Monocytes, like other innate immune cells, sense bacteria via conserved pattern recognition receptors (PRR), including nucleotide-binding and oligomerization domain containing type 2 (NOD2) [2]. It is obvious that a very tight inhibitor Imatinib Mesylate control of PRR activation is crucial for tolerance towards commensal gut flora. NOD2 is a cytosolic receptor that recognizes invading bacteria by ligation to muramyl-dipeptide (MDP) [3], a highly conserved bacterial cell wall component. Presence of certain polymorphisms within the gene encoding NOD2, that result in aberrant receptor activation, are associated with IBD [4] [5], and malfunction in NOD2 receptor activation interferes with effective clearance of intracellular bacteria in the gut [6].

Upon activation, NOD2 induces the phosphorylation of proteins of the nuclear factor ��B (NF-��B) and mitogen-activated protein kinase (MAPK) signaling pathways, resulting in enhanced expression of adhesions molecules and the secretion of pro-inflammatory cytokines [7]. Additionally, NOD2 ligation leads to the induction of autophagy [8]. Autophagy is a homeostatic process involved in removal of damaged proteins and organelles in the cytosol, but it also plays an important role in host defense and clearance of intracellular bacteria [9]. Changes in autophagy are involved in IBD pathogenesis, and variants in autophagy-16 like 1 (ATG16L1), a protein crucial for autophagosome formation, result in an enhanced risk for developing CD [10].

Genome-wide association studies revealed that variants within the gene locus encoding for protein tyrosine phosphatase non-receptor type 22 (PTPN22) are linked with the risk to develop autoimmune disorders, including rheumatoid arthritis, type 1 diabetes, UC and CD [11]. Yet, the functional link between the presence of PTPN22 variants and inflammatory diseases is still not well understood. By dephosphorylation of signaling molecules, tyrosine phosphatases are generally involved in the regulation of immune receptor activity. PTPN22 in particular, has been shown to negatively regulate signaling molecules downstream of T- and B-cell receptors [12], [13] and disease associated variants lead to altered B-cell, NK-cell and dendritic cell (DC) activation [13]�C[15]. However it has not been addressed if PTPN22 also interferes with pattern recognition receptor induced signaling cascades.

We have previously shown that PTPN22 expression is decreased in the intestine of patients with active CD, in particular in CD68-positive monocytes/macrophages. Loss of PTPN22 results in decreased signal transducer and activator of transcription (STAT)-1, but increased MAPK-signaling in human monocytes. On a functional level, PTPN22-deficiency results in elevated levels of interleukin (IL)-6 and IL-17 secretion [16]. Here, we address the question whether PTPN22 affects NOD2-induced signaling pathways, cytokine secretion, and autophagy in myeloid Brefeldin_A cells.