Biomedical and environmental sciences : BES | 2021
Ptpn22 Arg>Trp Polymorphism Improves Macrophage-Mediated Adipocyte Homeostasis.
Abstract
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), which encodes an intracellular phosphatase protein Lyp, is preferentially expressed in hematopoietic and immune cells. The function of PTPN22 and its biological role have been studied intensely in both human and mouse models during the last decade, because the Arg-to-Trp single nucleotide polymorphism at position 620 has been identified as one of the top genetic risk factors for a variety of autoimmune diseases, including type I diabetes, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Hashimoto’s thyroiditis, and Grave’s disease, which are related to adaptive immunity. However, only a few studies have investigated the function of PTPN22 in innate immunity, which could also contribute to autoimmune risk as well as auto-inflammation, such as seen in obesity. Macrophages are important in obesity, which is a chronic, low-grade inflammatory disease and leads to infiltration of immune cells, including macrophages, T cells, B cells, etc., into adipose tissue. Cytokines and chemokines produced by the recruited immune cells, especially macrophages, influence the gene expression profile in adipocytes, which could lead to type II diabetes and other metabolic diseases. Past research on PTPN22, which concentrated mostly on lymphoid cells, has identified it as a negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases as well as other key signaling molecules in T cells. Recent studies in antigenpresenting cells (APCs) also gradually revealed the important roles of PTPN22 in APC function and performance, such as protein ubiquitination, cell polarization and antigen presentation, acting through the TLR signaling pathway. Especially, 620 Trp macrophages are found to be associated with enhanced phagocytic and antigen presenting function, as well as morphological changes associated with Vav dephosphorylation and higher TRAF3 lysine 63-linked ubiquitination. In this study, we focused on the effect of PTPN22 619 Arg>Trp on macrophage function by investigating a high-fat diet (HFD)-induced obesity mouse model which was knocked in with either PTPN22 619 Arg or PTPN22 619 Trp allele on the endogenous mouse genetic background. We describe significant effects of the mutant macrophages on adipocytes in vitro, but not in vivo on obesity or insulin resistance, contributing to the explanation of the strong contribution of this polymorphism to autoimmunity risk. C57BL/6 mice knocked in with either PTPN22 619 Arg or PTPN22 619 Trp human allele that had been processed in our own lab were used throughout the study; the details were described in our recent paper. Homozygous Ptpn22 619 Trp and Ptpn22 619 Arg littermates with C57BL/6 background were used throughout the study. All animals were housed under specific pathogen free conditions in compliance with guidelines of the Animal Care Committee of McGill University (IACUC number: A5006-01). Mice were allowed libitum access to water and a standard chow laboratory diet. Animal room was maintained under controlled conditions of temperature at 25 ± 1 °C, humidity at 55% ± 5%, and a 12 h light/12 dark cycle. For the HFD-induced obesity model, mice were fed with HFD from 6 weeks of age and lasting for16 weeks. Body weights were recorded every 7 days from the start of feeding. For the glucose tolerance test, an