title: Genome-wide expression profiling identifies an impairment of negative feedback signals in the Crohn's disease-associated NOD2 variant L1007fsinsC.
abstract: NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide (MDP), and variants of NOD2 are associated with chronic inflammatory diseases of barrier organs (e.g., Crohn's disease, asthma, and atopic eczema). It is known that activation of NOD2 induces a variety of inflammatory and antibacterial factors. The exact transcriptomal signatures that define the cellular programs downstream of NOD2 activation and the influence of the Crohn-associated variant L1007fsinsC are yet to be defined. To describe the MDP-induced activation program, we analyzed the transcriptomal reactions of isogenic HEK293 cells expressing NOD2(wt) or NOD2(L1007fsinsC) to stimulation with MDP. Importantly, a clear loss of function could be observed in the cells carrying the Crohn-associated variant L1007fsinsC, whereas the NOD2(wt) cells showed differential regulation of growth factors, chemokines, and several antagonists of NF-κB (e.g., TNFAIP3 [A20] and IER3). This genotype-dependent regulation pattern was confirmed in primary human myelomonocytic cells. The influence of TNFAIP3 and IER3 in the context of NOD2 signaling was characterized, and we could validate the predicted role as inhibitors of NOD2-induced NF-κB activation. We show that IER3 impairs the protective effect of NOD2(wt) against bacterial cytoinvasion. These results further our understanding of NOD2 as a first-line defense molecule and emphasize the importance of simultaneous upregulation of counterregulatory anti-inflammatory factors as an integral part of the NOD2-induced cellular program. Lack of these regulatory events due to the L1007fsinsC variant may pivotally contribute to the induction and perpetuation of chronic inflammation.
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University, 24105 Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Billmann-Born
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Simone
authors.initials: S
authors.lastname: Lipinski
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.forename: Anna
authors.initials: A
authors.lastname: Latiano
authors.forename: Vito
authors.initials: V
authors.lastname: Annese
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Martin
authors.initials: M
authors.lastname: Kerick
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.forename: Dirk
authors.initials: D
authors.lastname: Seegert
authors.forename: Adedayo
authors.initials: A
authors.lastname: Hanidu
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
authors.forename: David
authors.initials: D
authors.lastname: van Heel
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D016368:Frameshift Mutation / Q000276:immunology*; D020869:Gene Expression Profiling / Q000379:methods; D015894:Genome, Human; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000473:pathology; D053473:Nod2 Signaling Adaptor Protein / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse