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Regulation and Function of the Inhibitory C-Type Lectin Clec12A/MICL

  • Konstantin NeumannEmail author
  • Jürgen RulandEmail author
Chapter

Abstract

The C-type lectin domain family 12 member A (Clec12A/MICL) is an inhibitory receptor encoded in the Dectin-1 cluster. It is widely expressed in myeloid cells and was identified as a specific marker for cancer stem cells in acute myeloid leukemia. Clec12A possesses an immunoreceptor tyrosine-based inhibition motif (ITIM), which can counteract activating signals from immunoreceptor tyrosine-based activation motifs (ITAMs). The receptor can sense necrotic cell death and limit ITAM-coupled receptor-induced inflammation in response to cell death or tissue damage. One Clec12A agonist released from dead cells was identified as uric acid in its crystallized form. Clec12A limits ITAM-dependent respiratory burst and IL-8 release from neutrophils in response to uric acid crystal binding but does not interfere with crystal-induced inflammasome activation. This review discusses recent insights into the regulation and biological functions of Clec12A.

Keywords

Clec12A MICL CLL1 CLL-1 DCAL2 DCAL-2 KLRL1 MSU Sodium urate Uric acid Crystals ITAM ITIM Sterile inflammation 

Notes

Acknowledgments

We thank Paul-Albert Koenig for helpful discussions. This work was supported by SFB grants from Deutsche Forschungsgemeinschaft and an ERC Advanced Grant to J.R.

References

  1. Ahrens S, Zelenay S, Sancho D, Hanc P, Kjaer S, Feest C, Fletcher G, Durkin C, Postigo A, Skehel M, Batista F, Thompson B, Way M, Reis e Sousa C, Schulz O (2012) F-actin is an evolutionarily conserved damage-associated molecular pattern recognized by DNGR-1, a receptor for dead cells. Immunity 36(4):635–645CrossRefPubMedGoogle Scholar
  2. An LL, Mehta P, Xu L, Turman S, Reimer T, Naiman B, Connor J, Sanjuan M, Kolbeck R, Fung M (2014) Complement C5a potentiates uric acid crystal-induced IL-1beta production. Eur J Immunol 44(12):3669–3679. doi: 10.1002/eji.201444560 CrossRefPubMedGoogle Scholar
  3. Arslan F, Smeets MB, O’Neill LAJ, Keogh B, McGuirk P, Timmers L, Tersteeg C, Hoefer IE, Doevendans PA, Pasterkamp G, de Kleijn DPV (2010) Myocardial ischemia/reperfusion injury is mediated by leukocytic toll-like receptor-2 and reduced by systemic administration of a novel anti-toll-like receptor-2 antibody. Circulation 121(1):80–90. doi: 10.1161/Circulationaha.109.880187 CrossRefPubMedGoogle Scholar
  4. Bakker AB, van den Oudenrijn S, Bakker AQ, Feller N, van Meijer M, Bia JA, Jongeneelen MA, Visser TJ, Bijl N, Geuijen CA, Marissen WE, Radosevic K, Throsby M, Schuurhuis GJ, Ossenkoppele GJ, de Kruif J, Goudsmit J, Kruisbeek AM (2004) C-type lectin-like molecule-1: a novel myeloid cell surface marker associated with acute myeloid leukemia. Cancer Res 64(22):8443–8450. doi: 10.1158/0008-5472.CAN-04-1659 CrossRefPubMedGoogle Scholar
  5. Barabe F, Gilbert C, Liao N, Bourgoin SG, Naccache PH (1998) Crystal-induced neutrophil activation VI. Involvement of FcgammaRIIIB (CD16) and CD11b in response to inflammatory microcrystals. FASEB J 12(2):209–220PubMedGoogle Scholar
  6. Begun J, Lassen KG, Jijon HB, Baxt LA, Goel G, Heath RJ, Ng A, Tam JM, Kuo SY, Villablanca EJ, Fagbami L, Oosting M, Kumar V, Schenone M, Carr SA, Joosten LA, Vyas JM, Daly MJ, Netea MG, Brown GD, Wijmenga C, Xavier RJ (2015) Integrated genomics of Crohn’s disease risk variant identifies a role for CLEC12A in antibacterial autophagy. Cell reports 11(12):1905–1918. doi: 10.1016/j.celrep.2015.05.045 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chen CH, Floyd H, Olson NE, Magaletti D, Li C, Draves K, Clark EA (2006) Dendritic-cell-associated C-type lectin 2 (DCAL-2) alters dendritic-cell maturation and cytokine production. Blood 107(4):1459–1467. doi: 10.1182/blood-2005-08-3264 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Dick JE (2005) Acute myeloid leukemia stem cells. Ann N Y Acad Sci 1044:1–5. doi: 10.1196/annals.1349.001 CrossRefPubMedGoogle Scholar
  9. Flach TL, Ng G, Hari A, Desrosiers MD, Zhang P, Ward SM, Seamone ME, Vilaysane A, Mucsi AD, Fong Y, Prenner E, Ling CC, Tschopp J, Muruve DA, Amrein MW, Shi Y (2011) Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity. Nat Med 17(4):479–U121. doi: 10.1038/Nm.2306 CrossRefPubMedGoogle Scholar
  10. Gagne V, Marois L, Levesque JM, Galarneau H, Lahoud MH, Caminschi I, Naccache PH, Tessier P, Fernandes MJ (2013) Modulation of monosodium urate crystal-induced responses in neutrophils by the myeloid inhibitory C-type lectin-like receptor: potential therapeutic implications. Arthritis Res Ther 15(4):R73. doi: 10.1186/ar4250 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Project Team MGC et al (2004) The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res 14(10B):2121–2127. doi: 10.1101/gr.2596504 CrossRefPubMedGoogle Scholar
  12. Gronwald W, Loewen MC, Lix B, Daugulis AJ, Sonnichsen FD, Davies PL, Sykes BD (1998) The solution structure of type II antifreeze protein reveals a new member of the lectin family. Biochemistry 37(14):4712–4721. doi: 10.1021/bi972788c CrossRefPubMedGoogle Scholar
  13. Gross O, Poeck H, Bscheider M, Dostert C, Hannesschlager N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, Mocsai A, Tschopp J, Ruland J (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459(7245):433–U149. doi: 10.1038/Nature07965 CrossRefPubMedGoogle Scholar
  14. Han Y, Zhang M, Li N, Chen T, Zhang Y, Wan T, Cao X (2004) KLRL1, a novel killer cell lectin like receptor, inhibits natural killer cell cytotoxicity. Blood 104(9):2858–2866. doi: 10.1182/blood-2004-03-0878 CrossRefPubMedGoogle Scholar
  15. Hangalapura BN, van Loo PF, Leenders M, de Kruif J, Bakker AB, Dolstra H (2014) A novel Clec12axcd3 bispecific antibody efficiently induces T-cell mediated lysis of Clec12a+Aml blasts. Haematologica 99:294Google Scholar
  16. Hara H, Tsuchiya K, Kawamura I, Fang RD, Hernandez-Cuellar E, Shen YN, Mizuguchi J, Schweighoffer E, Tybulewicz V, Mitsuyama M (2013) Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol 14(12):1247. doi: 10.1038/Ni.2749 CrossRefPubMedGoogle Scholar
  17. Hari A, Zhang Y, Tu Z, Detampel P, Stenner M, Ganguly A, Shi Y (2014) Activation of NLRP3 inflammasome by crystalline structures via cell surface contact. Sci Rep 4:7281. doi: 10.1038/srep07281 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hari A, Ganguly A, Mu LB, Davis SP, Stenner MD, Lam R, Munro F, Namet I, Alghamdi E, Furstenhaupt T, Dong W, Detampel P, Shen LJ, Amrein MW, Yates RM, Shi Y (2015) Redirecting soluble antigen for MHC class I cross-presentation during phagocytosis. Eur J Immunol 45(2):383–395. doi: 10.1002/Eji.201445156 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Hasselbacher P (1979) C3-activation by monosodium urate monohydrate and other crystalline material. Arthritis Rheum 22(6):571–578. doi: 10.1002/Art.1780220603 CrossRefPubMedGoogle Scholar
  20. Heng TS, Painter MW, Immunological Genome Project C (2008) The immunological genome project: networks of gene expression in immune cells. Nat Immunol 9(10):1091–1094. doi: 10.1038/ni1008-1091 CrossRefPubMedGoogle Scholar
  21. Hoffmann SC, Schellack C, Textor S, Konold S, Schmitz D, Cerwenka A, Pflanz S, Watzl C (2007) Identification of CLEC12B, an inhibitory receptor on myeloid cells. J Biol Chem 282(31):22370–22375. doi: 10.1074/jbc.M704250200 CrossRefPubMedGoogle Scholar
  22. Iborra S, Sancho D (2014) Signalling versatility following self and non-self sensing by myeloid C-type lectin receptors. Immunobiology. doi: 10.1016/j.imbio.2014.09.013 PubMedPubMedCentralGoogle Scholar
  23. Iborra S, Izquierdo HM, Martinez-Lopez M, Blanco-Menendez N, Reis e Sousa C, Sancho D (2012) The DC receptor DNGR-1 mediates cross-priming of CTLs during vaccinia virus infection in mice. J Clin Invest 122(5):1628–1643. doi: 10.1172/JCI60660 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehall WZ (2009) Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome. J Clin Invest 119(2):305–314. doi: 10.1172/Jci35958 PubMedPubMedCentralGoogle Scholar
  25. Jiang DH, Liang JR, Fan J, Yu S, Chen SP, Luo Y, Prestwich GD, Mascarenhas MM, Garg HG, Quinn DA, Homer RJ, Goldstein DR, Bucala R, Lee PJ, Medzhitov R, Noble PW (2005) Regulation of lung injury and repair by toll-like receptors and hyaluronan. Nat Med 11(11):1173–1179. doi: 10.1038/Nm1315 CrossRefPubMedGoogle Scholar
  26. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12(10):1167–1174. doi: 10.1038/nm1483 CrossRefPubMedGoogle Scholar
  27. Kanevets U, Sharma K, Dresser K, Shi Y (2009) A role of IgM antibodies in monosodium urate crystal formation and associated adjuvanticity. J Immunol 182(4):1912–1918. doi: 10.4049/Jimmunol.0803777 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kasahara S, Clark EA (2012) Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8alpha- dendritic cell subset. J Leukoc Biol 91(3):437–448. doi: 10.1189/jlb.0711384 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kono H, Chen CJ, Ontiveros F, Rock KL (2010) Uric acid promotes an acute inflammatory response to sterile cell death in mice. J Clin Invest 120(6):1939–1949CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lahoud MH, Proietto AI, Ahmet F, Kitsoulis S, Eidsmo L, Wu L, Sathe P, Pietersz S, Chang HW, Walker ID, Maraskovsky E, Braley H, Lew AM, Wright MD, Heath WR, Shortman K, Caminschi I (2009) The C-type lectin Clec12A present on mouse and human dendritic cells can serve as a target for antigen delivery and enhancement of antibody responses. J Immunol 182(12):7587–7594. doi: 10.4049/Jimmunol.0900464 CrossRefPubMedGoogle Scholar
  31. Lahoud MH, Ahmet F, Kitsoulis S, Wan SS, Vremec D, Lee CN, Phipson B, Shi W, Smyth GK, Lew AM, Kato Y, Mueller SN, Davey GM, Heath WR, Shortman K, Caminschi I (2011) Targeting antigen to mouse dendritic cells via Clec9A induces potent CD4 T cell responses biased toward a follicular helper phenotype. J Immunol 187(2):842–850. doi: 10.4049/Jimmunol.1101176 CrossRefPubMedGoogle Scholar
  32. Lanier LL (2003) Natural killer cell receptor signaling. Curr Opin Immunol 15(3):308–314CrossRefPubMedGoogle Scholar
  33. Larsen HO, Roug AS, Just T, Brown GD, Hokland P (2012) Expression of the hMICL in acute myeloid leukemia-a highly reliable disease marker at diagnosis and during follow-up. Cytometry B Clin Cytom 82(1):3–8. doi: 10.1002/cyto.b.20614 CrossRefPubMedGoogle Scholar
  34. Long EO (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70–84. doi: 10.1111/j.1600-065X.2008.00660.x CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lu H, Zhou Q, Deshmukh V, Phull H, Ma J, Tardif V, Naik RR, Bouvard C, Zhang Y, Choi S, Lawson BR, Zhu S, Kim CH, Schultz PG (2014) Targeting human C-type lectin-like molecule-1 (CLL1) with a bispecific antibody for immunotherapy of acute myeloid leukemia. Angew Chemie 53(37):9841–9845. doi: 10.1002/anie.201405353 CrossRefGoogle Scholar
  36. Marshall AS, Willment JA, Lin HH, Williams DL, Gordon S, Brown GD (2004) Identification and characterization of a novel human myeloid inhibitory C-type lectin-like receptor (MICL) that is predominantly expressed on granulocytes and monocytes. J Biol Chem 279(15):14792–14802. doi: 10.1074/jbc.M313127200 CrossRefPubMedGoogle Scholar
  37. Marshall ASJ, Willment JA, Pyz E, Dennehy KM, Reid DM, Dri P, Gordon S, Wong SYC, Brown GD (2006) Human MICL (CLEC12A) is differentially glycosylated and is down-regulated following cellular activation. Eur J Immunol 36(8):2159–2169. doi: 10.1002/Eji.200535628 CrossRefPubMedGoogle Scholar
  38. Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440(7081):237–241. doi: 10.1038/nature04516 CrossRefPubMedGoogle Scholar
  39. Mccarty DJ, Hollander JL (1961) Identification of urate crystals in gouty synovial fluid. Ann Intern Med 54(3):452CrossRefPubMedGoogle Scholar
  40. Miyake Y, Toyonaga K, Mori D, Kakuta S, Hoshino Y, Oyamada A, Yamada H, Ono KI, Suyama M, Iwakura Y, Yoshikai Y, Yamasaki S (2013) C-type lectin MCL is an FcR gamma-coupled receptor that mediates the adjuvanticity of mycobacterial cord factor. Immunity 38(5):1050–1062. doi: 10.1016/J.Immuni.2013.03.010 CrossRefPubMedGoogle Scholar
  41. Neumann K, Castineiras-Vilarino M, Hockendorf U, Hannesschlager N, Lemeer S, Kupka D, Meyermann S, Lech M, Anders HJ, Kuster B, Busch DH, Gewies A, Naumann R, Gross O, Ruland J (2014) Clec12a is an inhibitory receptor for uric acid crystals that regulates inflammation in response to cell death. Immunity 40(3):389–399. doi: 10.1016/J.Immuni.2013.12.015 CrossRefPubMedGoogle Scholar
  42. Ng G, Sharma K, Ward SM, Desrosiers MD, Stephens LA, Schoel WM, Li T, Lowell CA, Ling CC, Amrein MW, Shi Y (2008) Receptor-independent, direct membrane binding leads to cell-surface lipid sorting and Syk kinase activation in dendritic cells. Immunity 29(5):807–818. doi: 10.1016/j.immuni.2008.09.013 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Noordhuis P, Terwijn M, Rutten AP, Smit L, Ossenkoppele GJ, Schuurhuis GJ (2010) Targeting of CLEC12A in acute myeloid leukemia by antibody-drug-conjugates and bispecific CLL-1 x CD3 BiTE antibody. Blood 116(21):1191Google Scholar
  44. Pyz E, Huysamen C, Marshall ASJ, Gordon S, Taylor PR, Brown GD (2008) Characterisation of murine MICL (CLEC12A) and evidence for an endogenous ligand. Eur J Immunol 38(4):1157–1163. doi: 10.1002/Eji.200738057 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Reth M (1989) Antigen receptor tail clue. Nature 338(6214):383–384. doi: 10.1038/338383b0 CrossRefPubMedGoogle Scholar
  46. Roug AS, Larsen HO, Nederby L, Just T, Brown G, Nyvold CG, Ommen HB, Hokland P (2014) hMICL and CD123 in combination with a CD45/CD34/CD117 backbone – a universal marker combination for the detection of minimal residual disease in acute myeloid leukaemia. Br J Haematol 164(2):212–222. doi: 10.1111/bjh.12614 CrossRefPubMedGoogle Scholar
  47. Russell IJ, Mansen C, Kolb LM, Kolb WP (1982) Activation of the 5th component of human-complement (C5) induced by monosodium urate crystals – C5 convertase assembly on the crystal-surface. Clin Immunol Immunopathol 24(2):239–250. doi: 10.1016/0090-1229(82)90235-5 CrossRefPubMedGoogle Scholar
  48. Ryckman C, Gilbert C, de Medicis R, Lussier A, Vandal K, Tessier PA (2004) Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils. J Leukoc Biol 76(2):433–440. doi: 10.1189/jlb.0603294 CrossRefPubMedGoogle Scholar
  49. Sancho D, Joffre OP, Keller AM, Rogers NC, Martinez D, Hernanz-Falcon P, Rosewell I, Reis e Sousa C (2009) Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458(7240):899–903CrossRefPubMedPubMedCentralGoogle Scholar
  50. Savina A, Jancic C, Hugues S, Guermonprez P, Vargas P, Moura IC, Lennon-Dumenil AM, Seabra MC, Raposo G, Amigorena S (2006) NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126(1):205–218. doi: 10.1016/J.Cell.2006.05.035 CrossRefPubMedGoogle Scholar
  51. Scott P, Ma H, Viriyakosol S, Terkeltaub R, Liu-Bryan R (2006) Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol 177(9):6370–6378CrossRefPubMedGoogle Scholar
  52. Shi Y, Evans JE, Rock KL (2003) Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425(6957):516–521CrossRefPubMedGoogle Scholar
  53. Shi Y, Mucsi AD, Ng G (2010) Monosodium urate crystals in inflammation and immunity. Immunol Rev 233(1):203–217. doi: 10.1111/j.0105-2896.2009.00851.x CrossRefPubMedGoogle Scholar
  54. Shio MT, Eisenbarth SC, Savaria M, Vinet AF, Bellemare MJ, Harder KW, Sutterwala FS, Bohle DS, Descoteaux A, Flavell RA, Olivier M (2009) Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk Kinases. PLos Pathog 5(8). doi: 10.1371/Journal.Ppat.1000559 Google Scholar
  55. Tramontini N, Huber C, Liu-Bryan R, Terkeltaub RA, Kilgore KS (2004) Central role of complement membrane attack complex in monosodium urate crystal-induced neutrophilic rabbit knee synovitis. Arthritis Rheum 50(8):2633–2639. doi: 10.1002/art.20386 CrossRefPubMedGoogle Scholar
  56. van Rhenen A, van Dongen GA, Kelder A, Rombouts EJ, Feller N, Moshaver B, Stigter-van Walsum M, Zweegman S, Ossenkoppele GJ, Jan Schuurhuis G (2007) The novel AML stem cell associated antigen CLL-1 aids in discrimination between normal and leukemic stem cells. Blood 110(7):2659–2666. doi: 10.1182/blood-2007-03-083048 CrossRefPubMedGoogle Scholar
  57. Yamasaki S, Ishikawa E, Sakuma M, Hara H, Ogata K, Saito T (2008) Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol 9(10):1179–1188CrossRefPubMedGoogle Scholar
  58. Zelenay S, Keller AM, Whitney PG, Schraml BU, Deddouche S, Rogers NC, Schulz O, Sancho D, Reis e Sousa C (2012) The dendritic cell receptor DNGR-1 controls endocytic handling of necrotic cell antigens to favor cross-priming of CTLs in virus-infected mice. J Clin Invest 122(5):1615–1627. doi: 10.1172/JCI60644 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Zelensky AN, Gready JE (2005) The C-type lectin-like domain superfamily. FEBS J 272(24):6179–6217. doi: 10.1111/j.1742-4658.2005.05031.x CrossRefPubMedGoogle Scholar
  60. Zhang JG, Czabotar PE, Policheni AN, Caminschi I, Wan SS, Kitsoulis S, Tullett KM, Robin AY, Brammananth R, van Delft MF, Lu J, O’Reilly LA, Josefsson EC, Kile BT, Chin WJ, Mintern JD, Olshina MA, Wong W, Baum J, Wright MD, Huang DC, Mohandas N, Coppel RL, Colman PM, Nicola NA, Shortman K, Lahoud MH (2012) The dendritic cell receptor Clec9A binds damaged cells via exposed actin filaments. Immunity 36(4):646–657CrossRefPubMedGoogle Scholar
  61. Zhao X, Singh S, Pardoux C, Zhao J, Hsi ED, Abo A, Korver W (2010) Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia. Haematologica 95(1):71–78. doi: 10.3324/haematol.2009.009811 CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Japan 2016

Authors and Affiliations

  1. 1.Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany

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