Abstract
BackgroundVariations within the gene locus encoding protein tyrosine phosphatase non-receptor type 22 (PTPN22) are associated with the risk to develop inflammatory bowel disease (IBD). PTPN22 is involved in the regulation of T- and B-cell receptor signaling, but although it is highly expressed in innate immune cells, its function in other signaling pathways is less clear. Here, we study whether loss of PTPN22 controls muramyl-dipeptide (MDP)-induced signaling and effects in immune cells.Material & MethodsStable knockdown of PTPN22 was induced in THP-1 cells by shRNA transduction prior to stimulation with the NOD2 ligand MDP. Cells were analyzed for signaling protein activation and mRNA expression by Western blot and quantitative PCR; cytokine secretion was assessed by ELISA, autophagosome induction by Western blot and immunofluorescence staining. Bone marrow derived dendritic cells (BMDC) were obtained from PTPN22 knockout mice or wild-type animals.ResultsMDP-treatment induced PTPN22 expression and activity in human and mouse cells. Knockdown of PTPN22 enhanced MDP-induced activation of mitogen-activated protein kinase (MAPK)-isoforms p38 and c-Jun N-terminal kinase as well as canonical NF-κB signaling molecules in THP-1 cells and BMDC derived from PTPN22 knockout mice. Loss of PTPN22 enhanced mRNA levels and secretion of interleukin (IL)-6, IL-8 and TNF in THP-1 cells and PTPN22 knockout BMDC. Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells.ConclusionsOur data demonstrate that PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products, what might explain the association of PTPN22 variants with IBD pathogenesis.
Highlights
In the healthy gut, commensal bacteria populate our intestine without provoking a significant immune reaction
Knockdown of protein tyrosine phosphatase non-receptor type 22 (PTPN22) enhanced MDP-induced activation of mitogen-activated protein kinase (MAPK)-isoforms p38 and c-Jun N-terminal kinase as well as canonical NF-kB signaling molecules in THP-1 cells and Bone marrow derived dendritic cells (BMDC) derived from PTPN22 knockout mice
Our data demonstrate that PTPN22 controls nucleotide-binding and oligomerization domain containing type 2 (NOD2) signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products, what might explain the association of PTPN22 variants with inflammatory bowel disease (IBD) pathogenesis
Summary
Commensal bacteria populate our intestine without provoking a significant immune reaction. Monocytes and macrophages initiate and orchestrate effective immune responses by the secretion of pro-inflammatory cytokines, as soon pathogenic bacterial components are present. If the discrimination between pathogenic and commensal bacteria in the gut is disturbed, tolerance is lost and hyper-activated intestinal macrophages drive intestinal inflammation, resulting in chronic inflammatory conditions as can be observed during inflammatory bowel diseases (IBD) with its major subforms, ulcerative colitis (UC) and Crohn’s disease (CD). Like other innate immune cells, sense bacteria via conserved pattern recognition receptors (PRR), including nucleotide-binding and oligomerization domain containing type 2 (NOD2) [2]. NOD2 is a cytosolic receptor that recognizes invading bacteria by ligation to muramyl-dipeptide (MDP) [3], a highly conserved bacterial cell wall component. We study whether loss of PTPN22 controls muramyl-dipeptide (MDP)-induced signaling and effects in immune cells
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