Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis.

BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. METHODS: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. RESULTS: Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor ß (IR-ß) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-ß phosphorylation, ultimately resulting in IR-ß inactivation. This inactivation of IR-ß suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. CONCLUSIONS: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

Ficolin-A induces macrophage polarization to a novel pro-inflammatory phenotype distinct from classical M1.

BACKGROUND: Macrophages are key inflammatory immune cells that orchestrate the initiation and progression of autoimmune diseases. The characters of macrophage in diseases are determined by its phenotype in response to the local microenvironment. Ficolins have been confirmed as crucial contributors to autoimmune diseases, with Ficolin-2 being particularly elevated in patients with autoimmune diseases. However, whether Ficolin-A stimulates macrophage polarization is still poorly understood. METHODS: We investigated the transcriptomic expression profile of murine bone marrow-derived macrophages (BMDMs) stimulated with Ficolin-A using RNA-sequencing. To further confirm a distinct phenotype activated by Ficolin-A, quantitative RT-PCR and Luminex assay were performed in this study. Additionally, we assessed the activation of underlying cell signaling pathways triggered by Ficolin-A. Finally, the impact of Ficolin-A on macrophages were investigated in vivo through building Collagen-induced arthritis (CIA) and Dextran Sulfate Sodium Salt (DSS)-induced colitis mouse models with Fcna-/- mice. RESULTS: Ficolin-A activated macrophages into a pro-inflammatory phenotype distinct to LPS-, IFN-γ- and IFN-γ + LPS-induced phenotypes. The transcriptomic profile induced by Ficolin-A was primarily characterized by upregulation of interleukins, chemokines, iNOS, and Arginase 1, along with downregulation of CD86 and CD206, setting it apart from the M1 and M2 phenotypes. The activation effect of Ficolin-A on macrophages deteriorated the symptoms of CIA and DSS mouse models, and the deletion of Fcna significantly alleviated the severity of diseases in mice. CONCLUSION: Our work used transcriptomic analysis by RNA-Seq to investigate the impact of Ficolin-A on macrophage polarization. Our findings demonstrate that Ficolin-A induces a novel pro-inflammatory phenotype distinct to the phenotypes activated by LPS, IFN-γ and IFN-γ + LPS on macrophages.

A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile.

The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE. Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.

Diagnostic and prognostic value of H-ficolin for functionally relevant coronary artery disease.

BACKGROUND: We aimed to test the diagnostic and prognostic ability of H-ficolin, an initiator of the lectin pathway of the complement system, for functionally relevant coronary artery disease (fCAD), and explore its determinants. METHODS: The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography and coronary angiography. H-ficolin levels were measured by a sandwich-type immunoassay at rest, peak stress-test, and 2 h after stress-test. Cardiovascular death and non-fatal myocardial infarction were assessed during 5-year follow-up. RESULTS: Among 1,571 patients (32.3 % women), fCAD was detected in 462 patients (29.4 %). H-ficolin concentration at rest was 18.6 (15.3-21.8) µg/ml in patients with fCAD versus 17.8 (15.4-21.5) µg/ml, p = 0.33, in patients without fCAD, resulting in an AUC of 0.53 (95 %CI 0.48-0.56). During follow-up, 107 patients (6.8 %) had non-fatal myocardial infarction and 99 patients (6.3 %) experienced cardiovascular death. In Cox regression analysis, H-ficolin was not a predictor of events in the overall cohort. Subgroup analysis suggested a potential link between H-ficolin and non-fatal myocardial infarction in patients without fCAD (adjusted HR 1.03, 95 % CI 1.02-1.15, p = 0.005). H-ficolin concentration showed a weak positive correlation with systolic (r = 0.069, p < 0.001) and diastolic blood pressure (r = 0.111, p < 0.001). CONCLUSION: H-ficolin concentration did not have diagnostic and/or prognostic value in patients referred for fCAD work-up.

Loss of ficolin-3 expression is associated with poor prognosis in patients with hepatocellular carcinoma.

Background: Ficolin-3 (FCN3) is a well-known circulating pattern recognition molecule which plays a role in host immune responses to cancer via activation of the lectin complement pathway. Nevertheless, the clinical significance of FCN3 in patients with hepatocellular carcinoma (HCC) is unclear. Methods: Eighty-seven HCC patients who received hepatectomy at our hospital were included. Immunohistochemical staining was used to assess the FCN3 expression in both tumorous and non-tumorous tissues from the patients, who were classified into high and low expression groups. Differences in clinicopathological characteristics between the two groups were then analyzed. Results: Survival was significantly associated with FCN3 immunohistochemical score (p for trend = 0.048). Kaplan-Meier analysis revealed a higher overall survival rate in the patients with a high FCN3 expression than in those with a low FCN3 expression (p=0.031). A high FCN3 expression in tumor tissue was independently associated with better overall survival (p=0.042). However, multivariate analysis showed that FCN3 expression was not an independent risk factor for overall survival. Conclusion: Our findings suggest that FCN3 is significantly related to the prognosis of HCC. FCN3 may be a prognostic marker in patients with HCC.

Ficolin A knockout alleviates sepsis-induced severe lung injury in mice by restoring gut Akkermansia to inhibit S100A4/STAT3 pathway.

Acute lung injury (ALI) is a life-threatening disease with high morbidity and mortality. Our previous results demonstrated that Ficolin A (FcnA) protected against lipopolysaccharide (LPS)-induced mild ALI via activating complement, however the mechanism of severe lung damage caused by sepsis remains unclear. This study aimed to investigate whether FcnA modulated gut microbiota to affect the progression of sepsis-induced severe ALI. Fcna-/- and Fcnb-/- C57BL/6 mice were applied to establish the ALI model by injection of LPS intraperitoneally. Mice were treated with antibiotics, fecal microbiota transplantation (FMT), and intratracheal administration of recombinant protein S100A4. Changes in body weight of mice were recorded, and lung injury were assessed. Then lung tissue wet/dry weight was calculated. We found knockout of FcnA, but not FcnB, alleviated sepsis-induced severe ALI evidenced by increased body weight change, decreased wet/dry weight of lung tissue, reduced inflammatory infiltration, decreased lung damage score, decreased Muc-2, TNF-α, IL-1ß, IL-6, and Cr levels, and increased sIgA levels. Furthermore, knockout of FcnA restored gut microbiota homeostasis in mice. Correlation analysis showed that Akkermansia was significantly negatively associated with TNF-α, IL-1ß, and IL-6 levels in serum and bronchoalveolar lavage fluid (BALF). Moreover, knockout of FcnA regulated gut microbiota to protect ALI through S100A4. Finally, we found knockout of FcnA alleviated ALI by inhibiting S100A4 via gut Akkermansia in mice, which may provide further insights and new targets into treating sepsis-induced severe lung injury.

Association of low ficolin-2 concentration in cord serum with respiratory distress syndrome in preterm newborns.

Introduction: Ficolin-2 is a serum pattern recognition molecule, involved in complement activation via the lectin pathway. This study aimed to investigate the association of ficolin-2 concentration in cord blood serum with complications related to premature birth. Methods: 546 premature neonates were included. The concentration of ficolin-2 in cord blood serum was determined by a sandwich TRIFMA method. FCN2 genetic variants were analysed with RFLP-PCR, allele-specific PCR, Sanger sequencing or allelic discrimination using TaqMan probes method. Findings: Cord blood serum ficolin-2 concentration correlated positively with Apgar score and inversely with the length of hospitalisation and stay at Neonatal Intensive Care Unit (NICU). Multivariate logistic regression analysis indicated that low ficolin-2 increased the possibility of respiratory distress syndrome (RDS) diagnosis [OR=2.05, 95% CI (1.24-3.37), p=0.005]. Median ficolin-2 concentration was significantly lower in neonates with RDS than in premature babies without this complication, irrespective of FCN2 gene polymorphisms localised to promoter and 3'untranslated regions: for patients born <33 GA: 1471 ng/ml vs. 2115 ng/ml (p=0.0003), and for patients born ≥33 GA 1610 ng/ml vs. 2081 ng/ml (p=0.012). Ficolin-2 level was also significantly lower in neonates requiring intubation in the delivery room (1461 ng/ml vs. 1938 ng/ml, p=0.023) and inversely correlated weakly with the duration of respiratory support (R=-0.154, p<0.001). Interestingly, in the neonates born at GA <33, ficolin-2 concentration permitted differentiation of those with/without RDS [AUC=0.712, 95% CI (0.612-0.817), p<0.001] and effective separation of babies with mild RDS from those with moderate/severe form of the disease [AUC=0.807, 95% CI (0.644-0.97), p=0.0002]. Conclusion: Low cord serum ficolin-2 concentration (especially in neonates born at GA <33 weeks) is associated with a higher risk of developing moderate/severe RDS, requiring respiratory support and intensive care.

A large-scale plasma proteome Mendelian randomization study identifies novel causal plasma proteins related to primary biliary cholangitis.

Background and aims: Primary biliary cholangitis (PBC) is a progressive chronic autoimmune cholestatic liver disease characterized by the destruction of small intrahepatic bile ducts leading to biliary cirrhosis. Liver biopsy is required in the diagnosis of Antimitochondrial antibody-negative patients. Therefore, novel biomarkers are needed for the non-invasive diagnosis of PBC. To identify novel biomarkers for PBC, we conducted large-scale plasma proteome Mendelian randomization (MR). Methods: A total of 21,593 protein quantitative trait loci (pQTLs) for 2297 circulating proteins were used and classified into four different groups. MR analyses were conducted in the four groups separately. Furthermore, the results were discovered and replicated in two different cohorts of PBC. Colocalization analysis and enrichment analysis were also conducted. Results: Three plasma proteins (ficolin-1, CD40 and protein FAM177A1) were identified and replicated as being associated with PBC. All of them showed significant protective effects against PBC. An increase in ficolin-1 (OR=0.890 [0.843-0.941], p=3.50×10-5), CD40 (OR=0.814 [0.741-0.895], p=1.96×10-5) and protein FAM177A1 (OR=0.822 [0.754-0.897], p=9.75×10-6) reduced the incidence of PBC. Ficolin-1 (PP4 = 0.994) and protein FAM177A1 (PP4 = 0.995) colocalized with the expression of the genes FCN1 and FAM177A1 in whole blood, respectively. Furthermore, CD40 (PP4 = 0.977) and protein FAM177A1 (PP4 = 0.897) strongly colocalized with PBC. Conclusions: We expand the current biomarkers for PBC. In total, three (ficolin-1, CD40, and protein FAM177A1) plasma proteins were identified and replicated as being associated with PBC in MR analysis. All of them showed significant protective effects against PBC. These proteins can be potential biomarkers or drug targets for PBC.

l-ficolin-MASP arm of the complement system in schizophrenia.

The abnormal neurodevelopment secondary to in utero adversities, such as hypoxia, malnutrition and maternal infections, underlies schizophrenia (SZ) etiology. As the genes of MBL-associated serine proteases (MASP) of the complement lectin pathway, MASP1 and MASP2, are expressed in the developing cortex and are functionally important for neuronal migration, we hypothesize that the malfunction ofl-ficolin-MASP arm may also be involved in schizophrenia pathophysiology as it was shown for MBL-MASP complexes. We investigated serum l-ficolin and plasma MASP-2 levels, the activity of l-ficolin-bound MASP-2, as well as an array of the complement-related variables in chronic schizophrenic patients in the acute phase of the disease and controls without physical or mental diagnoses. The median concentration of l-ficolin in Armenian controls was 3.66 µg/ml and similar to those reported for other Caucasian populations. SZ-cases had âˆ¼40 % increase in serum l-ficolin (median 5.08 µg/ml; P < 0.0024). In the pooled sample, l-ficolin level was higher in males than in females (P < 0.0031), but this gender dichotomy was not affecting the variable association with schizophrenia (P < 0.016). Remarkably, MASP-2 plasma concentration showed gender-dependent significant variability in the group of patients but not in controls. When adjusted for gender and gender*diagnosis interaction, a significantly high MASP-2 level in female patients versus female controls was observed (median: 362 ng/ml versus 260 ng/ml, respectively; P < 0.0020). A significant increase in l-ficolin-bound MASP-2 activity was also observed in schizophrenia (on the median, cases vs controls: 7.60 vs 6.50 RU; P < 0.021). Correlation analyses of the levels of l-ficolin and MASP-2, l-ficolin-(MASP-2) activity and the demographic data did not show any significant association with the age of individuals, family history, age at onset and duration of the illness, and smoking. Noteworthy, the levels of l-ficolin and MASP-2 in circulation were significantly associated with the type of schizophrenia (paranoid SZ-cases had much higher l-ficolin (P < 0.0035) and lower MASP-2 levels than the other types combined (P < 0.049)). Correlations were also found between: (i) the classical pathway functional activity and l-ficolin level (rs = 0.19, P < 0.010); (ii) the alternative pathway functional activity and MASP-2 level (rs = 0.26, P < 0.00035); (iii) the activity of l-ficolin-bound MASP2 and the downstream C2 component haemolytic activity (rs = -0.19, P < 0.017); and (iv) l-ficolin and the upstream C-reactive protein (CRP) serum concentrations (r = 0.28, P < 0.018). Overall, the results showed l-ficolin-related lectin pathway alterations in schizophrenia pathophysiology. It is likely that in addition to the MBL-MASP component over-activity reported previously, the alterations of the lectin pathway in schizophrenia also involve variations of l-ficolin-(MASP-2) on protein concentration and activity levels.

Collectins and ficolins in neonatal health and disease.

The immune system starts to develop early in embryogenesis. However, at birth it is still immature and associated with high susceptibility to infection. Adaptation to extrauterine conditions requires a balance between colonization with normal flora and protection from pathogens. Infections, oxidative stress and invasive therapeutic procedures may lead to transient organ dysfunction or permanent damage and perhaps even death. Newborns are primarily protected by innate immune mechanisms. Collectins (mannose-binding lectin, collectin-10, collectin-11, collectin-12, surfactant protein A, surfactant protein D) and ficolins (ficolin-1, ficolin-2, ficolin-3) are oligomeric, collagen-related defence lectins, involved in innate immune response. In this review, we discuss the structure, specificity, genetics and role of collectins and ficolins in neonatal health and disease. Their clinical associations (protective or pathogenic influence) depend on a variety of variables, including genetic polymorphisms, gestational age, method of delivery, and maternal/environmental microflora.

Association of the FCN2 Gene Promoter Region Polymorphisms with Very Low Birthweight in Preterm Neonates.

Single nucleotide polymorphisms (SNPs) localised to the promoter region of the FCN2 gene are known to influence the concentration of ficolin-2 in human serum and therefore potentially have clinical associations. We investigated the relationships between SNPs at positions −986 (A > G), −602 (G > A), −64 (A > C) and −4 (A > G) and clinical complications in 501 preterms. Major alleles at positions −986 and −64 and A/A homozygosity for both polymorphisms were less frequent among babies with very low birthweight (VLBW, ≤1500 g) compared with the reference group (OR = 0.24, p = 0.0029; and OR = 0.49, p = 0.024, respectively for A/A genotypes). A lower frequency of G/G homozygosity at position −4 was associated with gestational age <33 weeks and VLBW (OR = 0.38, p = 0.047; and OR = 0.07, p = 0.0034, respectively). The AGAG haplotype was protective for VLBW (OR = 0.6, p = 0.0369), whilst the GGCA haplotype had the opposite effect (OR = 2.95, p = 0.0249). The latter association was independent of gestational age. The AGAG/GGAA diplotype favoured both shorter gestational age and VLBW (OR = 1.82, p = 0.0234 and OR = 1.95, p = 0.0434, respectively). In contrast, AGAG homozygosity was protective for lower body mass (OR = 0.09, p = 0.0155). Our data demonstrate that some FCN2 variants associated with relatively low ficolin-2 increase the risk of VLBW and suggest that ficolin-2 is an important factor for fetal development/intrauterine growth.

Ficolin-2: A potential immune-related therapeutic target with low expression in liver cancer.

Objective: This study aimed to investigate the role of ficolin-2 (FCN2) in the development and course of hepatocellular carcinoma (HCC) and to contribute to the evolution of innovative HCC therapeutics. Methods: Oncomine, GEPIA (Gene Expression Profiling Interactive Analysis), TISIDB (Tumor Immune System Interactions and Drug Bank database), UALCAN (University of Alabama at Birmingham Cancer data analysis portal), UCSC (University of California, Santa Cruz), R package, the Kaplan-Meier technique, Cox regression analysis, LinkedOmics, Pearson's correlation, and a nomogram were used to investigate the prognostic value of FCN2 in HCC. Co-expressed genes were screened. A protein-protein interaction network was created using the STRING database. Finally, immunohistochemistry was performed to establish the expression of FCN2 in HCC tissues. A pan-cancer study centered on HCC-related molecular analysis was also conducted to look for a link between FCN2 and immune infiltration, immune modulators, and chemokine receptors. Results: In HCC tissues, the expression of FCN2 was observed to be lower than that in normal tissues. This was connected to the HCC marker alpha-fetoprotein, showing that FCN2 is involved in the development and progression of cancer. FCN2 may act through Staphylococcus aureus infection, lectins, and other pathways. Furthermore, at the immune level, the expression of FCN2 in HCC was associated with some immune cell infiltration, immunomodulators, and chemokine receptors. Conclusion: FCN2 may be an immune checkpoint inhibitor for HCC, creating a breakthrough in the treatment of HCC.

A pattern recognition receptor ficolin from Portunus trituberculatus (Ptficolin) regulating immune defense and hemolymph coagulation.

Ficolins, belonging to the fibrinogen-related protein superfamily, are important pattern recognition receptors in innate immunity. Here, a ficolin gene Ptficolin was characterized from the swimming crab Portunus trituberculatus. The completed cDNA sequence of Ptficolin encoded a signal peptide, a coiled-coil region and a fibrinogen-like domain but without the typical collagen region of vertebrate ficolins. Ptficolin showed higher expression in stomach and hepatopancreas, and presented a time-dependent response after pathogen challenge and injury stimulation. The recombinant Ptficolin (rPtficolin) could bind to various PAMPs and microorganisms, and agglutinate microorganisms and rabbit erythrocytes in a Ca2+-dependent manner, with strong binding ability to N-acetyl sugars. Meanwhile, rPtficolin promoted the hemocyte phagocytosis and clearance activity of Vibrio, while Ptficolin knockdown impaired the bacterial phagocytosis and clearance ability, suggesting the opsonin activity of Ptficolin. Knockdown of Ptficolin could downregulate the transcription of most complement-like genes and AMPs, but enhance the expression of most proPO system-related genes and key genes of Toll, IMD and JNK pathways. Moreover, knockdown of Ptficolin led to the increased hemolymph clotting time and the decreased expression of clotting-related genes. Our results indicate that Ptficolin could recognize and eliminate invading pathogens, and might be a prominent component in hemolymph coagulation of crab.

The role of ficolin as a pattern recognition receptor in antibacterial immunity in Eriocheir sinensis.

Ficolin, a member of the fibrinogen-related proteins family (FREPs), functions as a pattern recognition receptor (PRR) in vertebrates and in invertebrates as a novel lectin. In this study, we discovered the Ficolin homolog of Chinese mitten crab (Eriocheir sinensis), which we named EsFicolin. The obtained sequence showed that it has a highly conserved C-terminal fibrinogen-related domain (FReD) and a coiled-coil structure for trimer formation. EsFicolin was up-regulated in hemocytes after being stimulated by bacteria. Recombinant EsFicolin protein binds to gram-negative and gram-positive bacteria and agglutinates bacteria through pathogen-associated molecular patterns. In-depth study found that recombinant EsFicolin could effectively remove bacteria and showed direct antibacterial activity. EsFicolin could also promote the phagocytosis of hemocytes to enhance bacterial clearance. These findings suggest that EsFicolin plays an important role in the crab antibacterial immune response.

Comprehensive Analysis of Prognostic Value and Immune Infiltration of Ficolin Family Members in Hepatocellular Carcinoma.

Objective: Ficolin (FCN) family proteins are part of the innate immune system, play a role as recognition molecules in the complement system, and are associated with tumor development. The mechanism of its role in immunotherapy of hepatocellular carcinoma (HCC) is unclear. Methods: In this study, we used the TCGA database, HPA database, Gene Expression Profile Interaction Analysis (GEPIA), Kaplan-Meier plotter, TCGAportal, cBioPortal, GeneMANIA, TIMER, and TISIDB to analyze Ficolin family proteins (FCN1, FCN2 and FCN3, FCNs) in patients with hepatocellular carcinoma for differential expression, prognostic value, genetic alterations, functional enrichment, and immune factor correlation analysis. Results: The expression levels of FCN1/2/3 were significantly reduced in patients with HCC. Among them, FCN3 showed significant correlation with Overall Survival (OS), Progressive Free Survival (PFS) and Relapse Free Survival (RFS) in HCC. FCN1 and FCN3 may be potential prognostic markers for survival in patients with HCC. In addition, the functions of differentially expressed FCNs were mainly related to complement activation, immune response, apoptotic cell clearance and phagocytosis. FCNs were found to be significantly correlated with multiple immune cells and immune factors. Expression of FCN1 and FCN3 differed significantly in the immune and stromal cell component scores of HCC. analysis of the tumor mutation burden (TMB) and microsatellite instability (MSI) of FCNs with pan-cancer showed that FCN3 was significantly correlated with both. Conclusions: Our study provides new insights into the link between the FCN family and immunotherapy for HCC, and FCN3 may serve as a prognostic biomarker for HCC.

Calcium-dependent reversible coaggregation activity of C-reactive protein and M-ficolin.

C-reactive protein (CRP) and M-ficolin are the pattern recognition proteins of the innate immune system. In this report, a mixture of CRP and M-ficolin reversibly co-aggregated in a calcium-dependent manner. This coaggregation was enhanced at low pH (6.5) or low salt (35 mM NaCl) concentrations. The co-aggregate was dissolved by adding EDTA and reformed by adding calcium. The M-ficolin fibrinogen-like domain (FD1), the ligand-binding domain of M-ficolin, also showed calcium-dependent coaggregation with CRP, indicating that reversible coaggregation is caused by CRP interacting with FD1. Interestingly, adding phosphocholine (PC), the ligand of CRP, to a CRP-FD1 mixture abolished the reversible coaggregation activity. PC also inhibited the interaction between CRP and FD1. These results indicate that CRP retains PC-binding activity in the coaggregation state and that FD1 binds specifically to the PC-binding site on CRP but does not fully occupy the five PC-binding sites on a CRP pentamer as judged by SDS-PAGE analysis of precipitates. Coaggregation analysis using FD1 mutants showed that FD1 also retains ligand-binding activity in the coaggregation state and that coaggregation requires the trimeric form of FD1. It was also found that modifications to the ligand-binding site of FD1 affect coaggregation efficiency. Although the biological functions of the coaggregation activity of CRP and M-ficolin remain unresolved, the co-aggregates may function as bacteria-trapping particles with affinities for ligands of CRP and M-ficolin. In addition, coaggregation may be involved in CRP deposition in the lesions of several arterial diseases, such as atherosclerosis.

Distinct Roles of Classical and Lectin Pathways of Complement in Preeclamptic Placentae.

Pre-eclampsia is a pregnancy complication characterized by defective vascular remodeling in maternal decidua responsible for reduced blood flow leading to functional and structural alterations in the placenta. We have investigated the contribution of the complement system to decidual vascular changes and showed that trophoblasts surrounding unremodeled vessels prevalent in preeclamptic decidua fail to express C1q that are clearly detected in cells around remodeled vessels predominant in control placenta. The critical role of C1q is supported by the finding that decidual trophoblasts of female C1qa-/- pregnant mice mated to C1qa+/+ male mice surrounding remodeled vessels express C1q of paternal origin. Unlike C1qa-/- pregnant mice, heterozygous C1qa+/- and wild type pregnant mice share a high percentage of remodeled vessels. C1q was also found in decidual vessels and stroma of normal placentae and the staining was stronger in preeclamptic placentae. Failure to detect placental deposition of C1r and C1s associated with C1q rules out complement activation through the classical pathway. Conversely, the intense staining of decidual endothelial cells and villous trophoblast for ficolin-3, MASP-1 and MASP-2 supports the activation of the lectin pathway that proceeds with the cleavage of C4 and C3 and the assembly of the terminal complex. These data extend to humans our previous findings of complement activation through the lectin pathway in an animal model of pre-eclampsia and provide evidence for an important contribution of C1q in decidual vascular remodeling.

Ficolin-2 Lectin Complement Pathway Mediates Capsule-Specific Innate Immunity Against Invasive Pneumococcal Disease.

Reports conflict regarding which lectin-microbial ligand interactions elicit a protective response from the lectin pathway (LP) of complement. Using fluorescent microscopy, we demonstrate the human lectin ficolin-2 binds to Streptococcus pneumoniae serotype 11A capsule polysaccharide dependent on the O-acetyltransferase gene wcjE. This triggers complement deposition and promotes opsonophagocytosis of encapsulated pneumococci. Even partial loss of ficolin-2 ligand expression through wcjE mutation abrogated bacterial killing. Ficolin-2 did not interact with any pneumococcal non-capsule structures, including teichoic acid. We describe multiple 11A clonal derivatives expressing varying degrees of wcjE-dependent epitopes co-isolated from single blood specimens, likely representing microevolutionary shifts towards wcjE-deficient populations during invasive pneumococcal disease (IPD). We find epidemiological evidence of wcjE impairing pneumococcal invasiveness, supporting that the LP's ficolin-2 axis provides innate, serotype-specific serological protection against IPD. The fact that the LP is triggered by only a few discrete carbohydrate ligands emphasizes the need to reevaluate its impact in a glycopolymer-specific manner.

Components of the Lectin Pathway of Complement in Solid Tumour Cancers.

The complement system is an important branch of the humoral innate immune response that can be activated via three distinct pathways (classical, alternative, lectin), contributing to keeping/restoring homeostasis. It can also interact with cellular innate immunity and with components of acquired immunity. Cross-talk between the complement system and other enzyme-dependent cascades makes it a more influential defence system, but on the other hand, over- or chronic activation can be harmful. This short review is focused on the dual role of the lectin pathway of complement activation in human solid tumour cancers, including those of the female reproductive system, lung, and alimentary tract, with emphasis on the aforementioned cross-talk.

Increased Levels of serum Pentraxin 3 in Critical Coronavirus Disease-2019 Patients.

Pentraxin 3 (PTX3) and ficolin are the plasma phase of pattern recognition receptors (PRRs) and can activate complement through classical and lectin pathways, respectively, which may contribute to disease severity. This study aimed to investigate the association between PTX3 and ficolin with disease severity in patients with coronavirus disease-2019 (COVID-19). Seventy-three COVID-19 patients and 25 healthy controls were enrolled in this study. The participants were divided into three groups as follows: 14 patients as the intensive care unit (ICU) group, 59 patients as the non-ICU group, and 25 subjects as the healthy control group. The serum levels of PTX3 and ficolin were measured by enzyme-linked immunosorbent assay (ELISA) kits. Patients in ICU and non-ICU groups had significantly higher levels of PTX3 compared to the healthy control group (p = 0.0002 and p = 0.0072, respectively). Patients in the ICU group also had an increased amount of PTX3 (1957 ± 1769 pg/ml) compared to non-ICU patients (1220 ± 1784 pg/ml). However, this difference was not significant. On the other hand, serum levels of ficolin were not different among the three groups. PTX3, as an acute phase protein, may contribute to disease severity. Its probable inflammatory role could result from the high activation of the complement system. On the other hand, it could be suggested that ficolin has no crucial role in the disease severity of COVID-19 patients.