Humoral Arm Of Innate Immunity Research Articles

Current views of haemolytic streptococcal pathogenesis

Increasing disease caused by beta-haemolytic streptococci indicates the need for improved understanding of pathogenesis. Streptococcus pyogenes, or group A Streptococcus (GAS), causes significant disease worldwide. The closely related Streptococcus dysgalactiae subspecies equisimilis (SDSE) is increasingly recognized as causing a similar disease spectrum. Whole-genome sequencing applied to the study of outbreaks may reveal factors that contribute to pathogenesis and changes in epidemiology. The role of quorum sensing in biofilm formation, and interspecies communication with other streptococci, is discussed. GAS has evolved multiple mechanisms to evade the humoral arm of innate immunity, including complement, which is well known in protecting the host from bacteria, and the coagulation-fibrinolytic system, which is increasingly recognized as an innate immune effector. Molecular biology has enhanced our understanding of the intricate balance of host-pathogen interactions that result in clearance or establishment of invasive streptococcal infection. Although the skin and oropharynx remain the usual ecological niche of GAS and SDSE, occasionally the bacteria find themselves within deeper tissues and blood. Recent research has armed us with better knowledge of bacterial adaptations to this alternative environment. However, the challenge is to translate this knowledge into clinical practice, through the development of novel therapeutic options and ultimately a vaccine against GAS.

MicroRNA-224 regulates Pentraxin 3, a component of the humoral arm of innate immunity, in inner ear inflammation

microRNAs (miRNAs) are regulators of differentiation and development of inner ear cells. Mutations in miRNAs lead to deafness in humans and mice. Among inner ear pathologies, inflammation may lead to structural and neuronal defects and eventually to hearing loss and vestibular dysfunction. While the genetic factors of these pathways have not been defined, autoimmunity participates in these processes. We report that inflammatory stimuli in the inner ear induce activation of the innate immune system via miR-224 and pentraxin 3 (Ptx3). miR-224 is a transcriptional target of nuclear factor κB, a key mediator of innate immunity. Ptx3 is a regulator of the immune response. It is released in response to inflammation and regulated by nuclear factor κB. We show that miR-224 and Ptx3 are expressed in the inner ear and we demonstrate that miR-224 targets Ptx3. As a model of the innate immune response, we injected lipopolysaccharide into the scala tympani of mouse inner ears. This resulted in changes in the levels of miR-224 and Ptx3, in addition to activation of the complement system, as measured by immune cell infiltration and activated C3. This suggests that while miR-224 regulates Ptx3 under normal conditions, upon inflammation, both are recruited to offer a front line of defense in acting as responders to inflammation in the inner ear. miR-224 diminishes the innate immune response by down-regulating Ptx3 expression, while Ptx3 stimulates the innate immune response. An understanding of the molecular components of the inflammatory pathway may help develop therapeutics for reducing inflammation associated with inner ear injury.

Pentraxin 3 (PTX3) plasma levels and carotid intima media thickness progression in the general population

Background and aimPentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and, like C-reactive protein, is independently associated with the risk of developing vascular events. Aim of this study was to investigate, in two large population-based surveys, the Bruneck Study and the PLIC Study, whether PTX3 plasma levels predict the progression of common carotid artery intima–media thickness (CCA-IMT), a surrogate marker of atherosclerosis, in the general population during 5 or 6 years of follow-up. ResultsIn the Bruneck Study, PTX3 plasma levels did not predict a faster progression of CCA-IMT either in the carotid artery or in the femoral artery. This finding was confirmed in the PLIC Study where subjects within the highest tertile of PTX3 did not show an increased progression of CCA-IMT. PTX3 plasma levels were also not associated with the fastest maximum IMT progression.In summary, in more than 2400 subjects from the general population, PTX3 plasma level is neither an independent predictor of progression of subclinical atherosclerosis in different arterial territories, including carotid and femoral arteries nor of incident cardiovascular events. ConclusionThese findings support the relevance of investigating the predictive value of PTX3 plasma levels only in specific settings, like overt CVD, heart failure or acute myocardial infarction.

70 : Orchestration of tissue repair by the humoral pattern recognition molecule PTX3: Linking microbe and matrix recognition

Innate immunity includes a cellular and a humoral arm. Long pentraxin 3 (PTX3) is a fluid phase pattern recognition molecule and a key component of the humoral arm of innate immunity. PTX3 is normally produced in response to microbial recognition or inflammatory signals by different immune or stromal cells. In the early phase of skin wound healing, Pentraxin 3 (PTX3)- deficiency was associated with increased fibrin deposition and persistence, and thicker clots. At later phases, increased collagen deposition was observed in Ptx3-deficient mice. A similar phenotype was observed after liver injury. Ptx3-deficient macrophages and fibroblasts showed defective pericellular fibrinolysis in vitro. PTX3 bound fibrinogen/fibrin and plasminogen at acidic pH. The second exon-encoded N-terminal domain of PTX3 recapitulated the interactions observed with the whole molecule. Thus, a prototypic component of humoral innate immunity, PTX3, plays a non-redundant role in the orchestration of tissue repair and remodeling. We suggest that matrix and microbial recognition are commune, ancestral features of the humoral arm of innate immunity.

26: Role of the long pentraxin PTX3 in fibrosarcoma development and progression

Pentraxins (PTXs) are prototypic components of the humoral arm of innate immunity and constitute a superfamily of multifunctional multimeric proteins phylogenetically conserved from arachnids to mammals. The prototypic long pentraxin PTX3 plays a fundamental role in innate immunity, in regulation of the inflammatory response and in tissue remodeling (1), through different molecular mechanisms, including Complement regulation, P-selectin-dependent leukocyte recruitment and FGF2-regulation. Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion and metastasis. PTX3 is produced by diverse cell types present in the tumor stroma such as leukocytes, endothelial cells and fibroblasts (1, 2). To define the role of PTX3 in tumor development, we investigated the susceptibility to 3-Methylcholanthrene-induced fibrosarcoma or transplanted fibrosarcomas in Ptx3-/- and wild type mice. PTX3-deficiency was associated with increased tumor incidence, fast tumor growth and higher inflammatory response (e.g. leukocyte recruitment, inflammatory cytokines). Furthermore, the analysis of tumors revealed increased complement C3 and reduced Factor H deposition in PTX3-deficient mice, in agreement with the complement-regulatory function of PTX3. Finally, the genetic analysis of “hot” genes Tp53 and K-ras, classically mutated by 3-MCA, showed that PTX3-deficiency was associated with higher mutation frequency, possibly due to polyclonality of the lesions. All together, these results suggest that the regulation of inflammation mediated by PTX3 could play a crucial role in fibrosarcoma development. Mechanisms potentially involved in the mentioned phenotypes, which range from regulation of angiogenesis, complement deposition, leukocyte recruitment and gene instability are currently under investigation. 1. Bottazzi B, Doni A, Garlanda C, Mantovani A. An integrated view of humoral innate immunity: pentraxins as a paradigm. Annu Rev Immunol 2010;28:157–83. 2. Jaillon S, Peri G, Delneste Y, Fremaux I, Doni A, Moalli F, et al. The humoral pattern recognition receptor PTX3 is stored in neutrophil granules and localizes in extracellular traps. J Exp Med 2007;204:793–804.

The long pentraxin PTX3 as a correlate of cancer-related inflammation and prognosis of malignancy in gliomas

Inflammation is a component of glioma microenvironment. PTX3 is a component of the humoral arm of innate immunity and a candidate marker of inflammation.In the present study we assessed the expression of PTX3 in gliomas by immunohistochemistry. PTX3 expression differed across low and high-grade tumors based on histopathological diagnosis and clinical severity, positively correlating with tumor grade and severity. In a multivariate logistic regression model, only the PTX3 score was significantly associated with the presence of a high-grade tumor. Thus, PTX3 may represent a new marker of cancer-related inflammation and glioma malignancy.

Neutrophils in innate and adaptive immunity

Neutrophils have long been viewed as short-lived cells crucial for the elimination of extracellular pathogens, possessing a limited role in the orchestration of the immune response. This dogma has been challenged by recent lines of evidence demonstrating the expression of an increasing number of cytokines and effector molecules by neutrophils. Moreover, in analogy with their "big brother" macrophages, neutrophils integrate the environmental signals and can be polarized towards an antitumoural or protumoural phenotype. Neutrophils are a major source of humoral fluid phase pattern recognition molecules and thus contribute to the humoral arm of innate immunity. Neutrophils cross talk and shape the maturation and effector functions of other leukocytes in a direct or indirect manner, through cell-cell contact or cytokine production, respectively. Therefore, neutrophils are integrated in the activation and regulation of the innate and adaptive immune system and play an important role in the resolution or exacerbation of diverse pathologies, including infections, chronic inflammation, autoimmunity and cancer.

The long pentraxin PTX3: a paradigm for humoral pattern recognition molecules

Pattern recognition molecules (PRMs) are components of the humoral arm of innate immunity; they recognize pathogen-associated molecular patterns (PAMP) and are functional ancestors of antibodies, promoting complement activation, opsonization, and agglutination. In addition, several PRMs have a regulatory function on inflammation. Pentraxins are a family of evolutionarily conserved PRMs characterized by a cyclic multimeric structure. On the basis of structure, pentraxins have been operationally divided into short and long families. C-reactive protein (CRP) and serum amyloid P component are prototypes of the short pentraxin family, while pentraxin 3 (PTX3) is a prototype of the long pentraxins. PTX3 is produced by somatic and immune cells in response to proinflammatory stimuli and Toll-like receptor engagement, and it interacts with several ligands and exerts multifunctional properties. Unlike CRP, PTX3 gene organization and regulation have been conserved in evolution, thus allowing its pathophysiological roles to be evaluated in genetically modified animals. Here we will briefly review the general properties of CRP and PTX3 as prototypes of short and long pentraxins, respectively, emphasizing in particular the functional role of PTX3 as a prototypic PRM with antibody-like properties.

Incremental diagnostic value of circulating pentraxin in patients with intermediate risk of coronary artery disease

ObjectivesPentraxins are a superfamily of multifunctional conserved proteins, some of which are components of the humoral arm of innate immunity and behave as functional ancestors of antibodies. They are divided...

Biology of Human Pentraxin 3 (PTX3) in Acute and Chronic Kidney Disease

The pentraxin superfamily consists of highly conserved multimeric pattern recognition proteins, which are components of the humoral arm of innate immunity. Besides the classical pentraxins (C-reactive protein and serum amyloid P component), pentraxin 3 (PTX3) is a prototypic long pentraxin. In response to primary inflammatory signals, this multifunctional acute phase protein is produced by a variety of cell types. Recently, several clinical studies have demonstrated that PTX3 is significantly associated with kidney dysfunction and disease activity or severity in various inflammatory, cardiovascular and autoimmune diseases. In this paper, we will review the general characteristics of PTX3 focusing in particular on its fundamental biological functions in the course of acute and chronic kidney diseases.

Pentraxins as Key Disease Markers for Periodontal Diagnosis

Periodontal diseases are characterized by a complex set of biologic interactions between a diverse and dynamic microbial ecosystem and the host’s multifaceted and responsive immune and inflammatory machinery. Such interactions between microbial pathogens and various host response systems play a critical role in the development and progression of periodontal disease via the release of inflammatory and immune mediators. Advances in periodontal disease diagnostic are moving toward methods whereby periodontal risk can be identified and quantified by detecting such inflammatory mediators in its sequential pathophysiology. Pentraxins (PTXs) are classical mediators of inflammation and markers of acute-phase reaction. They are a super family of multifunctional molecules characterized by multimeric structure, divided into “short” PTXs and “long” PTXs. C-reactive protein (CRP) and pentraxin-3 (PTX3) are prototypic molecules of the short and long PTX family, respectively. Evidence suggests that PTXs acts as a non-redundant component of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition, as well as a tuner of inflammation. CRP is a cheaper biomarker and more readily available in everyday clinical practice compared with other inflammatory markers, on the other hand, PTX3 is believed to be the true independent indicator of disease activity and could have clinical implication in diagnosing the “at site” inflammatory status of the periodontal disease. These pentraxins are sensitive and specific in the diagnosis and prognosis of chronic diseases. Thus the pentraxins could be used as preferred biomarkers in periodontal disease diagnosis.

Pentraxins as key disease markers for periodontal diagnosis.

Periodontal diseases are characterized by a complex set of biologic interactions between a diverse and dynamic microbial ecosystem and the host’s multifaceted and responsive immune and inflammatory machinery. Such interactions between microbial pathogens and various host response systems play a critical role in the development and progression of periodontal disease via the release of inflammatory and immune mediators. Advances in periodontal disease diagnostic are moving toward methods whereby periodontal risk can be identified and quantified by detecting such inflammatory mediators in its sequential pathophysiology. Pentraxins (PTXs) are classical mediators of inflammation and markers of acute-phase reaction. They are a super family of multifunctional molecules characterized by multimeric structure, divided into “short” PTXs and “long” PTXs. C-reactive protein (CRP) and pentraxin-3 (PTX3) are prototypic molecules of the short and long PTX family, respectively. Evidence suggests that PTXs acts as a non-redundant component of the humoral arm of innate immunity, downstream of, and complementary to, cellular recognition, as well as a tuner of inflammation. CRP is a cheaper biomarker and more readily available in everyday clinical practice compared with other inflammatory markers, on the other hand, PTX3 is believed to be the true independent indicator of disease activity and could have clinical implication in diagnosing the “at site” inflammatory status of the periodontal disease. These pentraxins are sensitive and specific in the diagnosis and prognosis of chronic diseases. Thus the pentraxins could be used as preferred biomarkers in periodontal disease diagnosis.

Long Pentraxin 3: Experimental and Clinical Relevance in Cardiovascular Diseases

Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and belongs, together with the C-reactive protein (CRP) and other acute phase proteins, to the pentraxins' superfamily: soluble, multifunctional, pattern recognition proteins. Pentraxins share a common C-terminal pentraxin domain, which in the case of PTX3 is coupled to an unrelated long N-terminal domain. PTX3 in humans, like CRP, correlates with surrogate markers of atherosclerosis and is independently associated with the risk of developing vascular events. Studies addressing the potential physiopathological role of CRP in the cardiovascular system were so far inconclusive and have been limited by the fact that the sequence and regulation have not been conserved during evolution between mouse and man. On the contrary, the conservation of sequence, gene organization, and regulation of PTX3 supports the translation of animal model findings in humans. While PTX3 deficiency is associated with increased inflammation, cardiac damage, and atherosclerosis, the overexpression limits carotid restenosis after angioplasty. These observations point to a cardiovascular protective effect of PTX3 potentially associated with the ability of tuning inflammation and favor the hypothesis that the increased levels of PTX3 in subjects with cardiovascular diseases may reflect a protective physiological mechanism, which correlates with the immunoinflammatory response observed in several cardiovascular disorders.

Pentraxin‐3 in chronic heart failure: the CORONA and GISSI‐HF trials

Pentraxin-3 (PTX3) is a component of the humoral arm of innate immunity which can regulate inflammatory processes. Since the role of inflammation in the progression of chronic heart failure (HF) is debated, we investigated the prognostic value of PTX3 and the effect of a statin in two large populations of patients with HF. Plasma levels of PTX3 were measured at randomization and after 3 months in 1457 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and 1233 patients enrolled in the GISSI-Heart Failure trial (GISSI-HF). The relationships between baseline PTX3 levels or their changes over time and mortality were evaluated with multivariable Cox proportional hazard models including clinical factors, high sensitivity C-reactive protein (hsCRP), and N-terminal pro brain natriuretic peptide (NT-proBNP). PTX3 concentration [median (Q1-Q3) = 5.34 (3.55-7.64) ng/mL, n = 2690] was higher in females, in older patients, and those with lower body mass index. Baseline elevated PTX3 was associated with a higher risk of all-cause mortality [759 events, hazard ratio (HR) for 1 SD increase 1.20, 95% confidence interval (CI) 1.12-1.30, P < 0.0001], cardiovascular mortality (587 events, HR 1.27, 95% CI 1.17-1.38, P < 0.0001), or hospitalization for worsening HF (720 events, HR 1.21, 95% CI 1.12-1.30, P < 0.0001), and marginally improved discrimination. Three-month changes in PTX3 were associated with fatal events after adjustment for hsCRP or NT-proBNP. Rosuvastatin lowered hsCRP levels but significantly raised PTX3. In two independent clinical trials that enrolled patients with chronic HF, PTX3 was consistently associated with outcomes. The opposite effects of a statin on hsCRP and PTX3 call for further investigation. NCT00336336 (GISSI-HF), NCT00206310 (CORONA).

Increased Levels of PTX3 in Human Plasma in Septic Patients with DIC

Abstract 4347Sepsis is a life-threatening condition that is characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome, SIRS). Long pentraxin PTX3 is an inflammatory mediator and a component of the humoral arm of innate immunity produced by neutrophils, macrophages, myeloid dendritic and endothelial cells. During sepsis a massive inflammatory activation and coagulation/fibrinolysis dysfunction occur. However, little is known about PTX3 in septic patients with DIC. Therefore, we measured PTX3s in the plasma from septic patients with DIC (n=20). Also, we investigated PTX3 in the plasma from septic patients without DIC (n=8) and acute promyelocytic leukemia (APL)-induced DIC (n=5). PTX3 in the plasma from human were measured using enzyme-linked immunosorbent assay (ELISA) kits (Perseus Proteomics Inc, Japan).The thrombin antithrombin complexes (TAT) levels were higher in both DIC patients as reported by others. We detected high levels of PTX3 in the plasma of all septic patients with DIC. Also, plasma levels of PTX3 were positive in septic patients without DIC. However, plasma levels of PTX3 were significantly higher in septic patients with DIC than in septic patients without DIC. Plasma levels of PTX3 ware significantly correlated with severity of septic DIC (platelet count and TAT level). We did not find any difference plasma levels of PTX3 in the APL patients with DIC. Moreover, high-mobility group box 1 (HMGB1) concentrations in the human plasma were determined using ELISA kit (Shino-Test, Japan). Plasma levels of HMBG1 were positive for 14 cases in 20 septic patients with DIC. Also, we did not find any difference plasma levels of HMGB1 in the APL patients with DIC.These results suggest that assess of PTX3 and HMBG1 in the plasma may be helpful in the making the diagnosis in septic patients with DIC. However, PTX3 seemed to be a better biomarker than HMGB1. It appears that PTX3 may contribute to the severity of septic DIC. Disclosures:No relevant conflicts of interest to declare.

The long pentraxin PTX3 at the crossroads between innate immunity and tissue remodelling

Innate immunity represents the first line of defence against pathogens and plays key roles in the activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules that recognize pathogen-associated molecular patterns and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. Pentraxins are essential constituents of the humoral arm of innate immunity and represent a superfamily of highly conserved acute phase proteins, traditionally classified into short and long pentraxins. Pentraxin 3 (PTX3) is the prototypic member of the long pentraxins subfamily. As opposed to C-reactive protein, whose sequence and regulation have not been conserved during evolution from mouse to man, the evolutionary conservation of sequence, gene organization and regulation of PTX3 has allowed addressing its pathophysiological roles in genetically modified mice, in diverse conditions, ranging from infections to sterile inflammation, angiogenesis and female fertility. Despite this conservation, a number of predominantly non-coding polymorphisms have been identified in the PTX3 gene which, when associated in particular haplotypes, have been shown to be relevant in clinical conditions including infection and fertility. Here we review the studies on PTX3, with emphasis on pathogen recognition, tissue remodelling and crosstalk with other components of the innate immune system.

Role of complement and Fcγ receptors in the protective activity of the long pentraxin PTX3 against Aspergillus fumigatus

AbstractPentraxin 3 (PTX3) is a soluble pattern recognition molecule playing a nonredundant role in resistance against Aspergillus fumigatus. The present study was designed to investigate the molecular pathways involved in the opsonic activity of PTX3. The PTX3 N-terminal domain was responsible for conidia recognition, but the full-length molecule was necessary for opsonic activity. The PTX3-dependent pathway of enhanced neutrophil phagocytic activity involved complement activation via the alternative pathway; Fcγ receptor (FcγR) IIA/CD32 recognition of PTX3-sensitized conidia and complement receptor 3 (CR3) activation; and CR3 and CD32 localization to the phagocytic cup. Gene targeted mice (ptx3, FcR common γ chain, C3, C1q) validated the in vivo relevance of the pathway. In particular, the protective activity of exogenous PTX3 against A fumigatus was abolished in FcR common γ chain-deficient mice. Thus, the opsonic and antifungal activity of PTX3 is at the crossroad between complement, complement receptor 3-, and FcγR-mediated recognition. Because short pentraxins (eg, C-reactive protein) interact with complement and FcγR, the present results may have general significance for the mode of action of these components of the humoral arm of innate immunity.

Long pentraxin PTX3 deficiency worsens LPS-induced acute lung injury

Long pentraxin PTX3 is an inflammatory mediator and a component of the humoral arm of innate immunity. PTX3 expression is increased in animals with acute lung injury (ALI) and in patients with sepsis or acute respiratory distress syndrome and is considered to be a potential biomarker for these diseases. However, the role of PTX3 in the pathogenesis of ALI is not fully understood. We hypothesized that PTX3, as an important immune modulator, may determine the severity of ALI. Lipopolysaccharide (LPS) was intra-tracheally administrated to PTX3 knock-out (PTX3-KO) and wild-type (WT) mice. Lung injury, neutrophil infiltration, cell death, fibrin deposition, and tissue factor expression in the lung were determined. Local and systemic inflammatory responses were assessed by measuring cytokines in the lung and plasma. LPS instillation induced ALI in both PTX3-KO and WT mice. Interestingly, PTX3 deficiency significantly increased the magnitude/extent of lung injury compared to that in WT mice. The severe lung injury was accompanied by elevated neutrophil infiltration, cell death, and fibrin deposition in the lung. PTX3 deficiency also enhanced LPS-induced tissue factor expression/activation in the lung and increased tumor necrosis factor-alpha and monocyte chemoattractant protein-1 levels in the plasma. Our data suggest that the endogenously expressed PTX3 plays a protective role in the pathogenesis of ALI and that a lack of PTX3 may enhance neutrophil recruitment, cell death, activation of coagulation cascades, and inflammatory responses in the lung.

Evolution of the Pentraxin Family: The New Entry PTX4

Pentraxins (PTXs) are a superfamily of multifunctional conserved proteins, some of which are components of the humoral arm of innate immunity and behave as functional ancestors of Abs. They are divided into short (C-reactive protein and serum amyloid P component) and long pentraxins (PTX3 and neuronal pentraxins). Based on a search for pentraxin domain-containing sequences in databases, a phylogenetic analysis of the pentraxin family from mammals to arthropods was conducted. This effort resulted in the identification of a new long pentraxin (PTX4) conserved from mammals to lower vertebrates, which clusters alone in phylogenetic analysis. The results indicated that the pentraxins consist of five clusters: short pentraxins, which can be found in chordate and arthropods; neuronal pentraxins; the prototypic long pentraxin PTX3, which originated very early at the divergence of the vertebrates; the Drosophila pentraxin-like protein B6; and the long pentraxin PTX4 discovered in this study. Conservation of flanking genes in mammalian evolution indicates maintenance of synteny. Analysis of PTX4, in silico and by transcript expression, shows that the gene is well conserved from mammals to lower vertebrates and has a unique pattern of mRNA expression. Thus, PTX4 is a new unique member of the pentraxin superfamily, conserved in evolution.

Regulation of leukocyte recruitment by the long pentraxin PTX3

Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity. Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation.