Skip to main content
SpringerLink
Log in

Innate signaling mechanisms controlling Mycobacterium chelonae-mediated CCL2 and CCL5 expression in macrophages

  • Microbial Pathogenesis and Host-Microbe Interaction
  • Published:
Journal of Microbiology Aims and scope Submit manuscript

Abstract

Mycobacterium chelonae (Mch) is an atypical rapidly growing mycobacterium (RGM) that belongs to the M. chelonae complex, which can cause a variety of human infections. During this type of mycobacterial infection, macrophagederived chemokines play an important role in the mediation of intracellular communication and immune surveillance by which they orchestrate cellular immunity. However, the intracellular signaling pathways involved in the macrophage- induced chemokine production during Mch infections remain unknown. Thus, the present study aimed to determine the molecular mechanisms by which Mch activates the gene expressions of chemokine (C-C motif) ligand 2 (CCL2) and CCL5 in murine bone marrow-derived macrophages (BMDMs) and in vivo mouse model. Toll-like receptor 2 (TLR2)-deficient mice showed increased bacterial burden in spleen and lung and decreased protein expression of CCL2 and CCL5 in serum. Additionally, Mch infection triggered the mRNA and protein expression of CCL2 and CCL5 in BMDMs via TLR2 and myeloid differentiation primary response gene 88 (MyD88) signaling and that it rapidly activated nuclear factor (NF)-κB signaling, which is required for the Mch-induced expressions of CCL2 and CCL5 in BMDMs. Moreover, while the innate receptor Dectin-1 was only partly involved in the Mch-induced expression of the CCL2 and CCL5 chemokines in BMDMs, the generation of intracellular reactive oxygen species (ROS) was an important contributor to these processes. Taken together, the present data indicate that the TLR2, MyD88, and NF-κB pathways, Dectin-1 signaling, and intracellular ROS generation contribute to the Mch-mediated expression of chemokine genes in BMDMs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Alqumber, M.A., Mandal, R.K., Haque, S., Panda, A.K., Akhter, N., and Ali, A. 2013. A genetic association study of CCL5 -28 C>G (rs2280788) polymorphism with risk of tuberculosis: A meta-analysis. PLoS One 8, e83422.

    Article  PubMed Central  PubMed  Google Scholar 

  • Alvarez-Uria, G. 2010. Lung disease caused by nontuberculous mycobacteria. Curr. Opin. Pulm. Med. 16, 251–256.

    PubMed  Google Scholar 

  • Ansari, A.W., Kamarulzaman, A., and Schmidt, R.E. 2013. Multifaceted impact of host C-C chemokine CCL2 in the immunopathogenesis of HIV-1/M. tuberculosis co-infection. Front. Immunol. 4, 312.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bae, Y.S., Oh, H., Rhee, S.G., and Yoo, Y.D. 2011. Regulation of reactive oxygen species generation in cell signaling. Mol. Cells 32, 491–509.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Basu, J., Shin, D.M., and Jo, E.K. 2012. Mycobacterial signaling through toll-like receptors. Front. Cell. Infect. Microbiol. 2, 145.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bernatoniene, J., Zhang, Q., Dogan, S., Mitchell, T.J., Paton, J.C., and Finn, A. 2008. Induction of CC and CXC chemokines in human antigen-presenting dendritic cells by the pneumococcal proteins pneumolysin and CbpA, and the role played by tolllike receptor 4, NF-kappaB, and mitogen-activated protein kinases. J. Infect. Dis. 198, 1823–1833.

    Article  CAS  PubMed  Google Scholar 

  • Bulua, A.C., Simon, A., Maddipati, R., Pelletier, M., Park, H., Kim, K.Y., Sack, M.N., Kastner, D.L., and Siegel, R.M. 2011. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPs). J. Exp. Med. 208, 519–533.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cassidy, P.M., Hedberg, K., Saulson, A., McNelly, E., and Winthrop, K.L. 2009. Nontuberculous mycobacterial disease prevalence and risk factors: A changing epidemiology. Clin. Infect. Dis. 49, e124–129.

    Article  Google Scholar 

  • Chan, E.D., Bai, X., Kartalija, M., Orme, I.M., and Ordway, D.J. 2010. Host immune response to rapidly growing mycobacteria, an emerging cause of chronic lung disease. Am. J. Respir. Cell Mol. Biol. 43, 387–393.

    Article  CAS  PubMed  Google Scholar 

  • Chen, B., Guan, D., Cui, Z.J., Wang, X., and Shen, X. 2010. Thioredoxin 1 downregulates MCP-1 secretion and expression in human endothelial cells by suppressing nuclear translocation of activator protein 1 and redox factor-1. Am. J. Physiol. Cell Physiol. 298, C1170–1179.

    Article  Google Scholar 

  • Daley, C.L. and Griffith, D.E. 2010. Pulmonary non-tuberculous mycobacterial infections. Int. J. Tuberc. Lung Dis. 14, 665–671.

    CAS  PubMed  Google Scholar 

  • Dorhoi, A., Yeremeev, V., Nouailles, G., Weiner, J., 3rd, Jorg, S., Heinemann, E., Oberbeck-Muller, D., Knaul, J.K., Vogelzang, A., Reece, S.T., et al. 2014. Type I IFN signaling triggers immunopathology in tuberculosis-susceptible mice by modulating lung phagocyte dynamics. Eur. J. Immunol. 44, 2380–2393.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Falkinham, J.O., 3rd. 2009. Surrounded by mycobacteria: Nontuberculous mycobacteria in the human environment. J. Appl. Microbiol. 107, 356–367.

    Article  CAS  PubMed  Google Scholar 

  • Glass, W.G., Rosenberg, H.F., and Murphy, P.M. 2003. Chemokine regulation of inflammation during acute viral infection. Curr. Opin. Allergy Clin. Immunol. 3, 467–473.

    Article  CAS  PubMed  Google Scholar 

  • Gomes, A., Fernandes, E., and Lima, J.L. 2005. Fluorescence probes used for detection of reactive oxygen species. J. Biochem. Biophys. Methods 65, 45–80.

    Article  CAS  PubMed  Google Scholar 

  • Gong, T., Yang, M., Qi, L., Shen, M., and Du, Y. 2013. Association of MCP-1–2518A/G and -362G/C variants and tuberculosis susceptibility: A meta-analysis. Infect. Genet. Evol. 20, 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Hasan, Z., Cliff, J.M., Dockrell, H.M., Jamil, B., Irfan, M., Ashraf, M., and Hussain, R. 2009. CCL2 responses to Mycobacterium tuberculosis are associated with disease severity in tuberculosis. PLoS One 4, e8459.

    Article  PubMed Central  PubMed  Google Scholar 

  • Jo, E.K., Yang, C.S., Choi, C.H., and Harding, C.V. 2007. Intracellular signalling cascades regulating innate immune responses to mycobacteria: Branching out from toll-like receptors. Cell. Microbiol. 9, 1087–1098.

    Article  CAS  PubMed  Google Scholar 

  • Karin, M. and Delhase, M. 2000. The I kappa B kinase (IKK) and NF-kappa B: Key elements of proinflammatory signalling. Semin. Immunol. 12, 85–98.

    Article  CAS  PubMed  Google Scholar 

  • Kato, S., Yuzawa, Y., Tsuboi, N., Maruyama, S., Morita, Y., Matsuguchi, T., and Matsuo, S. 2004. Endotoxin-induced chemokine expression in murine peritoneal mesothelial cells: The role of toll-like receptor 4. J. Am. Soc. Nephrol. 15, 1289–1299.

    CAS  PubMed  Google Scholar 

  • Kim, K.H., Kim, T.S., Lee, J.G., Park, J.K., Yang, M., Kim, J.M., Jo, E.K., and Yuk, J.M. 2014a. Characterization of proinflammatory responses and innate signaling activation in macrophages infected with Mycobacterium scrofulaceum. Immune Netw. 14, 307–320.

    Article  PubMed Central  PubMed  Google Scholar 

  • Kim, T.S., Kim, Y.S., Yoo, H., Park, Y.K., and Jo, E.K. 2014b. Mycobacterium massiliense induces inflammatory responses in macrophages through Toll-like receptor 2 and c-Jun N-terminal kinase. J. Clin. Immunol. 34, 212–223.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kim, T.S., Lee, H.M., Yoo, H., Park, Y.K., and Jo, E.K. 2012. Intracellular signaling pathways that regulate macrophage chemokine expression in response to Mycobacterium abscessus. J. Bacteriol. Virol. 42, 121–132.

    Article  CAS  Google Scholar 

  • Kumar, M.G., Patel, N.M., Nicholson, A.M., Kalen, A.L., Sarsour, E.H., and Goswami, P.C. 2012. Reactive oxygen species mediate microRNA-302 regulation of AT-rich interacting domain 4a and C-C motif ligand 5 expression during transitions between quiescence and proliferation. Free Radic. Biol. Med. 53, 974–982.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Laroux, F.S., Romero, X., Wetzler, L., Engel, P., and Terhorst, C. 2005. Cutting edge: MyD88 controls phagocyte NADPH oxidase function and killing of Gram-negative bacteria. J. Immunol. 175, 5596–5600.

    Article  CAS  PubMed  Google Scholar 

  • Lee, J.G., Lee, S.H., Park, D.W., Lee, S.H., Yoon, H.S., Chin, B.R., Kim, J.H., Kim, J.R., and Baek, S.H. 2008. Toll-like receptor 9-stimulated monocyte chemoattractant protein-1 is mediated via JNK-cytosolic phospholipase A2-ROS signaling. Cell. Signal. 20, 105–111.

    Article  CAS  PubMed  Google Scholar 

  • Lee, H.M., Shin, D.M., Kim, K.K., Lee, J.S., Paik, T.H., and Jo, E.K. 2009a. Roles of reactive oxygen species in CXCL8 and CCL2 expression in response to the 30-kDa antigen of Mycobacterium tuberculosis. J. Clin. Immunol. 29, 46–56.

    Article  CAS  PubMed  Google Scholar 

  • Lee, H.M., Yuk, J.M., Shin, D.M., and Jo, E.K. 2009b. Dectin-1 is inducible and plays an essential role for mycobacteria-induced innate immune responses in airway epithelial cells. J. Clin. Immunol. 29, 795–805.

    Article  CAS  PubMed  Google Scholar 

  • Madrigal, J.L. and Caso, J.R. 2014. The chemokine (C-C motif) ligand 2 in neuroinflammation and neurodegeneration. Adv. Exp. Med. Biol. 824, 209–219.

    Article  CAS  PubMed  Google Scholar 

  • Monin, L. and Khader, S.A. 2014. Chemokines in tuberculosis: The good, the bad and the ugly. Semin. Immunol. 26, 552–558.

    Article  CAS  PubMed  Google Scholar 

  • Mortaz, E., Adcock, I.M., Tabarsi, P., Masjedi, M.R., Mansouri, D., Velayati, A.A., Casanova, J.L., and Barnes, P.J. 2015. Interaction of pattern recognition receptors with Mycobacterium tuberculosis. J. Clin. Immunol. 35, 1–10.

    Article  PubMed Central  CAS  Google Scholar 

  • Moser, B., Wolf, M., Walz, A., and Loetscher, P. 2004. Chemokines: Multiple levels of leukocyte migration control. Trends Immunol. 25, 75–84.

    Article  CAS  PubMed  Google Scholar 

  • Ono, S.J., Nakamura, T., Miyazaki, D., Ohbayashi, M., Dawson, M., and Toda, M. 2003. Chemokines: Roles in leukocyte development, trafficking, and effector function. J. Allergy Clin. Immunol. 111, 1185–1199; quiz 1200.

    Article  CAS  PubMed  Google Scholar 

  • Park, Y.S., Lee, C.H., Lee, S.M., Yang, S.C., Yoo, C.G., Kim, Y.W., Han, S.K., Shim, Y.S., and Yim, J.J. 2010. Rapid increase of non-tuberculous mycobacterial lung diseases at a tertiary referral hospital in South Korea. Int. J. Tuberc. Lung Dis. 14, 1069–1071.

    CAS  PubMed  Google Scholar 

  • Pathak, S.K., Bhattacharyya, A., Pathak, S., Basak, C., Mandal, D., Kundu, M., and Basu, J. 2004. Toll-like receptor 2 and mitogenand stress-activated kinase 1 are effectors of Mycobacterium avium-induced cyclooxygenase-2 expression in macrophages. J. Biol. Chem. 279, 55127–55136.

    Article  CAS  PubMed  Google Scholar 

  • Plato, A., Willment, J.A., and Brown, G.D. 2013. C-type lectin-like receptors of the dectin-1 cluster: Ligands and signaling pathways. Int. Rev. Immunol. 32, 134–156.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Power, M.R., Li, B., Yamamoto, M., Akira, S., and Lin, T.J. 2007. A role of Toll-IL-1 receptor domain-containing adaptor-inducing IFN-beta in the host response to Pseudomonas aeruginosa lung infection in mice. J. Immunol. 178, 3170–3176.

    Article  CAS  PubMed  Google Scholar 

  • Quesniaux, V., Fremond, C., Jacobs, M., Parida, S., Nicolle, D., Yeremeev, V., Bihl, F., Erard, F., Botha, T., Drennan, M., et al. 2004a. Toll-like receptor pathways in the immune responses to mycobacteria. Microbes Infect. 6, 946–959.

    Article  CAS  PubMed  Google Scholar 

  • Quesniaux, V.J., Nicolle, D.M., Torres, D., Kremer, L., Guerardel, Y., Nigou, J., Puzo, G., Erard, F., and Ryffel, B. 2004b. Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independentnegative regulation of proinflammatory cytokines by mycobacterial lipomannans. J. Immunol. 172, 4425–4434.

    Article  CAS  PubMed  Google Scholar 

  • Ringuet, H., Akoua-Koffi, C., Honore, S., Varnerot, A., Vincent, V., Berche, P., Gaillard, J.L., and Pierre-Audigier, C. 1999. Hsp65 sequencing for identification of rapidly growing mycobacteria. J. Clin. Microbiol. 37, 852–857.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rottman, M., Catherinot, E., Hochedez, P., Emile, J.F., Casanova, J.L., Gaillard, J.L., and Soudais, C. 2007. Importance of T cells, gamma interferon, and tumor necrosis factor in immune control of the rapid grower Mycobacterium abscessus in C57BL/6 mice. Infect. Immun. 75, 5898–5907.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sadek, M.I., Sada, E., Toossi, Z., Schwander, S.K., and Rich, E.A. 1998. Chemokines induced by infection of mononuclear phagocytes with mycobacteria and present in lung alveoli during active pulmonary tuberculosis. Am. J. Respir. Cell Mol. Biol. 19, 513–521.

    Article  CAS  PubMed  Google Scholar 

  • Schorey, J.S. and Lawrence, C. 2008. The pattern recognition receptor Dectin-1: from fungi to mycobacteria. Curr. Drug Targets 9, 123–129.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Shin, D.M., Yang, C.S., Yuk, J.M., Lee, J.Y., Kim, K.H., Shin, S.J., Takahara, K., Lee, S.J., and Jo, E.K. 2008. Mycobacterium abscessus activates the macrophage innate immune response via a physical and functional interaction between TLR2 and dectin-1. Cell. Microbiol. 10, 1608–1621.

    Article  CAS  PubMed  Google Scholar 

  • Simons, S., van Ingen, J., Hsueh, P.R., Van Hung, N., Dekhuijzen, P.N., Boeree, M.J., and van Soolingen, D. 2011. Nontuberculous mycobacteria in respiratory tract infections, eastern Asia. Emer. Infect. Diseases 17, 343–349.

    Article  Google Scholar 

  • Torraca, V., Cui, C., Boland, R., Bebelman, J.P., van der Sar, A.M., Smit, M.J., Siderius, M., Spaink, H.P., and Meijer, A.H. 2015. The CXCR3-CXCL11 signaling axis mediates macrophage recruitment and dissemination of mycobacterial infection. Dis. Model. Mech. 8, 253–269.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tsuboi, N., Yoshikai, Y., Matsuo, S., Kikuchi, T., Iwami, K., Nagai, Y., Takeuchi, O., Akira, S., and Matsuguchi, T. 2002. Roles of toll-like receptors in C-C chemokine production by renal tubular epithelial cells. J. Immunol. 169, 2026–2033.

    Article  CAS  PubMed  Google Scholar 

  • Vignal, C., Guerardel, Y., Kremer, L., Masson, M., Legrand, D., Mazurier, J., and Elass, E. 2003. Lipomannans, but not lipoarabinomannans, purified from Mycobacterium chelonae and Mycobacterium kansasii induce TNF-a and IL-8 secretion by a CD14-toll-like receptor 2-dependent mechanism. J. Immunol. 171, 2014–2023.

    Article  CAS  PubMed  Google Scholar 

  • Yadav, M. and Schorey, J.S. 2006. The ß-glucan receptor dectin-1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108, 3168–3175.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yang, C.S., Lee, H.M., Lee, J.Y., Kim, J.A., Lee, S.J., Shin, D.M., Lee, Y.H., Lee, D.S., El-Benna, J., and Jo, E.K. 2007. Reactive oxygen species and p47phox activation are essential for the Mycobacterium tuberculosis-induced pro-inflammatory response in murine microglia. J. Neuroinflammation 4, 27.

    Article  PubMed Central  PubMed  Google Scholar 

  • Yang, C.S., Lee, J.S., Rodgers, M., Min, C.K., Lee, J.Y., Kim, H.J., Lee, K.H., Kim, C.J., Oh, B., Zandi, E., et al. 2012. Autophagy protein rubicon mediates phagocytic NADPH oxidase activation in response to microbial infection or TLR stimulation. Cell Host Microbe 11, 264–276.

    Article  PubMed Central  PubMed  Google Scholar 

  • Yang, C.S., Shin, D.M., Kim, K.H., Lee, Z.W., Lee, C.H., Park, S.G., Bae, Y.S., and Jo, E.K. 2009. NADPH oxidase 2 interaction with TLR2 is required for efficient innate immune responses to mycobacteria via cathelicidin expression. J. Immunol. 182, 3696–3705.

    Article  CAS  PubMed  Google Scholar 

  • Yim, J.J., Kim, H.J., Kwon, O.J., and Koh, W.J. 2008. Association between microsatellite polymorphisms in intron IIof the human Toll-like receptor 2 gene and nontuberculous mycobacterial lung disease in a Korean population. Hum. Immunol. 69, 572–576.

    Article  CAS  PubMed  Google Scholar 

  • Yu, H.B., Yurieva, M., Balachander, A., Foo, I., Leong, X., Zelante, T., Zolezzi, F., Poidinger, M., and Ricciardi-Castagnoli, P. 2015. NFATc2 mediates epigenetic modification of dendritic cell cytokine and chemokine responses to dectin-1 stimulation. Nucleic Acids Res. 43, 836–847.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yuk, J.M. and Jo, E.K. 2011. Toll-like receptors and innate immunity. J. Bacteriol. Virol. 41, 225–235.

    Article  CAS  Google Scholar 

  • Yuk, J.M., Shin, D.M., Lee, H.M., Kim, J.J., Kim, S.W., Jin, H.S., Yang, C.S., Park, K.A., Chanda, D., Kim, D.K., et al. 2011. The orphan nuclear receptor SHP acts as a negative regulator in inflammatory signaling triggered by toll-like receptors. Nat. Immunol. 12, 742–751.

    Article  CAS  PubMed  Google Scholar 

  • Yuk, J.M., Shin, D.M., Lee, H.M., Yang, C.S., Jin, H.S., Kim, K.K., Lee, Z.W., Lee, S.H., Kim, J.M., and Jo, E.K. 2009. Vitamin D3 induces autophagy in human monocytes/macrophages via cathelicidin. Cell Host Microbe 6, 231–243.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Microbiology, College of Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea

    Yi Sak Kim, Tae-sung Kim & Eun-Kyeong Jo

  2. Infection Biology, College of Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea

    Ji Hye Kim, Tae-sung Kim, Young-Ha Lee & Jae-Min Yuk

  3. Infection Signaling Network Research Center, College of Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea

    Yi Sak Kim, Ji Hye Kim, Young-Ha Lee, Eun-Kyeong Jo & Jae-Min Yuk

  4. Institute Pasteur Korea, Seongnam, 13488, Republic of Korea

    Minjeong Woo

  5. Division of Infectious Diseases, Chungnam National University Hospital, Daejeon, 34134, Republic of Korea

    Kyung Mok Sohn

Authors
  1. Yi Sak Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji Hye Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Minjeong Woo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tae-sung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyung Mok Sohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Young-Ha Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eun-Kyeong Jo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jae-Min Yuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae-Min Yuk.

Additional information

These authors contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, Y.S., Kim, J.H., Woo, M. et al. Innate signaling mechanisms controlling Mycobacterium chelonae-mediated CCL2 and CCL5 expression in macrophages. J Microbiol. 53, 864–874 (2015). https://doi.org/10.1007/s12275-015-5348-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12275-015-5348-1

Keywords

Search

Navigation