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Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins

Inflammation Research volume 63, pages 885–893 (2014)Cite this article

Abstract

Objective

Innate immune protein C1q plays a dual role in the chronic inflammatory disease of atherosclerosis. Complement activation via C1q exacerbates pathology in the atherosclerotic lesion in later stages of the disease. However, in early stages of disease C1q is protective. We hypothesize that complement-independent activities of C1q are involved in reprogramming macrophage inflammatory polarization.

Methods

The influence of C1q on macrophage inflammatory responses during clearance of oxLDL was examined. Changes in cytokines at the gene and protein level were measured by quantitative PCR and ELISA assay.

Results

C1q modulated cytokine expression in Raw264.7 macrophages during ingestion of oxLDL. Levels of pro-inflammatory cytokines IL-1β and IL-6 were downregulated by C1q, whereas levels of the anti-inflammatory cytokine IL-10 were increased. In addition, data from an NFκB-luciferase gene reporter assay suggest that C1q suppresses activation of NFκB during lipoprotein clearance in macrophages, providing one mechanism by which C1q downregulates pro-inflammatory cytokine production.

Conclusions

C1q-polarization of macrophages toward an anti-inflammatory (M2-like) phenotype may be important in dampening inflammation in the early atherosclerotic lesion. Further investigation of molecular pathways targeted by C1q may provide novel therapeutic targets for this disease.

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References

  1. Bohlson SS, Fraser DA, Tenner AJ. Complement proteins c1q and mbl are pattern recognition molecules that signal immediate and long-term protective immune functions. Mol Immunol. 2007;44:33–43.

    PubMed  Article  CAS  Google Scholar 

  2. Haskard DO, Boyle JJ, Mason JC. The role of complement in atherosclerosis. Curr Opin Lipidol. 2008;19:478–82.

    PubMed  Article  CAS  Google Scholar 

  3. Minino AM. Death in the United States, 2009. NCHS Data Brief. 2011;1–8.

  4. Yasojima K, Schwab C, McGeer EG, McGeer PL. Complement components, but not complement inhibitors, are upregulated in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001;21:1214–9.

    PubMed  Article  CAS  Google Scholar 

  5. Buono C, Come CE, Witztum JL, Maguire GF, Connelly PW, Carroll M, Lichtman AH. Influence of c3 deficiency on atherosclerosis. Circulation. 2002;105:3025–31.

    PubMed  Article  CAS  Google Scholar 

  6. Schmiedt W, Kinscherf R, Deigner HP, Kamencic H, Nauen O, Kilo J, Oelert H, Metz J, Bhakdi S. Complement c6 deficiency protects against diet-induced atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol. 1998;18:1790–5.

    PubMed  Article  CAS  Google Scholar 

  7. Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology. 1998;199:265–85.

    PubMed  Article  CAS  Google Scholar 

  8. Andres V, Pello OM, Silvestre-Roig C. Macrophage proliferation and apoptosis in atherosclerosis. Curr Opin Lipidol. 2012;23:429–38.

    PubMed  Article  CAS  Google Scholar 

  9. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. 2011;108:235–48.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  10. Kojima C, Ino J, Ishii H, Nitta K, Yoshida M. Mmp-9 inhibition by ace inhibitor reduces oxidized ldl-mediated foam-cell formation. J Atheroscler Thromb. 2010;17:97–105.

    PubMed  Article  CAS  Google Scholar 

  11. Tabas I. Cholesterol and phospholipid metabolism in macrophages. Biochim Biophys Acta. 2000;1529:164–74.

    PubMed  Article  CAS  Google Scholar 

  12. Hansson GK, Robertson AK, Soderberg-Naucler C. Inflammation and atherosclerosis. Annu Rev Pathol. 2006;1:297–329.

    PubMed  Article  CAS  Google Scholar 

  13. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E. Nlrp3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  14. Mantovani A, Garlanda C, Locati M. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arterioscler Thromb Vasc Biol. 2009;29:1419–23.

    PubMed  Article  CAS  Google Scholar 

  15. Pello OM, Silvestre C, De Pizzol M, Andres V. A glimpse on the phenomenon of macrophage polarization during atherosclerosis. Immunobiology. 2011;216:1172–6.

    PubMed  Article  CAS  Google Scholar 

  16. Feig JE, Rong JX, Shamir R, Sanson M, Vengrenyuk Y, Liu J, Rayner K, Moore K, Garabedian M, Fisher EA. Hdl promotes rapid atherosclerosis regression in mice and alters inflammatory properties of plaque monocyte-derived cells. Proc Natl Acad Sci USA. 2011;108:7166–71.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  17. Herranz S, Traves PG, Luque A, Hortelano S. Role of the tumor suppressor ARF in macrophage polarization: enhancement of the m2 phenotype in ARF-deficient mice. Oncoimmunology. 2012;1:1227–38.

    PubMed  Article  PubMed Central  Google Scholar 

  18. Raes G, Noel W, Beschin A, Brys L, de Baetselier P, Hassanzadeh GH. Fizz1 and ym as tools to discriminate between differentially activated macrophages. Dev Immunol. 2002;9:151–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  19. Stoger JL, Gijbels MJ, van der Velden S, Manca M, van der Loos CM, Biessen EA, Daemen MJ, Lutgens E, de Winther MP. Distribution of macrophage polarization markers in human atherosclerosis. Atherosclerosis. 2012;225:461–8.

    PubMed  Article  Google Scholar 

  20. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, Asano M, Moriwaki H, Seishima M. Lack of interleukin-1beta decreases the severity of atherosclerosis in apoE-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23:656–60.

    PubMed  Article  CAS  Google Scholar 

  21. Han X, Kitamoto S, Wang H, Boisvert WA. Interleukin-10 overexpression in macrophages suppresses atherosclerosis in hyperlipidemic mice. FASEB J. 2010;24:2869–80.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  22. Benoit ME, Clarke EV, Morgado P, Fraser DA, Tenner AJ. Complement protein c1q directs macrophage polarization and limits inflammasome activity during the uptake of apoptotic cells. J Immunol. 2012;188:5682–93.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  23. Fraser DA, Laust AK, Nelson EL, Tenner AJ. C1q differentially modulates phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells. J Immunol. 2009;183:6175–85.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  24. Fraser DA, Pisalyaput K, Tenner AJ. C1q enhances microglial clearance of apoptotic neurons and neuronal blebs, and modulates subsequent inflammatory cytokine production. J Neurochem. 2010;112:733–43.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  25. Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ. Homozygous c1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet. 1998;19:56–9.

    PubMed  Article  CAS  Google Scholar 

  26. de Winther MP, Kanters E, Kraal G, Hofker MH. Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol. 2005;25:904–14.

    PubMed  Article  Google Scholar 

  27. Fraser DA, Arora M, Bohlson SS, Lozano E, Tenner AJ. Generation of inhibitory nfkappaB complexes and phosphorylated camp response element-binding protein correlates with the anti-inflammatory activity of complement protein c1q in human monocytes. J Biol Chem. 2007;282:7360–7.

    PubMed  Article  CAS  Google Scholar 

  28. Adamson S, Leitinger N. Phenotypic modulation of macrophages in response to plaque lipids. Curr Opin Lipidol. 2011;22:335–42.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  29. Im SS, Yousef L, Blaschitz C, Liu JZ, Edwards RA, Young SG, Raffatellu M, Osborne TF. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab. 2011;13:540–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  30. Fraser DA, Tenner AJ. Innate immune proteins c1q and mannan-binding lectin enhance clearance of atherogenic lipoproteins by human monocytes and macrophages. J Immunol. 2010;185:3932–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  31. Petry F, Botto M, Holtappels R, Walport MJ, Loos M. Reconstitution of the complement function in c1q-deficient (c1qa−/−) mice with wild-type bone marrow cells. J Immunol. 2001;167:4033–7.

    PubMed  Article  CAS  Google Scholar 

  32. Greenlee MC, Sullivan SA, Bohlson SS. Detection and characterization of soluble cd93 released during inflammation. Inflamm Res. 2009;58:909–19.

    PubMed  Article  CAS  Google Scholar 

  33. Nauta AJ, Castellano G, Xu W, Woltman AM, Borrias MC, Daha MR, van Kooten C, Roos A. Opsonization with c1q and mannose-binding lectin targets apoptotic cells to dendritic cells. J Immunol. 2004;173:3044–50.

    PubMed  Article  CAS  Google Scholar 

  34. Nauta AJ, Raaschou-Jensen N, Roos A, Daha MR, Madsen HO, Borrias-Essers MC, Ryder LP, Koch C, Garred P. Mannose-binding lectin engagement with late apoptotic and necrotic cells. Eur J Immunol. 2003;33:2853–63.

    PubMed  Article  CAS  Google Scholar 

  35. Korb LC, Ahearn JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol. 1997;158:4525–8.

    PubMed  CAS  Google Scholar 

  36. Monaco C, Paleolog E. Nuclear factor kappaB: a potential therapeutic target in atherosclerosis and thrombosis. Cardiovasc Res. 2004;61:671–82.

    PubMed  Article  CAS  Google Scholar 

  37. Bhatia VK, Yun S, Leung V, Grimsditch DC, Benson GM, Botto MB, Boyle JJ, Haskard DO. Complement c1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice. Am J Pathol. 2007;170:416–26.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  38. Galvan MD, Greenlee-Wacker MC, Bohlson SS. C1q and phagocytosis: the perfect complement to a good meal. J Leukoc Biol. 2012;92:489–97.

    PubMed  Article  CAS  Google Scholar 

  39. Fraser DA, Tenner AJ. Directing an appropriate immune response: the role of defense collagens and other soluble pattern recognition molecules. Curr Drug Targets. 2008;9:113–22.

    PubMed  Article  CAS  Google Scholar 

  40. Galvan MD, Foreman DB, Zeng E, Tan JC, Bohlson SS. Complement component c1q regulates macrophage expression of mer tyrosine kinase to promote clearance of apoptotic cells. J Immunol. 2012;188:3716–23.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  41. Jiang Y, Wang M, Huang K, Zhang Z, Shao N, Zhang Y, Wang W, Wang S. Oxidized low-density lipoprotein induces secretion of interleukin-1beta by macrophages via reactive oxygen species-dependent NLRP3 inflammasome activation. Biochem Biophys Res Commun. 2012;425:121–6.

    PubMed  Article  CAS  Google Scholar 

  42. Kannan Y, Sundaram K, Aluganti Narasimhulu C, Parthasarathy S, Wewers MD. Oxidatively modified low density lipoprotein (ldl) inhibits tlr2 and tlr4 cytokine responses in human monocytes but not in macrophages. J Biol Chem. 2012;287:23479–88.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  43. Min KJ, Cho KH, Kwon TK. The effect of oxidized low density lipoprotein (oxldl)-induced heme oxygenase-1 on lps-induced inflammation in raw 264.7 macrophage cells. Cell Signal. 2012;24:1215–21.

    PubMed  Article  CAS  Google Scholar 

  44. Hartman J, Frishman WH. Inflammation and atherosclerosis: a review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev. 2014;22:147–51.

    PubMed  Article  Google Scholar 

  45. Lawrence T. The nuclear factor nf-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1:a001651.

    PubMed  Article  PubMed Central  Google Scholar 

  46. Cominacini L, Pasini AF, Garbin U, Davoli A, Tosetti ML, Campagnola M, Rigoni A, Pastorino AM, Lo Cascio V, Sawamura T. Oxidized low density lipoprotein (ox-ldl) binding to ox-ldl receptor-1 in endothelial cells induces the activation of nf-kappaB through an increased production of intracellular reactive oxygen species. J Biol Chem. 2000;275:12633–8.

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to Christopher Quan and Minh-Minh Ho for technical assistance. Some of the research reported in this publication was supported by a CSULB-RISE grant to P.M. via the National Institute of General Medical Sciences of the National Institutes of Health under Award Number 5R25GM071638.

Conflict of interest

The authors declare no conflict of interest.

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Affiliations

  1. Department of Biological Sciences, California State University Long Beach, 1250 Bellflower Blvd, Long Beach, CA, 90840, USA

    Weston Spivia, Patrick S. Magno, Patrick Le & Deborah A. Fraser

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  1. Weston Spivia
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  2. Patrick S. Magno
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  3. Patrick Le
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  4. Deborah A. Fraser
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Correspondence to Deborah A. Fraser.

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Responsible Editor: Liwu Li.

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Spivia, W., Magno, P.S., Le, P. et al. Complement protein C1q promotes macrophage anti-inflammatory M2-like polarization during the clearance of atherogenic lipoproteins. Inflamm. Res. 63, 885–893 (2014). https://doi.org/10.1007/s00011-014-0762-0

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  • DOI: https://doi.org/10.1007/s00011-014-0762-0

Keywords

  • Complement
  • Macrophage
  • Cytokine
  • Innate immunity
  • Atherosclerosis
  • Oxidized LDL