Sialic Acid-Binding Immunoglobulin-like Lectin G Promotes Atherosclerosis and Liver Inflammation by Suppressing the Protective Functions of B-1 Cells

摘要

class="head no_bottom_margin" id="sec1title">IntroductionAtherosclerosis is a lipid-driven chronic disease of the artery wall and the underlying cause of heart attacks and strokes, which accounts for the majority of mortalities and morbidities in the world (). It is characterized by chronic inflammatory responses to endogenous sterile triggers, such as oxidized LDL (OxLDL), dying cells, and their metabolic byproducts that trigger tissue inflammation if not efficiently cleared (, ). Persistence of this inflammatory response or its impaired resolution paves the way for chronic inflammatory responses, which have been shown to propagate associated pathologies such as vascular and hepatic inflammation (). Thus, there is growing interest in identifying mechanisms that enhance the immune system’s capacity to prevent endogenously triggered inflammation and/or promote its resolution.B cells, which can be subdivided into B-1 and B2 cells, are emerging players in the chronic inflammation of metabolic diseases, such as obesity, diabetes, and atherosclerosis (, , , ). B2 cells, which include follicular (FO) B cells and marginal zone (MZ) B cells, have been shown to promote atherosclerotic lesion formation in murine models of atherosclerosis via mechanisms that are largely unclear (, ). On the other hand, selective transfer of B-1 cells, which can be further divided into B-1a and B-1b cells, protects mice from atherosclerosis (, ). One of the main functions of B-1 cells is the production of natural IgM antibodies (NAb), which are pre-existing germline encoded antibodies that arise without any conventional T cell help and comprise approximately 80% of IgM antibodies in unchallenged mice (). B-1a cells seem to exhibit their atheroprotective effects via the secretion of NAb (). Indeed, atherosclerosis-prone soluble IgM-deficient mice develop accelerated atherosclerosis, though the exact mechanism by which NAb protect is not entirely clear (). We and others have suggested that NAb promote the neutralization and clearance of self-antigens, such as dying cells and oxidized lipids (href="#bib48" rid="bib48" class=" bibr popnode">Tsiantoulas et al., 2012). These studies indicate the importance of selective regulation of individual B cell subsets for appropriate responses to inflammatory triggers. Moreover, the role of B-1 cells in atherosclerosis has only been studied in immune-compromised animals, and their role in animals that do not lack major compartments of the immune system remains elusive. In this regard, the sialic acid-binding immunoglobulin-like lectin G (Siglec-G) is of particular interest as it acts as negative regulator of the B-1a cell population size, presumably via inhibiting B cell receptor dependent signaling (href="#bib22" rid="bib22" class=" bibr popnode">Hoffmann et al., 2007, href="#bib19" rid="bib19" class=" bibr popnode">Ding et al., 2007). We and others have previously shown that mice deficient in Siglec-G exhibit a nearly 10-fold expansion of B-1a cells along with a robust increase in total serum IgM (href="#bib22" rid="bib22" class=" bibr popnode">Hoffmann et al., 2007, href="#bib19" rid="bib19" class=" bibr popnode">Ding et al., 2007). Moreover, we also found that Siglec-G deficiency results in an expansion of IgM with specificity for oxidation-specific epitopes (OSE), which represent prototypic metabolic byproducts present on OxLDL, dying cells, and circulating microparticles (href="#bib18" rid="bib18" class=" bibr popnode">Chou et al., 2009, href="#bib50" rid="bib50" class=" bibr popnode">Tsiantoulas et al., 2015, href="#bib13" rid="bib13" class=" bibr popnode">Chang et al., 1999, href="#bib14" rid="bib14" class=" bibr popnode">Chang et al., 2004, href="#bib28" rid="bib28" class=" bibr popnode">Jellusova et al., 2010). As excessive accumulation of OSE has been suggested to be a key driver for inflammatory reactions in metabolic diseases, such as atherosclerosis, non-alcoholic steatohepatitis, and diabetes (href="#bib35" rid="bib35" class=" bibr popnode">Miller et al., 2011, href="#bib52" rid="bib52" class=" bibr popnode">Walenbergh et al., 2013, href="#bib23" rid="bib23" class=" bibr popnode">Horie et al., 1997), targeting Siglec-G may have beneficial therapeutic effects in chronic inflammation.The expansion of B-1a cells has also been associated with increased autoimmunity (href="#bib12" rid="bib12" class=" bibr popnode">Chan et al., 1997, href="#bib39" rid="bib39" class=" bibr popnode">Pao et al., 2007, href="#bib27" rid="bib27" class=" bibr popnode">Ishida et al., 2006), which could accelerate atherosclerosis (href="#bib42" rid="bib42" class=" bibr popnode">Roman and Salmon, 2007, href="#bib34" rid="bib34" class=" bibr popnode">Ma et al., 2008). Siglec-G deficiency has been shown to result in an earlier onset of autoimmune disease in the Murphy Roths Large/lymphoproliferative (MRL/lpr) lupus mouse model and leads to mild autoimmunity in aging mice with an over-activation of adaptive T and B cells (href="#bib36" rid="bib36" class=" bibr popnode">Müller et al., 2015, href="#bib10" rid="bib10" class=" bibr popnode">Bökers et al., 2014). In addition, Siglec-G has also been found to be expressed in and influence responses of myeloid cells. For example, Siglec-G has been shown to be upregulated by RNA viruses and to inhibit retinoic acid-inducible gene 1 (RIG-I) mediated IFN-β secretion by macrophages and dendritic cells. In line with this, vesicular stomatitis virus (VSV)-infected Siglec-G-deficient mice were found to display increased IFN-β production and decreased viral load compared to control mice (href="#bib17" rid="bib17" class=" bibr popnode">Chen et al., 2013). Moreover, dendritic cells of Siglec-G-deficient mice have been found to exhibit increased pro-inflammatory cytokine secretion in response to multiple danger-associated molecular patterns (DAMPs) (e.g., HSP70, HSP90, and HMGB1). A detrimental role of Siglec-G deficiency is further supported by the findings that Siglec-G-deficient mice exhibit increased mortality in models of acetaminophen-induced liver necrosis (href="#bib15" rid="bib15" class=" bibr popnode">Chen et al., 2009) and cecal ligation and puncture-induced sepsis (href="#bib16" rid="bib16" class=" bibr popnode">Chen et al., 2011). Thus, all studies so far indicate that Siglec-G functions as negative regulator of inflammation, and Siglec-G deficiency may actually propagate inflammatory responses. Because pro-inflammatory cytokine production is a hallmark of metabolic inflammation, the role of Siglec-G and the consequences of Siglec-G deficiency in chronic inflammation and specifically in atherosclerosis are entirely unknown.Here, we investigated the role of Siglec-G in sterile chronic inflammation in vivo. We demonstrate that total as well as B cell-specific Siglec-G deficiency reduces atherosclerotic lesion formation as well as hepatic inflammation in hypercholesterolemic Ldlr^−/− mice. Moreover, we show that Siglec-G-deficient mice are protected form OxLDL-induced inflammation in vivo.