Regulation of neutrophil migration by tissue macrophages

• Applicant: Professor Dr. Daniel Robert Engel
• Subject Area: Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320670639

• Final Report Year: 2021

Final Report Abstract

In published preliminary findings we could show a close interaction of macrophages and neutrophils in an experimental urinary tract infection 1. The goal of this DFG funding was to characterize this interaction by state-of-the-art techniques, such as microscopy and mass spectrometry to further evaluate the interplay at the molecular level. The local mechanisms that enable this interaction could be investigated in the experimental urinary tract infection and in shiga toxin-mediated kidney damage. In the urinary tract infection model, we observed a local migration of macrophages into the infected urothelium that was dependent on the chemokine CX3CL1. Significant amounts of neutrophils are located at this site, so a potential interaction of both cells can be postulated. Indeed, aberrant interferon signaling could decrease neutrophil activation and the crosstalk with macrophages, so potentially macrophage-dependent regulation of interferon production could influence the interaction of both cells. These data thus suggest a context-dependent exchange of information that regulates the local interplay of both cell types at the infected foci. Furthermore, we investigated the role of the integrin CD11b in the model of shiga toxin-mediated kidney damage. Here we could show that macrophages mediate the regulation of CD11b on neutrophils and that this regulation is stimulated by the activation of macrophages and their production of TNFα. Thus, we postulate that the interaction of CD11b with ICAM-1 and thus the migration and recruitment of neutrophils in shiga toxin-mediated kidney injury is mediated by the interaction of macrophages with neutrophils. Technologically, these findings could be confirmed by intravital microscopy, mass spectrometry and cell-specific deletion approaches. It is important to note here that by studying the macrophage-neutrophil axis via the molecule TNFα, a first potential therapeutic option against shiga toxin-mediated kidney damage is now available. Thus, we were not only able to further decipher the cellular communication between macrophages and neutrophils, but also to identify a potential therapy for a usually severe disease via an already approved drug.

Publications

• Analysis and manipulation of cell-mediated immune responses in shiga toxin-induced kidney injury. PhD thesis
  Judith-Mira Pohl
  
• Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus. Gut, 12, 2110-2120 (2017)
  Pohl JM, Gutweiler S, Thiebes S, Volke J, Klein-Hitpass L, Zwanziger D, Gunzer M, Jung S, Agace W, Kurts C, Engel DR
  
• CCR2-dependent Gr1high monocytes promote kidney injury in shiga toxin-induced hemolytic uremic syndrome in mice. Eur J Immunol, 48, 990- 1000 (2018)
  Pohl JM, Volke JK, Thiebes S, Brenzel A, Fuchs K, Beziere N, Ehrlichmann W, Pichler BJ, Squire A, Gueler F, Engel DR
  
• Proliferation of Ly6C+ monocytes during urinary tract infections is regulated by IL-6 trans-signaling. J Leukoc Biol, 1, 13-22 (2018)
  Dixit A, Bottek J, Beerlage AL, Schuettpelz J, Thiebes S, Brenzel A, Garbers C, Rose-John S, Mittrücker HW, Squire A, Engel DR
  
• Neutrophil biology in chronic lymphocytic leukaemia and infections
  Vijitha, Nirojah
  
• Spatial proteomics revealed a CX3CL1-dependent crosstalk between the urothelium and relocated macrophages through IL-6 during an acute bacterial infection in the urinary bladder. Mucosal Immunol, 13, 702-714 (2020)
  Bottek J, Soun C, Lill JK, Dixit A, Thiebes S, Beerlage AL, Horstmann M, Urbanek A, Heuer H, Uszkoreit J, Eisenacher M, Bracht Th, Sitek B, Hoffmann F, Vijitha N, Eggeling F, Engel DR
  
• Proteomic and bioinformatic profiling of neutrophils in CLL reveals functional defects that predispose to bacterial infections. Blood Advances, 5, 1259–1272 (2021)
  Subramaniam N, Bottek J, Thiebes S, Zec K, Kudla M, Soun C, de Dios Panal E, Lill J K, Pfennig A, Herrmann R, Bruderek K, Rahmann S, Brandau S, Johansson P, Reinhardt H C, Dürig J, Seiffert M, Bracht T, Sitek B, Engel DR
  
• Tissueresident macrophages mediate neutrophil recruitment and kidney injury in shiga toxin-induced hemolytic uremic syndrome, Kidney Int (2021)
  Lill J K, Thiebes S, Pohl JM, Bottek J, Subramaniam N, Christ R, Soun C, Gueler F, Zwanziger D, Hoffmann F, Eggeling F, Bracht Th, Sitek B, Hickey M. J., Hofnagel O, Engel DR