Björn Schumacher / Ashley Williams - B 5

Chronic inflammatory responses to persistent cytoplasmic DNA

We have recently identified that DNase II-deficient C. elegans are hypersensitive to infection by uropathogenic E. coli isolated from human patients. In this project, we have started to illuminate the cellular and molecular underpinnings of this sensitivity. This characterisation has led to new insights into possible options for managing the detrimental outcomes of tissue degeneration associated with chronic inflammation.

Introduction 

Innate immune responses are important defence mechanisms against cellular damage and elevate stress resistance but when incorrectly regulated can lead to tissue damage through processes such as inflammation. In higher organisms, undigested cytoplasmic DNA can trigger inflammation that ultimately results in arthritis or heart failure in mammals. The inflammatory consequences are complex and simpler in vivo models could shed new light on how responses to cytoplasmic DNA lead to tissue damage. 

DNase II deficiency leads to an inflammation-like condition in C. elegans

We determined that DNase II deficiency in C. elegans leads to a systemic decline in tissue functionality in the presence of either pathogen-derived or artificially introduced cytoplasmic DNA in intestinal cells. Similar to clinical outcomes of chronic induction of innate immune responses in mammals, this response disrupts protein homeostasis in intestinal cells leading to tissue degeneration and functional declines and, ultimately, premature death. 

Therapeutic interventions to maintain proteostasis alleviate the inflammation-like condition

The negative outcomes of this inflammation-like condition can be overcome by alleviating protein-folding stress in the endoplasmic reticulum. We have identified two chemotherapeutic interventions, which whose mechanisms we have backed up using a genetic approach (see Figure 1).

Perspectives 

This project (i) establishes C. elegans as a simple metazoan system for investigating inflammation-like conditions, (ii) assigns the G-protein coupled receptor FSHR-1 as the mediator of an innate-immunity associated stress response (IIASE), (iii) implicates disrupted ER homeostasis as a contributor to inflammation-associated tissue declines, and (iv) shows that chemical induction of the UPRER or stimulation of protein folding can antagonize the inflammation-like condition and restore tissue function. We propose that these findings lay a strong foundation for translational studies to develop novel therapeutic approaches for the treatment of certain types of inflammatory conditions

Selected publications

Bianco J, Schumacher B. (2018) MPK-1/ERK pathway regulates DNA damage response during development through DAF-16/FOXO. Nucleic Acids Res.

Ou HL, Schumacher B. (2017) DNA damage responses and p53 in the aging process. Blood. 131: 488-495.

Edifizi D, Schumacher B. (2017) Omics Approaches for Identifying Physiological Adaptations to Genome Instability in Aging, Int. J. Mol. Sci. 18:2329.

Edifizi D, Nolte H, Babu V, Castells-Roca L, Mueller MM, Brodesser S, Krüger N, Schumacher B. (2017), Multilayered reprogramming in response to persistent DNA damage in C. elegans.  20(9): 2026-2043.


Prof. Dr. Björn Schumacher

Institute for Genome Stability in Ageing and Disease, CECAD Cologne

Prof. Dr. Björn Schumacher

Work +49 221 478 84202

CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne

http://schumacher.cecad-labs.uni-koeln.de/Home.66.0.html

Publications - Björn Schumacher

Link to PubMed


Dr. Ashley Williams

Inst. for Genome Stability in Aging and Disease and CECAD Cologne

Dr. Ashley Williams

Co-Principal Investigator B 5

awilliam@uni-koeln.de

Work +49 221 478 84205

CECAD Research Center
Joseph-Stelzmann-Str. 26
50931 Cologne

Publications - Ashley Williams

Link to PubMed

Figure 1

Model for the tissue functionality declines caused by persistent cytoplasmic DNA. Cytoplasmic DNA triggers an innate immunity-associated response that provides early protection against infection; however, when foreign DNA persists as a result of DNase II-deficiency, the chronic response results in an inflammation-like condition that causes disruption of the ER leading to declines in tissue functionality and ultimately reduced survival. Therapeutic activation of the endoplasmic reticulum unfolded protein response or augmentation of protein folding can rescue these tissue declines.