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R. Lutter PhD

Main activities
Research, Teaching
Focus of research

Chronic and exaggerated inflammatory responses are key features in asthma and chronic obstructive pulmonary disease (COPD) and are associated with clinical symptoms. Our studies are aimed at identifying molecular and cellular mechanisms that control an inflammatory response and that may be aberrant in asthma and/or COPD. In this context we explore two topics. More recently a third focus has been added, that appears crucial in controlling inflammation in patients with acute respiratory distress syndrome (ARDS)/acute lung injury (ALI).

  1. Inflammatory mediators such as interleukins and chemokines drive an inflammatory response. Most inflammatory mediators are encoded by mRNAs that contain AU-rich elements in their 3’-untranslated region, which targets these mRNAs for rapid degradation and ensures their transient expression. Surprisingly, this AU-rich mediated mRNA decay (AMD) is attenuated relatively easy by various mediators (IL-17, IL-1beta) and conditions (metabolic stress, viral infection), which leads to exaggerated inflammatory mediator production. The molecular machinery involved in AMD is not clear yet but involves a number of AU-binding proteins and possibly also microRNAs. We aim to identify the constituents that facilitate degradation of a number of mRNA (encoding IL-6, IL-8, VEGF and IP-10) and assess the effect of IL-17 on this molecular machinery. In addition we wil analyze this machinery in bronchial epithelial cells from patients with asthma and COPD.
  2. Indoleamine 2,3-dioxygenase (IDO) is an inducible tryptophan-catabolizing enzyme, which has anti-microbial properties and has been implicated in blocking T cell activation by promoting apoptosis and halting cell cycle progression. Our studies indicate that IDO activity attenuates not only T cell numbers and function, but also that of granulocytes and macrophages. In fact, we propose that IDO promotes resolution of inflammation. So, when a microbial challenge occurs parallel to a profound IDO activity, the challenge is not controlled well. IDO is also expressed in granuloma, and currently we are determining its contribution to the function of granuloma in chronic granulomatous disease, tuberculosis and sarcoidosis.
  3. Earlier studies have indicated that angiotensin-converting enzyme (ACE) mediates the inflammatory response in lungs of experimental ARDS/ALI. Our recent studies have shown that ARDS in animals that were exposed to LPS, as a model of lung infection, is dependent on ACE as well as ACE2. ACE2, a recently recognized enzyme, is shed in LPS exposed lungs, as a consequence of which there is no or reduced generation of angiotensin 1-7. The addition of a stable form of angiotensin 1-7 to a large extent prevents the development of inflammation. Currently, we aim to clarify the underlying mechanism and are exploring this stable angiotensin 1-7 as a treatment modality.

The findings of these studies may also be relevant to other chronic inflammatory diseases.

 

Key publications
  • Ravanetti L, Dijkhuis A, Sabogal Pineros YS, Bal SM, Dierdorp BS, Dekker T, Logiantara A, Adcock IM, Rao NL, Boon L, Villetti G, Sterk PJ, Facchinetti F, Lutter R, An early innate response underlies severe influenza-induced exacerbations of asthma in a novel steroid-insensitive and anti-IL-5-responsive mouse model. ALLERGY 2017;72 (5):737-753 [PubMed]
  • Chowdhury S, Dijkhuis A, Steiert S, Lutter R, IL-17 attenuates degradation of ARE-mRNAs by changing the cooperation between AU-binding proteins and microRNA16. PLOS GENET 2013;9 (9):e1003747 [PubMed]
  • van der Sluijs KF, van de Pol MA, Kulik W, Dijkhuis A, Smids BS, van Eijk HW, Karlas JA, Molenkamp R, Wolthers KC, Johnston SL, van der Zee JS, Sterk PJ, Lutter R [Contributors: Berger M, Fens N, Yick D, Wagener AH , Amelink M, Reesink HJ, Bresser P, Kunst PWA , Venekamp LN, Majoor CJ , van Steenwijk RP, Jonkers RE]] , Systemic tryptophan and kynurenine catabolite levels relate to severity of rhinovirus-induced asthma exacerbation: a prospective study with a parallel-group design. THORAX 2013;68 (12):1122-1130 [PubMed]
  • Sterk PJ, Lutter R, Asthma phenotyping: TH2-high, TH2-low, and beyond. J ALLERGY CLIN IMMUN 2014;133 (2):395-396 [PubMed]
  • Kuijpers T, Lutter R, Inflammation and repeated infections in CGD: two sides of a coin. CELL MOL LIFE SCI 2012;69 (1):7-15 [PubMed]
All Publications
Research programmes

Controlling lung inflammation

Post-transcriptional regulation of inflammatory mediators by bronchial epithelial cells from patients with asthma or COPD: Saheli Chowdhury (post-doc; Netherlands Asthma Foundation). Pilot study into kinetics of inflammatory response (collaboration with dr. Sanja Kezic)

Resolution of inflammation by indoleamine 2,3-dioxygenase; Resolve study (Koen van der Sluijs (post-doc), Marianne van de Pol; Netherlands Asthma Foundation). Pilot studies on chronic granulomatous disease (collaboration with Prof. Taco Kuijpers), and on sarcoidosis (collaboration with dr. Rene Jonkers)

ACE, cyclic angiotensin 1-7 and inflammation in ARDS/ALI; (Roelie Wösten, PhD project, EKZ)

Virus-induced exacerbations in asthma; experimental infections with rhinovirus 16: Resolve study (see above). The generation of GMP batch of rhinovirus 16 (EU FP6; UBiopred; Marianne van de Pol). Anti IL-5 treatment to temper virus-induced exacerbations of asthma (Suzanne Bal (post-doc); Koen van der Sluijs: applicant) 

start in March 2012: Development of an animal model for corticosteroid insensitive inflammation during virus-induced exacerbation in asthma (EU FP6; UBiopred, Chiesi), Lara Ravanetti (post-doc)
 

Faculty
R. Lutter PhD

Postdocs
L. Ravanetti PhD

PhD Students
C. Folisi
L.E.S. de Groot
L. Guo
A. Ravi MSc
Y.S. Sabogal Pineros MSc
Drs. A. Sutterland MD
T.A. van der Veen MSc (UMCG)

Others
T. Dekker BSc
A. Dijkhuis MSc
B.S. Smids BSc

Other research related activities
  • member of European Respiratory Society Evaluation comittee, European Respiratory Society
  • Membership of advisory board / Consultant, Sanofi-Aventis
  • Board of directors / Trustees / Supervisory board, Dr. A.S. Groenstichting
  • Membership of advisory board / Consultant, GlaxoSmithKline
  • Membership of advisory board / Consultant, Global Alliance Probiotics (GAP)
  • Membership of editorial board / Editorship, INFLAMMATION
Current research funding
  • AMC
  • Foresee Phamaceuticals CO. Ltd
  • Longfonds
  • Nutrileads BV
  • QPS Netherlands B.V.
  • Unlversitäts·Kinderspltal beider Basel (UKBB)