682 5. Chert XS, Sheller JR, Johnson EN, Funk CD (1994) Role of leukotrienes revealed by targeted disrup- tion of the 5-1ipoxygenase gene. Nature 372:179 6. Feng Y, Broder CC, Kennedy PE, Berger EA (1996) HIV-I entry co-factor; functional cDNA cloning of a seven transmembrane, G protein-coupled receptor. Science 272:872 7. Furukawa Y, Matsumori A, Ohashi N, Shioi T, Ono K, Harada A, Matsushima K (1999) Anti-monocyte chemoattractant protein-l/monocyte chemotactic and activating factor antibody inhibits neointi- mat hyperplasia in injured rat carotid arteries. Circ Res 784:306 8. Holmes WE, Lee J, Kuang W-J, Rice GC, Wood Wi (1991) Structure and functional expression of a human interleukin-8 receptor. Science 253:1278 9. Hopken UE, Lu B, Gerard NP, Gerard C (t996) The C5a chemoattractant receptor mediates mucosal defense to infection. Nature 383:86 10. Hopken UE, Lu B, Gerard NP, Gerard C (1997) Impaired inflammatory responses in the reverse arthus reaction through genetic deletion of the C5a receptor. J Exp Med 186:749 11. Kimura H, Kasahara T, Kurosu K, Sugito K, Takiguchi Y, Terai M, Mikata A, Natsume M, Mukaida N, Matsushima K, Kuriyama T (1998) Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating factor/ monocyte chemoattractant protein-l. Lab Invest 78:571 12. Laterveer L, Zijimans JM, Lindley IJ, Hamilton MS, Willemze R, Fibbe WE (1996) Improved surviv- al of lethally irradiated recipient mice transplanted with circulating progenitor cells mobilized by IL-8 after pretreatment with stem cell factor. Exp Hematol 24:1387 t3. Ma Q, Jones D, Borgbesani PR, Segal RA, Nagasawa T, Kishimoto T, Bronson RT, Springer TA (1998) Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebeltar neuron migration in CXCR4- and SDF-l-deficient mice. Proc Natl Acad Sci USA 95:9448 328 K. Matsushima

14. Matsushima K, Morishita K, Yoshimura T, Lavu S, Kobayashi Y, Lew W, Appella E, Kung HE Leonard EJ, Oppenheim JJ (1988) Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med 167:924 15. Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ (1989) Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med 169:1485 16. Murphy PM, Tiffany HL (1991) Cloning of complementary DNA encoding a functional interleukin-8 receptor. Science 253:I280 I7. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, Kitamura Y, Yoshida N, Kikutani H, Kishimoto T (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382:635 18. Sekido N, Mukaida N, Harada A, Nakanishi l, Watanabe Y, Matsushima K (1993) Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature 365:654 19. Sonoda Y, Mukaida N, Wang JB, Shimada-Hiratsuka M, Naito M, Kasahara T, Harada A, Inoue M, Matsushima K (1998) Physiologic regulation of postovulatory neutrophil migration into vagina in mice by a C-X-C chemokine(s). J Immunol 160:6159 20. Stricter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, Dzuiba J, VanDamme J, Walz A, Marriott D, Chan S-Y, Roczniak S, Shanafelt AB (1995) The functional role of the ELR motif in C-X-C chemokine-mediated angiogenesis. J Biol Chem 270:27348 21. Su S, Mukaida N, Wang J, Zhang Y, Takami A, Nakao S, Matsushima K (1997) Inhibition of immature erythroid progenitor cell proliferation by macrophage inflammatory protein-1 alpha by interacting mainly with a C-C chemokine receptor, CCR1. Blood 90:605 22. Yoshimura T, Matsushima K, Oppenheim JJ, Leonard EJ (1987) Neutrophit chemotactic factor produced by lipopolysaccharide (LPS)-stimulated human blood mononuclear leukocytes: partial characterization and separation from interteukin l (IL-1). J lmmunol 139:788 23. Yoshimura T, Matsushima K, Tanaka S, Robinson EA, Appella E, Oppenheim JJ, Leonard EJ (1987) Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci USA 84:9233 24_ Wada T, Yokoyama H~ Furuichi K, Kobayashi KI, Harada K, Naruto M, Su SB, Akiyama M, Mukaida N, Matsushima K (1996) Intervention of crescentic glomerulonephritis by antibodies to monocyte chemotactic and activating factor (MCAF/MCP-1). FASEB J 10:1418