Control of circadian lymphocyte migration in lymphoid and non-lymphoid tissues by the sympathetic nervous system

Final Report Abstract

The recruitment of hematopoietic cells plays a crucial role in the immune response. In this proposal we have investigated whether circadian and neural influences regulate the migration of leukocytes to tissues. We could demonstrate that migratory oscillations of leukocytes exist for myeloid cells and lymphocytes into lymphoid and non-lymphoid organs. We could further show that also the egress from lymph nodes is dictated by the time of day. We have in this proposal demonstrated that even weeks after antigen exposure the adaptive immune response is governed by the specific time of day when the initial stimulus was applied. Mechanistically, we showed that deficiency in key clock genes in different leukocyte lineages ablates rhythmicity. Our data enforce the emerging paradigm that a properly tuned adaptive immune response is critical in immunity. Circadian, ~24 hour rhythms are emerging as critical regulators of immune cell function, which impacts innate and adaptive inflammatory diseases. Inducing or inhibiting adaptive immunity at the proper times provides an option for therapy that would maximize the clinical impact of drugs and vaccinations and minimize side effects.

Publications

• Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013 502:637-43
  Kunisaki, Y., Bruns, I., Scheiermann, C., Ahmed, J., Pinho, S., Zhang, D., Mizoguchi, T., Wei, Q., Lucas, D., Ito, K., Mar, J. C., Bergman, A., and Frenette, P. S.
  
• Circadian control of the immune system. Nat. Rev. Immunol. 2013 13:190-8
  Scheiermann, C., Kunisaki Y., and Frenette, P. S.
  
• Some monocytes got rhythm. Science. 2013 341:1462-4
  Druzd, D. and Scheiermann, C.
  
• Megakaryocytes regulate haematopoietic stem cell quiescence via Cxcl4 secretion. Nat. Med. 2014 20:1315-20
  Bruns, I., Lucas, D., Pinho, S., Ahmed, J., Lambert, M. P., Kunisaki, K., Scheiermann, C., Schiff, L., Poncz, M., Bergman, A., and Frenette, P. S.
  
• Neutrophil ageing is regulated by the microbiome. Nature. 2015 525:528-32
  Zhang, D., Chen, G., Manwani, D., Mortha, A., Xu, C., Faith, J. J., Burk, R. D., Kunisaki, Y., Jang, J. E., Scheiermann, C., Merad, M., and Frenette, P. S.
  
• Cathepsin G Controls Arterial But Not Venular Myeloid Cell Recruitment. Circulation. 2016 134:1176-1188
  Ortega-Gomez, A., Salvermoser, M., Rossaint, J., Pick, R., Brauner, J., Lemnitzer, P., Tilgner, J., de Jong, R.J., Megens, R.T., Jamasbi, J., Döring, Y., Pham, C.T., Scheiermann, C., Siess, W., Drechsler, M., Weber, C., Grommes, J., Zarbock, A., Walzog, B. and Soehnlein, O.
  
• Lymphocyte circadian clocks control lymph node trafficking and adaptive immune responses. Immunity. 2017 46:120-132
  Druzd, D., Matveeva, O., Ince, L., Harrison, U., He, W., Schmal, C., Herzel, H., Tsang, A., Kawakami, N., Leliavski, A., Uhl, U., Yao, L., Sander, L., Chen, C., Kraus, K., de Juan, A., Hergenhan, S., Ehlers, M., Koletzko, B., Haas, R., Solbach, W., Oster, H. and Scheiermann, C.
  
• Chrono-pharmacological Targeting of the CCL2- CCR2 Axis Ameliorates Atherosclerosis. 2018 Cell Metab. 28:175-182
  Winter, C., Silvestre-Roig, C., Ortega-Gomez, A., Lemnitzer, P., Poelman, H., Schumski, A., Winter, J., Drechsler, M., de Jong, R., Immler, R., Sperandio, M., Hristov, M., Zeller, T., Nicolaes, G.A.F., Weber, C., Viola, J.R., Hidalgo, A., Scheiermann, C., and Soehnlein, O.
  
• Circadian expression of migratory factors establishes lineage specific signatures that guide the homing of leukocyte subsets to tissues. Immunity. 2018 49:1175-1190
  He, W., Holtkamp, S., Hergenhan, S.M., Kraus, K., de Juan, A., Weber, J., Bradfield, P., Grenier, J., Pelletier, J., Druzd, D., Chen, C., Ince, L., Bierschenk, S., Pick, R., Sperandio, M., Aurrand-Lions, M., and Scheiermann, C.
  
• Clocking in to immunity. Nat. Rev. Immunol. 2018 18:423-437
  Scheiermann, C., Gibbs, J., Ince, L., Loudon, A.