Regulation of inflammasomes by host- and pathogen-derived factors

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The term inflammasome was first coined in 2002 and describes an intracellular multiprotein complex mediating inflammation by inducing the release of pro-inflammatory cytokines (IL-1β and IL-18) and a lytic form of cell death called pyroptosis. Since then, an impressive amount of research has revealed many details about the mechanisms of inflammasome activation as well as the functional relevance of inflammasome activation in different contexts. Yet, the continuously expanding inflammasome field has still many open, unresolved questions to answer and there is a need for further knowledge to help us navigate the sometimes confusing and challenging complexity of inflammasomes.

Inflammasomes have been suggested to have a crucial role in host defense against pathogens. Their significance in host protection is highlighted by a large number of studies identifying immune evasion strategies interfering with inflammasomes. However, these complexes can also be detrimental for the host. Signaling leading to inflammasome activation requires tight regulation, as uncontrolled activation can promote inflammatory, metabolic as well as neurodegenerative disorders. The work presented in this thesis is focused on how inflammasomes and the subsequent release of IL-1β are regulated by different host- and pathogen-derived factors.

In Paper I and II, we investigated the effect of two structurally and functionally related virulence factors of the major human pathogen Group A Streptococcus (streptolysin O and NAD+-glycohydrolase) linked to invasive streptococcal diseases, on NLRP3 inflammasome activation. We identified two immune evasion strategies, both down-regulating GAS-induced IL-1β levels. In Paper I, we demonstrate that extracellularly located NAD+-glycohydrolase inhibits the secretion of inflammasome-dependent IL-1β from infected macrophages without effecting inflammasome assembly. In Paper II, we established a role for streptolysin O in promoting the ubiquitination and subsequent degradation of pro-IL-1β. We propose that both immune evasion strategies could limit IL-1β-induced inflammation and immune cell recruitment to the site of infection, potentially benefiting bacterial survival and/or spread.

In Paper III, we propose a role for extracellular histone H4 in increasing the inflammatory potential of macrophages by licensing them for a previously

unknown, TLR-mediated inflammasome activation. TLR-mediated inflammasome activation leads to IL-1β secretion but proceeds without IL-18 release or pyroptosis, supporting recent findings suggesting that inflammasome effector functions can be uncoupled from each other. We suggest that upon tissue injury, histone H4-licensed macrophages may exhibit a lowered inflammatory threshold and thus react to a single microbial challenge with inflammasome activation to fight the infection. However, macrophages continuously releasing IL-1β in response to TLR stimulation may also contribute to an undesired extended inflammatory response under conditions such as sepsis or sterile inflammation, disorders with known pathological role for both extracellular histones and IL-1β.

Overall, studies presented in this thesis expand our understanding on the mechanism of inflammasome activation as well as the regulation of IL-1β levels in infectious as well as inflammatory settings.

Details

Authors
  • Dora Hancz
Organisations
Research areas and keywords

Keywords

  • Innate Immunity, pattern recognition receptors, inflammasome, Streptococcus pyogenes
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2019 Feb 25
Place of PublicationLund
Publisher
  • Lund University, Faculty of Medicine
Print ISBNs978-91-7619-745-5
Publication statusPublished - 2019
Publication categoryResearch

Bibliographic note

Defence details Date: 2019-02-25 Time: 13:00 Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund External reviewer(s) Name: Brodsky, Igor E. Title: PhD Affiliation: University of Pennsylvania, Philadelphia, USA

Related research output

Hancz, D., Elsa Westerlund, Bastiat-Sempe, B., Sharma, O., Valfridsson, C., Meyer, L., Love, J. F., O’Seaghdha, M., Wessels, M. R. & Jenny J Persson, 2017 Jul 1, In : mBio. 8, 4, e00756-17.

Research output: Contribution to journalArticle

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