Loss of protein tyrosine phosphatase non-receptor type 2 reduces IL-4-driven alternative macrophage activation

Abstract

Macrophages are a heterogeneous population of innate immune cells that are often divided into two major subsets: classically activated, typically pro-inflammatory (M1) macrophages that mediate host defense, and alternatively activated, tolerance-inducing (M2) macrophages that exert homeostatic and tissue-regenerative functions. Disturbed macrophage function/differentiation results either in inadequate, excessive immune activation or in a failure to induce efficient protective immune responses against pathogens. Loss-of-function variants in protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with chronic inflammatory disorders, but the effect of macrophage-intrinsic PTPN2 loss is still poorly understood. Here we report that PTPN2-deficient macrophages fail to acquire an alternatively activated/M2 phenotype. This was the consequence of reduced IL-6 receptor expression and a failure to induce IL-4 receptor in response to IL-6, resulting in an inability to respond to the key M2-inducing cytokine IL-4. Ultimately, failure to adequately respond to IL-6 and IL-4 resulted in increased levels of M1 macrophage marker expression in vitro and exacerbated lung inflammation upon infection with Nippostrongylus brasiliensis in vivo. These results demonstrate that PTPN2 loss interferes with the ability of macrophages to adequately respond to inflammatory stimuli and might explain the increased susceptibility of PTPN2 loss-of-function carriers to developing inflammatory diseases.

Macrophage regulation & function in helminth infection

“…To enable tissue repair following Nippostrongylus or Taenia infection, macrophages undergo a switch from a pro-inflammatory (M1-like) to an anti-inflammatory AAM state [79,80]. This is exemplified by the IL-4Ra-dependent induction of IGF-1-, Arg1-, metalloproteinase 13-(Mmp13) and IL-10-expressing macrophages that were essential for controlling lung damage during N. brasiliensis infection [8].…”

Critical roles of PTPN family members regulated by non-coding RNAs in tumorigenesis and immunotherapy

“…In Dendritic cells (DCs), ablation of PTPN1 and PTPN12 impairs motility in vivo and prevents efficient antigen presentation to T cells (171, 172). These results indicate that PTPN1 and PTPN12 hold a significant regulatory role in Pro-inflammatory macrophages M1 and tolerance-inducible macrophages M2 are the two major subpopulations of macrophages, the former mediating host defense and the latter undertaking homeostatic and tissue regeneration functions (173). PTPN1 negatively regulates macrophage development through macrophage-colony stimulating factor 1 (CSF-1) signaling.…”

“…Pro-inflammatory macrophages M1 and tolerance-inducible macrophages M2 are the two major subpopulations of macrophages, the former mediating host defense and the latter undertaking homeostatic and tissue regeneration functions ( 173 ). PTPN1 negatively regulates macrophage development through macrophage-colony stimulating factor 1 (CSF-1) signaling.…”

“…PTPN2 is a negative regulator of cytokine signaling, and its loss-of-function carriers have increased susceptibility to the development of inflammatory diseases ( 173 ). For instance, PTPN2 -/- mice develop progressive systemic inflammatory diseases with dermatitis, liver inflammation, chronic myocarditis, gastritis, nephritis, and salpingitis, as well as elevated serum interferon-γ (IFN-γ) ( 177 ).…”

Lessons from helminths: what worms have taught us about mucosal immunology

“…The theme of resolution and repair is continued in a study showing that the phosphatase PTPN2 is a critical signalling step in the alternative activation of macrophages, and its absence correlates with excessive lung damage in a model of pulmonary helminth infection 23 . Type 2 immunity (including macrophage alternative activation) is associated with distinct metabolic requirements, favouring oxidative phosphorylation over aerobic glycolysis and these metabolic changes can have both dietary and immunological determinants (Fig.…”