Physiological and pathophysiolgical role of NF-kB signaling

Research

From molecular mechanisms of NF-kB activation to diverse pathophysiological mechanisms of the IKK/NF-kB systems

In our research group we focus on the physiological and pathophysiological mechanisms of the IKK/NF-kB signaling and gene regulation, in particular in the central nervous system (CNS) and pancreas.

The IKK/NF-kB signal transduction and transcription factor system represents a highly conserved signaling pathway in intervertebrates and vertebrates being active in every nucleated cell. Discovered in 1986 as nuclear factor in mature B-cells NF-kB is one of the most important inducible, gene regulating factors. NF-kB plays a role especially in regulation of inflammatory processes and immune responses, but is also critical for differentiation, proliferation and cellular survival mechanisms. IKK/NF-kB induces genetic programs which are necessary for processing different cellular stress situations. Pathogenesis of different diseases like Diabetes, neurodegenerative diseases such as Alzheimer´s disease, Parkinson´s disease and amytrophic lateral sclerosis (ALS), as well as developmental retardation and traumatic injuries therefore often arise from a dysregulation of the IKK/NF-kB system.

If there is a causal link between an altered IKK/NF-kB system and disease specific pathogenesis is one of the central research questions we are focusing on.

In detail, we are investigating the mechanisms of the IKK/NF-kB signaling pathway and its role in diseases using mainly conditional transgenic mouse models as well as cell culture systems with either activation or inhibition of NF-kB. Using combined protein biochemical, cell biological and histological methods we analyze to what extent this specific modulation of NF-kB affects the pathogenesis of disease or traumatic injury models (diabetes, traumatic brain injury (TBI)).

Recently we were able to show that inhibited NF-kB activation impairs synapse formation (Cell cell contact and signal transduction between neurons) resulting in learning deficits. On the other hand, overactivation of the NF-kB system in different cell types leads to severe inflammation and pathological consequences, also seen in inflammatory autoimmune diseases in humans. Chronical NF-kB activation in astrocytes causes inflammation of the brain, so called neuroinflammation. During development formation of hydrocephalus is observed along with other neurodegenerative alterations, whereas adult animals are affected by selective cerebral degeneration, also known from several auto immune diseases.

Overactivation of the NF-kB system in pancreas induces conditional to the cell type either pancreatitis or inflammatory devastation of islets of Langerhans, a new model for auto immune mediated type 1 diabetes. Interestingly, specific inhibition of NF-kB in beta cells of the pancreas also leads to a diabetic phenotype mimicking type 2 diabetes of humans. Both model systems are currently used to investigate mechanisms relevant for regeneration of diabetic beta cells.

In our projects concerning the role of the IKK/NF-kB system in the CNS we study to what extent IKK/NF-kB driven neuroinflammation determines disease progression of ALS and also especially post traumatic consequences after TBI. We are also interested in aging related processes, which are promoted by so called “Inflammaging”, a NF-kB regulated process.

For the long term, from our studies we hope to gain detailed insight into the cell and context specific mechanisms of the IKK/NF-kB system to be able to develop new targeted therapies for diseases like ALS and traumatic brain injury as well as healthy aging.

 

Role of NF-kB signaling for the development and progression of PDAC

Current work in our group focuses on the role of NF-kB and upstream kinases in the evolution of pancreatic ductal adenocarcinoma (PDAC).

Previously, we could show that the ablation of NEMO (IKKγ), a regulatory subunit of the IKK complex upstream of NF-kB, almost completely abolishes the occurrence of precancerous lesions in the pancreas. It appears that oncogenes like KRAS, which is mutated in 90% of pancreatic carcinomas, require the function of NF-kB to fully unfold their tumor-promoting effect resulting in inflammation, fibrosis, acinar-to-ductal metaplasia (ADM), and pancreatic intraepithelial neoplasia (PanIN) formation.

Chronic pancreatitis is an important risk factor for pancreatic carcinoma, which can be mimicked in experimental mouse models by repetitive injections of the cholecystokinin analogue caerulein. Interestingly, we observed that deletion of NEMO in pancreatic epithelial cells in the context of caerulein-induced pancreatitis has a negative outcome, leading to exacerbation of fibrosis and defects in regeneration. This suggests a protective effect of parenchymal NEMO during pancreatitis and emphasizes the complex and diverse functions of the IKK/NF-κB signaling pathway. Therefore, we are now addressing the question which function of NEMO – tumor-promoting or restraining – prevails in the combination of both situations, PDAC plus pancreatitis.

Another characteristic of PDAC is its tumor microenvironment. PDAC is a prototypical example of a cancer with extensive desmoplastic reaction, where cancer cells are often outnumbered by stromal components such as cancer associated fibroblasts (CAFs). PDAC CAFs are predominantly derived from pancreatic stellate cells (PSCs), lipid-storing cells in healthy pancreas which can transdifferentiate to an activated myofibroblast phenotype and are producing and remodeling ECM. There is a controversial discussion regarding the exact role of these CAFs in PDAC – heterogenous CAF subtypes were described that can both promote and restrain disease progression. Our approach is to modulate the NF-κB signaling pathway in PSCs and to investigate the consequences on development and progression of PDAC.

Recent Publications

IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization
Yang, S., Magnutzki, A., Alami, N. O., Lattke, M., Hein, T. M., Scheller, J. S., Kröger, C., Oswald, F., Yilmazer-Hanke, D., & Wirth, T
Cells. 2021 Oct 6;10(10):2669.doi: 10.3390/cells10102669

Deletion of NEMO Inhibits EMT and Reduces Metastasis in KPC Mice
Tsesmelis, M., Tiwary, K., Steiger, K., Sperb, N., Gerstenlauer, M., Manfras, U., Maier, H. J., Hermann, P. C., Chan, L. K., & Wirth, T
Cancers (Basel).2021 Sep 10;13(18):4541.doi: 10.3390/cancers13184541.

 

Age-Related Gliosis Promotes Central Nervous System Lymphoma through CCL19-Mediated Tumor Cell Retention.
O'Connor T, Zhou X, Kosla J, Adili A, Garcia Beccaria M, Kotsiliti E, Pfister D, Johlke AL, Sinha A, Sankowski R, Schick M, Lewis R, Dokalis N, Seubert B, Höchst B, Inverso D, Heide D, Zhang W, Weihrich P, Manske K, Wohlleber D, Anton M, Hoellein A, Seleznik G, Bremer J, Bleul S, Augustin HG, Scherer F, Koedel U, Weber A, Protzer U, Förster R, Wirth T, Aguzzi A, Meissner F, Prinz M, Baumann B, Höpken UE, Knolle PA, von Baumgarten L, Keller U, Heikenwalder M.
Cancer Cell. 2019 Sep 16;36(3):250-267.e9. doi: 10.1016/j.ccell.2019.08.001. PubMed PMID: 31526758.

Elevated β-cell stress levels promote severe diabetes development in mice with MODY4.
Trojanowski B, Salem HH, Neubauer H, Simon E, Wagner M, Dorajo R, Boehm BO, Labriola L, Wirth T, Baumann B.
J Endocrinol. 2019 Nov 1. pii: JOE-19-0208.R1. doi: 10.1530/JOE-19-0208.  

IKK2/NF-kB signaling protects neurons after traumatic brain injury.
Mettang M, Reichel SN, Lattke M, Palmer A, Abaei A, Rasche V, Huber-Lang M, Baumann B, Wirth T.
FASEB J. 2018 Apr;32(4):1916-1932. doi: 10.1096/fj.201700826R.

NF-kB activation in astrocytes drives a stage-specific beneficial neuroimmunological response in ALS.
Ouali Alami N, Schurr C, Olde Heuvel F, Tang L, Li Q, Tasdogan A, Kimbara A, Nettekoven M, Ottaviani G, Raposo C, Röver S, Rogers-Evans M, Rothenhäusler B, Ullmer C, Fingerle J, Grether U, Knuesel I, Boeckers TM, Ludolph A, Wirth T, Roselli F, Baumann B.EMBO J. 2018 Jun 6. pii: e98697. doi: 10.15252/embj.201798697.

Transient IKK2 activation in astrocytes initiates selective non-cell-autonomous neurodegeneration. 
Lattke M, Reichel SN, Magnutzki A, Abaei A, Rasche V, Walther P, Calado DP, Ferger B, Wirth T, Baumann B.;
Mol Neurodegener. 2017 Feb 13;12(1):16. doi: 10.1186/s13024-017-0157-0.

NF-kB-mediated astrocyte dysfunction initiates neurodegeneration.
Lattke M, Reichel SN, Baumann B.
Oncotarget. 2017 May 31;8(31)

Epithelial NEMO/IKKγ limits fibrosis and promotes regeneration during pancreatitis.
Chan LK, Gerstenlauer M, Konukiewitz B, Steiger K, Weichert W, Wirth T, Maier HJ.
Gut. 2017 Nov;66(11):1995-2007. doi: 10.1136/gutjnl-2015-311028. Epub 2016 Jul 27.

Requirement of NEMO/IKKγ for effective expansion of KRAS-induced precancerous lesions in the pancreas.
Maier HJ, Wagner M, Schips TG, Salem HH, Baumann B, Wirth T.
Oncogene. 2013 May 23;32(21):2690-5. doi: 10.1038/onc.2012.272. Epub 2012 Jul 2.

 

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