Hit the brakes! Inhibitory immune receptors as therapeutic target for neutrophil-driven pathologies

Ruben Geerdink

Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

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Abstract

Neutrophils are the most abundant human leukocyte and crucial to antimicrobial defence. Their importance is starkly illustrated by patients with chronic granulomatous disease (CGD) whose neutrophils are defective due to a genetic mutation. CGD patients suffer repeatedly from severe infections. However, the antimicrobial armaments deployed by neutrophils lack specificity. Neutrophil-derived proteases can digest proteins, reactive oxygen species (ROS) can bind and disrupt a variety of molecules, and anti-microbial peptides can insert into and disrupt the membranes that encompass (microbial) cells. Moreover, neutrophils can sacrifice themselves by releasing neutrophil extracellular traps (NETs), which involves neutrophils decorating their DNA with antimicrobial proteins and peptides and then expelling it as a web to trap and kill microbes. While such methods are highly effective in the fight against many pathogens, they also result in collateral damage to surrounding tissue. As a result, neutrophils are also a driving force behind a plethora of pathologies, varying from viral respiratory infection and ischaemia-reperfusion injury to autoimmune disorders. At current, no medication exists that can supress neutrophil activity. This lack of therapeutics that can effectively ameliorate excessive neutrophilic inflammation is a major obstacle in the treatment of these diseases and represents a significant unmet clinical need.
In this thesis, we examine inhibitory immune receptors as possible modulators of neutrophil activity and their potential as targets for pharmaceutical intervention to supress pathological neutrophil responses. We identify the collagen receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) as a functional inhibitory receptor on neutrophils. Ex vivo stimulation of LAIR-1 on in vivo activated neutrophils obtained from the airways of ventilated, paediatric, respiratory syncytial virus (RSV) infection-induced bronchiolitis patients is able to suppress NET formation. In mice, absence of LAIR-1 inhibitory signalling exacerbates neutrophilic airway inflammation in response to RSV infection, cigarette-smoke inhalation, and intranasal inoculation with CXCL-1 (a neutrophil specific chemokine). Interestingly, the absence of another inhibitory immune receptor expressed by neutrophils that signals in a similar manner to LAIR-1, namely Allergin-1, does not impact disease severity or neutrophilic inflammation in mice infected with RSV. This finding highlights the functional diversity of inhibitory immune receptors. The work published in this thesis paves the way for further investigations into inhibitory immune receptors on neutrophils and accentuates their potential as a therapeutic target to ameliorate neutrophil-driven pathologies.
Original languageEnglish
Awarding Institution
  • University Medical Center (UMC) Utrecht
Supervisors/Advisors
  • Meyaard, Linde, Primary supervisor
  • Bont, Louis, Supervisor
Award date28 Jun 2023
Place of PublicationUtrecht
Publisher
Print ISBNs978-94-93315-84-6
DOIs
Publication statusPublished - 28 Jun 2023

Keywords

  • Neutrophils
  • inhibitory immune receptors
  • respiratory syncytial virus
  • LAIR-1
  • neutrophil extracellular traps
  • Allergin-1

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