The role for protein tyrosine phosphatase non-receptor type 22 in regulating intestinal homeostasis

Abstract

Inflammatory bowel disease represents a chronic intestinal inflammation. Recent knowledge suggests a crucial role for genetic, immunological and bacterial factors in inflammatory bowel disease pathogenesis. Variations within the gene locus encoding PTPN22 have been associated with inflammatory bowel disease. PTPN22 is critically involved in controlling immune cell activation and thereby plays an important role in maintaining intestinal homeostasis. Although in B and T cells the mechanism showing how PTPN22 affects cell signalling pathways is well studied, its role in myeloid cells remains less defined. Regulation of the innate immune system plays an essential role in the intestine, and levels of PTPN22 in myeloid cells are drastically reduced in the intestine of inflammatory bowel disease patients. Therefore, additional studies to define the role of PTPN22 in myeloid cells might clearly enhance our understanding of how PTPN22 contributes to intestinal homeostasis.

Keywords: Crohn’s disease; Inflammatory bowel disease; PTPN22; adaptive immunity; innate immunity; ulcerative colitis.

Figure 1.

PTPN22 controls IFN-γ and MDP induced signalling cascades. Loss of PTPN22 promotes p38 MAPK and canonical (p50/p65) NF-κB activation, and increases MDP induced autophagy, while ERK activation is reduced. On the other hand, loss of PTPN22 results in decreased STAT1 activity. Taken together, these events cause a highly imbalanced cytokine secretion pattern. ERK: Extracellular-signal regulated kinase; ICAM-1: intercellular adhesion molecule 1; IFN: interferon; IFNR: interferon receptor; IL: Interleukin; MCP-1: monocyte chemoattractant protein 1; mMDP: muramyl-dipeptide; NF-κB: nuclear factor κB; NOD2: nucleotide oligomerization containing protein 2; p38: mitogen activated protein kinase p38; STAT1; signal transducer and activator of transcription 1; TNFα: tumour necrosis factor alpha.

Figure 2.

Reduced PTPN22 expression in IBD patients. In the healthy intestine, high levels of IL-10 and TGF-β result in high expression of PTPN22 in all immune cells. Upon epithelial damage, the pro-inflammatory cytokine milieu results in reduced PTPN22 expression specifically in cells of the myeloid linage, while lymphoid cells still express high amounts of PTPN22. B: B cell; DC: dendritic cell; IFN: interferon; M: macrophage; T: T cell; TNFα: tumour necrosis factor alpha.

Figure 3.

Proposed mechanism showing how PTPN22 is involved in IBD pathogenesis. Inflammatory insults result in high levels of TNFα, IFN-γ and IL-1β. TNFα and IL-1β reduce PTPN22 expression in myeloid immune cells. Upon loss of PTPN22, monocytes/macrophages secrete increased levels of IL-6 and IL-8 and differentiate preferentially into pro-inflammatory macrophages. The increased expression of co-stimulatory molecules on DC results in an enhanced activation of the adaptive immune system. B: B cell; DC: dendritic cell; IFN: interferon; M: macrophage: M_inf: inflammatory macrophage; T: T cell; TNFα: tumour necrosis factor alpha.