PhD defense by Thomas Holst-Hasen

Title: Inflammation – Modelling function and failure of the innate immune system

Inflammation is an intricate response relying on the activation and response of both the innate immune system and the infected tissue to remove a threat. The pro-inflammatory NF-kappaB pathway has been studied extensively, among others because of its key role in regulation of inflammation. However, the spatial aspects of the inflammatory response are poorly understood, mainly because of experimental limitations. My thesis consists of three studies of spatial communication through cytokine signalling and one study of bimodal receptor expression.

We showed with a reaction-diffusion model and experiments that the NF-kappaB pathway can function as a decoder of an external TNF stimulus. This leads to robust signalling which translates a local diffusing stimulus into a well-defined spatial response. We further showed that a macrophage can control the spatial range and severity of the inflammatory response by fine-tuning the amplitude and duration of TNF secretion.

We extended the model analysis to systems where NF-kappaB activation causes additional secretion of cytokine, creating a self-amplifying feedback loop. Depending on the strength of the positive feedback, this model will respond either transiently or persistently to an external stimulus. This reproduces a dual purpose of the pro-inflammatory cytokine IL-1beta in pancreatic islets, and the persistent state can be interpreted as part of type 2 diabetes pathogenesis. Because cytokine signalling occurs through diffusion, the geometrical configuration of the cytokine secreting cells will affect the collective dynamical behaviour. By describing cytokine-releasing cells as an excitable medium, we related medium size and density to a transition between a collective excitable and bistable state.

Finally, we considered how a single cell model of bistable phenotype expression leads to bimodal expression on a population level and how the distribution of phenotype expression is altered by gene copy number variations. We assumed that a positive feedback is responsible for the bistability at the single cell level and show that the position of the feedback relative to gene transcription gives three qualitatively different effects of copy number variations. This can be used to infer the position of a positive feedback based on qualitative differences in the phenotype expression of donors of different zygosity.