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.

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) plays a pivotal role in immune homeostasis and has been associated with human autoimmune and chronic inflammatory diseases. Though PTPN2 is well-characterized in lymphocytes, little is known about its function in innate immune cells. Our findings demonstrate that dendritic cell (DC)-intrinsic PTPN2 might be the key to explain the central role for PTPN2 in the immune system to maintain immune tolerance. Partial genetic PTPN2 ablation in DCs resulted in spontaneous inflammation, particularly in skin, liver, lung and kidney 22 weeks post-birth. DC-specific PTPN2 controls steady-state immune cell composition and even incomplete PTPN2 deficiency in DCs resulted in enhanced organ infiltration of conventional type 2 DCs, accompanied by expansion of IFNγ-producing effector T-cells. Consequently, the phenotypic effects of DC-specific PTPN2 deficiency were abolished in T-cell deficient Rag knock-out mice. Our data add substantial knowledge about the molecular mechanisms to prevent inflammation and maintain tissue tolerance.

A variant within the gene locus encoding PTPN22 (protein tyrosine phosphatase, non-receptor type 22) emerged as an important risk factor for auto-inflammatory disorders, including rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes, but at the same time protects from Crohn disease, one of the 2 main forms of inflammatory bowel diseases. We have previously shown that loss of PTPN22 results in decreased NLRP3 (NLR family pyrin domain containing 3) activation and that this effect is mediated via enhanced NLRP3 phosphorylation. However, it is unclear how phosphorylation of NLRP3 mediates its inhibition. Here, we demonstrate that loss of macroautophagy/autophagy abrogates the inhibitory effect on NLRP3 activation observed upon loss of PTPN22. Phosphorylated, but not nonphosphorylated NLRP3 is found in autophagosomes, indicating that NLRP3 phosphorylation mediates its inactivation via promoting sequestration into phagophores, the precursors to autophagosomes. This finding shows that autophagy and NLRP3 inflammasome activation are connected, and that PTPN22 plays a key role in the regulation of those 2 pathways. Given its role in inflammatory disorders, PTPN22 might be an attractive therapeutic target, and understanding the cellular mechanisms modulated by PTPN22 is of crucial importance.