Microplastics, microglia, behavioural research in mice, immune cell infiltration and the Alzheimer’s brain (left to right). Inflammation is a fascinating subject to research. Inflammation can contribute to disease but it can also fight off infection and organize the body to begin repair. Adjusting the inflammatory response may be the key to treating numerous diseases

I am a lecturer at the University of Tasmania investigating the innate immune system with a  particular focus on how inflammation can contribute to disease.

Research projects

How do microplastics effect human health and the health of wildlife?

How does inflammation contribute to Alzheimer’s disease?

Developing novel drugs or re-purposing existing drugs to fight inflammatory disease.

How does the body control the inflammatory response?

If you are a national or international student interested in doing an Honours, Masters or Ph.D. research project on any of these topics please send an email to [email protected] for more information.

Research overview

My primary research goal is to understand adaptive and maladaptive signalling processes that occur during inflammatory stress and disease burden. Inflammation is a beneficial response to tissue damage or infection involving numerous systems within the body, primarily the immune, nervous and vascular systems. However, when inflammation is excessive or chronic it can damage surrounding healthy tissues, causing or contributing to pathological processes. Inflammation is orchestrated by numerous signalling molecules, of which, cytokines are the largest and most important group. Cytokines are small secreted proteins which commonly act through cell surface receptors to initiate the extraordinarily complex phenotypic changes in the numerous cells types involved in inflammation. Interleukin (IL)-1β and IL-1α are extremely potent keystone inflammatory cytokines that have been demonstrated to be central to both adaptive and maladaptive inflammatory responses. Inhibition of the IL-1 signalling cascade has been shown clinically to reduce cardiovascular pathology, cancer mortality, osteoarthritis and gout, and preclinically to be therapeutic in stroke, head trauma, Alzheimer’s disease, multiple sclerosis, irritable bowel syndrome and many other conditions. From this it is clear that improved understanding of triggers and pharmacological modulators of the IL-1 signalling cascade will have a tremendous impact on disease burden.

Aims

• Establish the inflammatory properties of environmental microplastics and what cellular mechanisms are mediating microplastic-induced inflammation.
• To understand how peripheral and central inflammatory responses contribute to Alzheimer’s disease.
• Use large epidemiological datasets, preclinical animal models and RNAseq pathway analysis, to determine the most protective class of anti-inflammatory drug for reducing Alzheimer’s disease risk.
• Ascertain the physiological importance of the unique features of pro-IL-1α.

Figure 1. The canonical pathways of IL-1α and IL-1β expression, processing and secretion. Pro-IL-1α and pro-IL-1β are typically expressed following NFκB activation. This can be initiated by TLR, IL-1R1 activation or other mechanisms (e.g. hypoxia). Pro-IL-1α is processed following membrane permeabilisation; Ca2+ influx causes the activation of calpain 1& 2 enzymes which work synergistically and in conjunction with the HAX-1 protein (unpublished data) to cleave pro-IL-1α into its active form. Pro-IL-1α has a nuclear localisation sequence and research is ongoing as to what the function of IL-1α has in the nucleus. Pro-IL-1β activation typically requires inflammasome formation, there are numerous inflammasome receptor molecules, however, in the case of sterile inflammation (relevant to microplastics and Alzheimer’s disease), the pattern recognition receptor NLRP3 is critical. NLRP3 responds to membrane permeabilisation and the subsequent potassium and chloride efflux. Following NLRP3 activation, conformational changes trigger the formation of the inflammasome, a multi protein complex composed of the adapter molecule ASC, the NLRP3 receptor and pro-caspase-1. Within the inflammasome caspase-1 becomes active and cleaves pro-IL-1β into its mature active form. Endolysosomal rupture induces NLRP3 activation in a potassium and chloride efflux dependent way and it is this pathway which is critical for microplastics and amyloid (Alzheimer’s disease) induced IL-1β secretion. Once cleaved both IL-1α and IL-1β are secreted through non-conventional secretory pathways including pyroptosis and act through IL-1R1 to induce their inflammatory effects.

Curriculum Vitae: Dr Rivers Auty CV March 2021

My history

Jack completed a Bachelor of Science in anatomy with a neuroscience focus at the southernmost university in the world – the University of Otago. During his degree, Jack took several botany papers and fell in love with the subject, so Jack continued studies at Otago with a post graduate diploma in botany followed by a Ph.D. which combined botany and neuroscience by investigating the effects of marijuana-like synthetic cannabinoids on inflammation in the ischemic brain. Jack continued his research at the University of Otago with projects on the rotten smelling gas hydrogen sulphide as an inflammatory signalling molecule and kamikaze neutrophils who spew their DNA contents onto unsuspecting bacteria. Then Jack moved 19,000km around the world to the University of Manchester. Jacks research primarily investigated the role of the inflammasome in Alzheimer’s disease and age related cognitive decline. Jack’s supervisors and collaborators Dr. Catherine Lawrence and Prof. David Brough were inspirational, sportive and scientifically on point. Under their supervision Jack was able to make significant contributions to the inflammation research field. Jack is now a lecturer in Medical Sciences at the University of Tasmania investigating inflammation. Jack is establishing the inflammatory properties of environmental microplastics and what cellular mechanisms are mediating microplastic-induced inflammation. And Jack aims to understand how peripheral and central inflammatory responses contribute to Alzheimer’s disease.

My major contributions to the field include: (i) Nature Communications paper in 2018 which used bioinformatics and in vitro techniques to establish that a function of the pro-domain of IL-1α has provided the evolutionary impetus for the divergence of IL-1α from IL-1β following a duplication event of the IL-1β to form IL-1α over 160 million years ago. My research Identified that binding to the cytosolic protein HAX-1 is likely essential to the as yet unknown function of IL-1α and that the nuclear localisation sequence in pro-IL-1α is not an essential distinguishing feature of IL-1α from IL-1β. (ii) Nature Communications 2016 paper identified that chloride efflux is essential for the formation of the multi-protein complex involved in IL-1β processing and release called the inflammasome. Additionally, this research was the first to pharmacologically target IL-1β processing in preclinical model of Alzheimer’s disease. I used behavioural memory tasks and immunohistochemistry in the 3xTg mouse model of AD, to establish that the inflammasome inhibiting non-steroidal anti-inflammatory (NSAID) mefenamic acid improves cognitive function and abates neuroinflammation seen in the model. (iii) ASC Nano 2018 paper discovered the cytokine modulating properties of graphene oxide nano particles. I used RNA sequencing, large data analysis, and pathway bioinformatics to establish the mechanism of action by which graphene oxide inhibited IL-1β and IL-6 expression without effecting TNF or NLRP3 expression. Following this I performed cell based experiments on primary mouse macrophages to confirm the mechanism of action identified by the bioinformatics approach. Graphene oxide induced the predicted shift in the immune-metabolism of the cell, resulting in the production of the altered citric acid cycle metabolite itaconate which inhibits NFκB-iζ dependent IL-1β/IL-6 translation. (iv) Cell Chemical Biology 2017 publication in collaboration with medicinal chemists, using cell based assays we synthesized and screened novel compounds for the specific inhibition of the NLRP3 inflammasome. I established a high throughput cell culture based methods to generate inhibitions curves for the novel compounds and then translated the most potent compounds to mouse models of acute NLRP3 dependent inflammation.