CD5L is upregulated upon infection with Mycobacterium tuberculosis with no effect on disease progression.

Tuberculosis (TB) alone caused over a billion deaths in the last 200 years, making it one of the deadliest diseases to humankind. Understanding the immune mechanisms underlying protection or pathology in TB is key to uncover the much needed innovative approaches to tackle TB. The scavenger receptor cysteine-rich molecule CD5 antigen-like (CD5L) has been associated with TB, but whether and how CD5L shapes the immune response during the course of disease remains poorly understood. Here, we show an upregulation of CD5L in circulation and at the site of infection in C57BL/6 Mycobacterium tuberculosis-infected mice. To investigate the role of CD5L in TB, we studied the progression of M. tuberculosis aerosol infection in a recently described genetically engineered mouse model lacking CD5L. Despite the increase of CD5L during infection of wild-type mice, absence of CD5L did not impact bacterial burden, histopathology or survival of infected mice. Absence of CD5L associated with a modest increase in the numbers of CD4+ T cells and the expression of IFN-γ in the lungs of infected mice, with no major effect in overall immune cell dynamics. Collectively, this study confirms CD5L as a potential diagnostic biomarker to TB, showing no discernible impact on the outcome of the infection.

Systematic review of the role of calprotectin in cirrhosis.

BACKGROUND: Calprotectin is a calcium-binding-S100-protein synthetized mainly in neutrophils which has been demonstrated to be an accurate biomarker of the presence of these cells. Gut barrier dysfunction in patients with advanced chronic liver disease (ACLD), in addition to the lack of noninvasive tools for diagnosis and prognosis of cirrhosis decompensations, has raised interest in this biomarker. AIMS: Our aim is to summarize the current evidence regarding the role of calprotectin in terms of its diagnostic and prognostic utility in ACLD. METHODS: We performed a systematic search (PROSPERO registration no. CRD42023389069) of original articles published without any restrictions on the publication date until January 2023 providing information about calprotectin for the prognosis or diagnosis of ACLD and its decompensations in adult patients. RESULTS: A total 227 articles were identified, and 26 observational studies finally met the inclusion criteria. In 14 studies, calprotectin was measured in ascitic fluid, all of which reported higher calprotectin values in spontaneous bacterial peritonitis, while cut-off points for its diagnosis were proposed in nine studies. Three studies reported higher faecal calprotectin levels in patients with hepatic encephalopathy and portal hypertension. Four studies evaluated faecal calprotectin and one plasma calprotectin as biomarkers for gut barrier integrity and bacterial translocation. CONCLUSIONS: Calprotectin is emerging as a promising biomarker in ACLD, particularly for the management of bacterial infections and alcohol-related liver disease. Further research with better study designs should help to determine the feasibility of calprotectin measurement in routine clinical practice.

Incidence, risk factors and clinical outcomes of multidrug-resistant microorganism infections among patients admitted for decompensated cirrhosis: A prospective study.

BACKGROUND: Bacterial infections remain one of the main complications in cirrhosis and worsen patients' prognosis and quality of life. An increase in multidrug resistant microorganism (MDRM) infections among patients with cirrhosis, together with infection-related mortality rates, have been reported in recent years. Therefore, adaptation of the initial empiric antibiotic approach to different factors, particularly the local epidemiology of MDRM infections, has been recommended. We aim to describe the main features, outcomes and risk factors of MDRM infections in patients with cirrhosis. METHODS: Prospective registry of all episodes of in-hospital infections occurring among cirrhotic patients admitted within a 2-year period at a single center. Clinical and microbiological data were collected at the time of infection diagnosis, and the in-hospital mortality rate of the infectious episode was registered. RESULTS: A total of 139 infectious episodes were included. The disease-causing microorganism was identified in 90 episodes (65%), of which 31 (22%) were caused by MDRM. The only two factors independently associated with MDRM infections were rectal colonization by MDRM and a nosocomial or healthcare-associated source. The infection-related mortality rate was 18.7%. MDRM infection and a past history of hepatic encephalopathy were independently associated with in-hospital mortality. CONCLUSIONS: Almost one fourth of bacterial infections occurring in admitted cirrhotic patients were due to MDRM. Rectal colonization was the most important risk factor for MDRM infections in decompensated cirrhosis. Screening for MDRM rectal colonization in patients admitted for decompensated cirrhosis should be assessed as a tool to improve local empiric antibiotic strategies.

Prevalence and outcomes of acute-on-chronic liver failure among cirrhotic patients admitted for an acute decompensation.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a common syndrome that occurs in patients with advanced chronic liver disease. It consists of the rapid failure of various organs and is associated with high short-term mortality. We aim to describe the main features and outcomes of inpatients who developed ACLF and to identify the factors associated with in-hospital and 28-day mortality. PATIENTS AND METHODS: All patients meeting ACLF criteria with advanced chronic liver disease admitted for decompensation from January 2014 to December 2016 were identified. Clinical and biological data were collected at the time of ACLF diagnosis and at 3-7 days thereafter, as well as in-hospital and 28-day mortality. RESULTS: Eighty nine out of 354 admission episodes (28%) developed ACLF, which was present at the time of admission in 72% of cases. A precipitating factor was identified in 83% of cases, the most frequent being infection (53%) and gastrointestinal bleeding (19%). In the multivariate regression analysis, the ACLF grade at 3-7 days after diagnosis was predictive of in-hospital mortality and 28-day mortality, and lower creatinine and bilirubin levels at the time of ACLF diagnosis and a precipitating factor other than bacterial infection were associated with ACLF reversion at 3-7 days. CONCLUSIONS: ACLF is a frequent complication among patients with chronic liver disease admitted for acute decompensations and is associated with a high mortality rate and is related to the number of organs involved. Bacterial infection is the most frequent precipitating factor of ACLF and probably entails a worse prognosis.

Multifaceted Roles of CD5L in Infectious and Sterile Inflammation.

CD5L, a protein expressed and secreted mainly by macrophages, is emerging as a critical immune effector. In addition to its well-defined function as an anti-apoptotic protein, research over the last decade has uncovered additional roles that range from pattern recognition to autophagy, cell polarization, and the regulation of lipid metabolism. By modulating all these processes, CD5L plays a key role in highly prevalent diseases that develop by either acute or chronic inflammation, including several infectious, metabolic, and autoimmune conditions. In this review, we summarize the current knowledge of CD5L and focus on the relevance of this protein during infection- and sterile-driven inflammatory pathogenesis, highlighting its divergent roles in the modulation of inflammation.

Role of the Scavenger Receptor CD36 in Accelerated Diabetic Atherosclerosis.

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in a medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxidized low-density lipoprotein (oxLDL) (24 h). The uptake of 1,1'-dioctadecyl-3,3,3',3-tetramethylindocarbocyanine perchlorate-fluorescently (DiI) labeled oxLDL was quantified by flow cytometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed induction in the expression of CD36, cytokines, calcification markers, and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labeled oxLDL was increased after exposure to high glucose. The silencing of CD36 reduced the induction of CD36 and the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is partially involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes.

CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).

CD5-like (CD5L) is a soluble scavenger cysteine-rich protein that modulates inflammatory responses. We studied the involvement of CD5L in liver cancer. Immunohistochemistry (IHC) of CD5L in 60 hepatocellular carcinomas and 34 adjacent nontumor livers, showed that CD5L staining was higher in tumor than in nontumor tissue (Mann-Whitney test; P = 0.0039). High CD5L correlated with elevated proliferation (Ki67, linear regression; P < 0.0001) and lower patient event-free survival (log-rank; P = 0.0185). Accordingly, CD5L expression was detected in the liver cancer cell lines Huh7, HepG2, and SNU-398. In vitro technologies using these cell lines, including small interfering RNA (siRNA) and cDNA transfection, showed that CD5L promoted colony formation and cell proliferation and protected against cisplatin-induced apoptosis. To find a molecular explanation for these roles, novel CD5L-interacting protein ligands in liver cancer cells were identified by immunoprecipitation followed by mass spectrometry. Among these, the molecular chaperone of the unfolded protein response (UPR), heat shock protein (HSP)-A5, was selected for validation. The interaction was confirmed by confocal microscopy in the Huh7 and HepG2 cell lines. Furthermore, functional experiments revealed that CD5L activates the UPR and autophagy mechanisms in Huh7 cells, thereby providing a novel molecular link between the UPR and autophagy in liver cancer.-Aran, G., Sanjurjo, L., Bárcena, C., Simon-Coma, M., Téllez, É., Vázquez-Vitali, M., Garrido, M., Guerra, L., Díaz, E., Ojanguren, I., Elortza, F., Planas, R., Sala, M., Armengol, C., Sarrias, M.-R. CD5L is upregulated in hepatocellular carcinoma and promotes liver cancer cell proliferation and antiapoptotic responses by binding to HSPA5 (GRP78).

Pentraxin-3 modulates lipopolysaccharide-induced inflammatory response and attenuates liver injury.

Acute-on-chronic liver injury is characterized by an important inflammatory response frequently associated with endotoxemia. In this context, acute-phase proteins such as Pentraxin-3 (PTX3) are released; however, little is known about their role in chronic liver disease. The aim of this study was to elucidate the role of PTX3 in liver injury. The role of PTX3 was evaluated in cultured human cells, liver tissue slices, and mice with acute-on-chronic liver injury. PTX3 expression was assessed in tissue and serum samples from 54 patients with alcoholic hepatitis. PTX3 expression was up-regulated in animal models of liver injury and strongly induced by lipopolysaccharide (LPS). Liver cell fractionation showed that macrophages and activated hepatic stellate cells were the main cell types expressing PTX3 in liver injury. Ex vivo and in vivo studies showed that PTX3 treatment attenuated LPS-induced liver injury, inflammation, and cell recruitment. Mechanistically, PTX3 mediated the hepatic stellate cell wound-healing response. Moreover, PTX3 modulated LPS-induced inflammation in human primary liver macrophages and peripheral monocytes by enhancing a TIR domain-containing adapter-inducing interferon-dependent response and favoring a macrophage interleukin-10-like phenotype. Additionally, hepatic and plasma PTX3 levels were increased in patients with alcoholic hepatitis, a prototypic acute-on-chronic condition; and its expression correlated with disease severity scores, endotoxemia, infections, and short-term mortality, thus suggesting that expression of PTX3 found in patients could be a counterregulatory response to injury. CONCLUSION: Experimental and human evidence suggests that, in addition to being a potential biomarker for alcoholic hepatitis, PTX3 participates in the wound-healing response and attenuates LPS-induced liver injury and inflammation; therefore, administration of PTX3 could be a promising therapeutic strategy in acute-on-chronic conditions, particularly those associated with endotoxemia. (Hepatology 2017;66:953-968).

Role of scavenger receptors in the pathophysiology of chronic liver diseases.

Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro-organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non-alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer.

Liver X receptors inhibit macrophage proliferation through downregulation of cyclins D1 and B1 and cyclin-dependent kinases 2 and 4.

Macrophages serve essential functions as regulators of immunity and homeostasis, and their proliferation contributes to pathogenesis of certain disorders. In this report, we show that induction of macrophage proliferation by the growth factor M-CSF is negatively modulated by agonists that activate the nuclear receptor liver X receptor (LXR), both in vitro and in vivo. Both isoforms LXR α and ß are involved in the antiproliferative actions of LXR ligands in macrophages. In contrast, M-CSF does not exert negative effects on LXR-mediated gene expression. Treatment with LXR agonists results in the accumulation of macrophages in the G(0)/G(1) phase of the cell cycle without affecting ERK-1/2 phosphorylation. The use of small interfering RNA or genetically modified mice revealed that, in contrast to other cellular models, functional expression of either the cyclin-dependent kinase inhibitor p27KIP1 or the cholesterol transporters ATP-binding cassette A1 or ATP-binding cassette G1 was not required for the antiproliferative effects of LXR agonists in macrophages. Western blot analysis revealed that protein expression of key molecules that regulate progression through the cell cycle, such as cyclins D1 and B1 and cyclin-dependent kinases 2 and 4, was downregulated upon LXR activation. These observations suggest a role for LXR agonists in limiting macrophage proliferative responses associated to pathogenic disorders.

Contribution of Elevated Glucose and Oxidized LDL to Macrophage Inflammation: A Role for PRAS40/Akt-Dependent Shedding of Soluble CD14.

Atherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. Elevated concentrations of serum-oxidized low-density lipoproteins (oxLDL) represent a common feature of both conditions. The main goal of this study was to determine the contribution of oxLDL to the inflammatory response of macrophages exposed to diabetic-mimicking conditions. THP1 cells and peripheral blood monocytes purified from non-diabetic healthy donors were cultured under normal (5 mM) or high glucose (HG) (15 mM) with oxLDL. Then, foam cell formation, expression of CD80, HLADR, CD23, CD206, and CD163, as well as toll-like receptor 4 (TLR4) and co-receptors CD36 and CD14 (both at the cell surface and soluble (sCD14)), and inflammatory mediators' production were measured by flow cytometry, RT-qPCR, or ELISA. Additionally, serum sCD14 was determined in subjects with subclinical atherosclerosis with and without diabetes by ELISA. Our results showed that oxLDL-mediated intracellular lipid accumulation via CD36 increased under HG and that HG + oxLDL enhanced TNF, IL1B, and IL8, and decreased IL10. Moreover, TLR4 was upregulated in macrophages under HG and monocytes of subjects with diabetes and atherosclerosis. Interestingly, HG-oxLDL upregulated CD14 gene expression, although its total cellular protein abundance remained unaltered. sCD14 shedding via PRAS40/Akt-dependent mechanisms, with pro-inflammatory activity, was significantly increased in cultured macrophages and plasma from subjects with diabetes and subclinical atherosclerosis or hypercholesterolemia. Our data support an enhanced synergistic pro-inflammatory effect induced by HG and oxLDL in cultured human macrophages, possibly explained by increased sCD14 shedding.

Mycobacterium manresensis induces trained immunity in vitro.

The COVID-19 pandemic posed a global health crisis, with new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants weakening vaccine-driven protection. Trained immunity could help tackle COVID-19 disease. Our objective was to analyze whether heat-killed Mycobacterium manresensis (hkMm), an environmental mycobacterium, induces trained immunity and confers protection against SARS-CoV-2 infection. To this end, THP-1 cells and primary monocytes were trained with hkMm. The increased secretion of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1ß, and IL-10, metabolic activity, and changes in epigenetic marks suggested hkMm-induced trained immunity in vitro. Healthcare workers at risk of SARS-CoV-2 infection were enrolled into the MANRECOVID19 clinical trial (NCT04452773) and were administered Nyaditum resae (NR, containing hkMm) or placebo. No significant differences in monocyte inflammatory responses or the incidence of SARS-CoV-2 infection were found between the groups, although NR modified the profile of circulating immune cell populations. Our results show that M. manresensis induces trained immunity in vitro but not in vivo when orally administered as NR daily for 14 days.

Macrophage CD5L is a target for cancer immunotherapy.

BACKGROUND: Reprogramming of immunosuppressive tumor-associated macrophages (TAMs) presents an attractive therapeutic strategy in cancer. The aim of this study was to explore the role of macrophage CD5L protein in TAM activity and assess its potential as a therapeutic target. METHODS: Monoclonal antibodies (mAbs) against recombinant CD5L were raised by subcutaneous immunization of BALB/c mice. Peripheral blood monocytes were isolated from healthy donors and stimulated with IFN/LPS, IL4, IL10, and conditioned medium (CM) from different cancer cell lines in the presence of anti-CD5L mAb or controls. Subsequently, phenotypic markers, including CD5L, were quantified by flow cytometry, IF and RT-qPCR. Macrophage CD5L protein expression was studied in 55 human papillary lung adenocarcinoma (PAC) samples by IHC and IF. Anti-CD5L mAb and isotype control were administered intraperitoneally into a syngeneic Lewis Lung Carcinoma mouse model and tumor growth was measured. Tumor microenvironment (TME) changes were determined by flow cytometry, IHC, IF, Luminex, RNAseq and RT-qPCR. FINDINGS: Cancer cell lines CM induced an immunosuppressive phenotype (increase in CD163, CD206, MERTK, VEGF and CD5L) in cultured macrophages. Accordingly, high TAM expression of CD5L in PAC was associated with poor patient outcome (Log-rank (Mantel-Cox) test p = 0.02). We raised a new anti-CD5L mAb that blocked the immunosuppressive phenotype of macrophages in vitro. Its administration in vivo inhibited tumor progression of lung cancer by altering the intratumoral myeloid cell population profile and CD4+ T-cell exhaustion phenotype, thereby significantly modifying the TME and increasing the inflammatory milieu. INTERPRETATION: CD5L protein plays a key function in modulating the activity of macrophages and their interactions within the TME, which supports its role as a therapeutic target in cancer immunotherapy. FUNDING: For a full list of funding bodies, please see the Acknowledgements.

The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome.

The CD5 lymphocyte surface receptor is a group B member of the ancient and highly conserved scavenger receptor cysteine-rich superfamily. CD5 is expressed on mature T and B1a cells, where it is known to modulate lymphocyte activation and/or differentiation processes. Recently, the interaction of a few group B SRCR members (CD6, Spalpha, and DMBT1) with conserved microbial structures has been reported. Protein binding assays presented herein indicate that the CD5 ectodomain binds to and aggregates fungal cells (Schizosaccharomyces pombe, Candida albicans, and Cryptococcus neoformans) but not to Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus) bacteria. Accordingly, the CD5 ectodomain binds to zymosan but not to purified bacterial cell wall constituents (LPS, lipotheicoic acid, or peptidoglycan), and such binding is specifically competed by beta-glucan but not by mannan. The K(d) of the rshCD5/(1-->3)-beta-d-glucan phosphate interaction is 3.7 +/- 0.2 nM as calculated from tryptophan fluorescence data analysis of free and bound rshCD5. Moreover, zymosan binds to membrane-bound CD5, and this induces both MAPK activation and cytokine release. In vivo validation of the fungal binding properties of the CD5 ectodomain is deduced from its protective effect in a mouse model of zymosan-induced septic shock-like syndrome. In conclusion, the present results indicate that the CD5 lymphocyte receptor may sense the presence of conserved fungal components [namely, (1-->3)-beta-d-glucans] and support the therapeutic potential of soluble CD5 forms in fungal sepsis.

Macrophages as a Therapeutic Target in Metastatic Prostate Cancer: A Way to Overcome Immunotherapy Resistance?

Prostate cancer (PC) is the most common malignancy and the fifth cause of cancer death in men. The treatment for localized or locally advanced stages offers a high probability of cure. Even though the therapeutic landscape has significantly improved over the last decade, metastatic PC (mPC) still has a poor prognosis mainly due to the development of therapy resistance. In this context, the use of immunotherapy alone or in combination with other drugs has been explored in recent years. However, T-cell directed immune checkpoint inhibitors (ICIs) have shown limited activity with inconclusive results in mPC patients, most likely due to the highly immunosuppressive PC tumor microenvironment (TME). In this scenario, targeting macrophages, a highly abundant immunosuppressive cell type in the TME, could offer a new therapeutic strategy to improve immunotherapy efficacy. In this review, we summarize the growing field of macrophage-directed immunotherapies and discuss how these could be applied in the treatment of mPC, focusing on their combination with ICIs.

Reduced Plasma Extracellular Vesicle CD5L Content in Patients With Acute-On-Chronic Liver Failure: Interplay With Specialized Pro-Resolving Lipid Mediators.

Acute-on chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated cirrhosis (AD). It is characterized by a systemic hyperinflammatory state, leading to multiple organ failure. Our objective was to analyze macrophage anti-inflammatory protein CD5L in plasma extracellular vesicles (EVs) and assess its as yet unknown relationship with lipid mediators in ACLF. With this aim, EVs were purified by size exclusion chromatography from the plasma of healthy subjects (HS) (n=6) and patients with compensated cirrhosis (CC) (n=6), AD (n=11) and ACLF (n=11), which were defined as positive for CD9, CD5L and CD63 and their size, number, morphology and lipid mediator content were characterized by NTA, EM, and LC-MS/MS, respectively. Additionally, plasma CD5L was quantified by ELISA in 10 HS, 20 CC and 149 AD patients (69 ACLF). Moreover, macrophage CD5L expression and the biosynthesis of specialized lipid mediators (SPMs) were characterized in vitro in primary cells. Our results indicate that circulating EVs were significantly suppressed in cirrhosis, regardless of severity, and showed considerable alterations in CD5L and lipid mediator content as the disease progressed. In AD, levels of EV CD5L correlated best with those of the SPM RvE1. Analysis of total plasma supported these data and showed that, in ACLF, low CD5L levels were associated with circulatory (p<0.001), brain (p<0.008) and respiratory (p<0.05) failure (Mann-Whitney test). Functional studies in macrophages indicated a positive feedback loop between CD5L and RvE1 biosynthesis. In summary, we have determined a significant alteration of circulating EV contents in ACLF, with a loss of anti-inflammatory and pro-resolving molecules involved in the control of acute inflammation in this condition.

Identification of the most vulnerable populations in the psychosocial sphere: a cross-sectional study conducted in Catalonia during the strict lockdown imposed against the COVID-19 pandemic.

DESIGN AND OBJECTIVES: A cross-sectional study to evaluate the impact of COVID-19 on the psychosocial sphere in both the general population and healthcare workers (HCWs). METHODS: The study was conducted in Catalonia (Spain) during the first wave of the COVID-19 pandemic when strict lockdown was in force. The study population included all people aged over 16 years who consented to participate in the study and completed the survey, in this case a 74-question questionnaire shared via social media using snowball sampling. A total of 56 656 completed survey questionnaires were obtained between 3 and 19 April 2020.The primary and secondary outcome measures included descriptive statistics for the non-psychological questions and the psychological impact of the pandemic, such as depression, anxiety, stress and post-traumatic stress disorder question scores. RESULTS: A n early and markedly negative impact on family finances, fear of working with COVID-19 patients and ethical issues related to COVID-19 care among HCWs was observed. A total of seven target groups at higher risk of impaired mental health and which may therefore benefit from an intervention were identified, namely women, subjects aged less than 42 years, people with a care burden, socioeconomically deprived groups, people with unskilled or unqualified jobs, patients with COVID-19 and HCWs working with patients with COVID-19. CONCLUSIONS: Active implementation of specific strategies to increase resilience and to prepare an adequate organisational response should be encouraged for the seven groups identified as high risk and susceptible to benefit from an intervention. TRIAL REGISTRATION NUMBER: NCT04378452.

The Circulating Fatty Acid Transporter Soluble CD36 Is Not Associated with Carotid Atherosclerosis in Subjects with Type 1 and Type 2 Diabetes Mellitus.

This study aimed to determine the association of fatty acid transporter plasma soluble cluster of differentiation 36 (sCD36) with subclinical carotid atherosclerosis (SCA). A cross-sectional study was conducted in 1023 subjects, 225 with type 1 diabetes (T1D), 276 with type 2 diabetes (T2D) and 522 who were nondiabetic. Carotid atherosclerotic plaque (CAP) presence was determined using B-mode carotid ultrasound imaging. sCD36 were analysed by ELISA, and CD36 surface receptor and mRNA expression were measured by flow cytometry and real-time PCR. Logistic regression models were used to evaluate sCD36 as a biomarker of SCA. Up to 376 (36.75%) participants had at least one CAP, 76 T1D, 164 T2D and 136 without diabetes, while the remaining 647 (63.25%) did not have any CAP. There were no differences in sCD36 between patients with and without CAP in T1D (p = 0.287) or T2D (p = 0.513). Although nondiabetic subjects with plaques had lower sCD36 levels than those without (p = 0.023), the multivariate models revealed no association of sCD36 with CAP in any of the three study groups. No differences were found in surface CD36 or CD36 mRNA expression between the patients with and without CAP. sCD36 is not associated with SCA in type 1 or type 2 diabetic or in nondiabetic subjects.

Circulating Soluble CD36 is Similar in Type 1 and Type 2 Diabetes Mellitus versus Non-Diabetic Subjects.

The aim of this study was to determine whether plasma concentrations of sCD36 (soluble CD36) are associated with the presence of type 1 or type 2 diabetes. Plasma levels of sCD36 were analysed in 1023 subjects (225 type 1 diabetes (T1D) patients, 276 type 2 diabetes (T2D) patients, and 522 non-diabetic control subjects) using an enzyme-linked immunosorbent assay (ELISA). Multinomial and logistic regression models were performed to evaluate associations with sCD36 and its association with diabetes types. There were no significant differences in sCD36 (p = 0.144) among study groups, neither in head-to-head comparisons: non-diabetic versus T1D subjects (p = 0.180), non-diabetic versus T2D subjects (p = 0.583), and T1D versus T2D patients (p = 0.151). In the multinomial model, lower sCD36 concentrations were associated with older age (p < 0.001), tobacco exposure (p = 0.006), T2D (p = 0.020), and a higher-platelets count (p = 0.004). However, in logistic regression models of diabetes, sCD36 showed only a weak association with T2D. The current findings show a weak association of circulating sCD36 with type 2 diabetes and no association with T1D.

CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content.

BACKGROUND: Chronic hepatic inflammation leads to liver fibrosis, which may progress to cirrhosis, a condition with high morbidity. Our aim was to assess the as yet unknown role of innate immunity protein CD5L in liver fibrosis. METHODS: CD5L was measured by ELISA in plasma samples from cirrhotic (n = 63) and hepatitis (n = 39) patients, and healthy controls (n = 7), by immunohistochemistry in cirrhotic tissue (n = 12), and by quantitative RT-PCR in mouse liver cell subsets isolated by cell sorting. Recombinant CD5L (rCD5L) was administered into a murine model of CCl4-induced fibrosis, and damage, fibrosis and hepatic immune cell infiltration, including the LyC6hi (pro-fibrotic)-LyC6low (pro-resolutive) monocyte ratio were determined. Moreover, rCD5L was added into primary human hepatic stellate cells to study transforming growth factor ß (TGFß) activation responses. FINDINGS: Cirrhotic patients showed elevated plasma CD5L concentrations as compared to patients with hepatitis and healthy controls (Mann-Whitney test p < 0·0001). Moreover, plasma CD5L correlated with disease progression, FIB4 fibrosis score (r:0·25, p < 0·0001) and tissue expression (r = 0·649; p = 0·022). Accordingly, CCl4-induced damage increased CD5L levels in total liver, particularly in hepatocytes and macrophages. rCD5L administration attenuated CCl4-induced injury and fibrosis as determined by reduced serum transaminase and collagen content. Moreover, rCD5L inhibited immune cell infiltration and promoted a phenotypic shift in monocytes from LyC6hi to LyC6low. Interestingly, rCD5L also had a direct effect on primary human hepatic stellate cells promoting SMAD7 expression, thus repressing TGFß signalling. INTERPRETATION: Our study identifies CD5L as a key pleiotropic inhibitor of chronic liver injury. FUND: Fundació Marató TV3, AGAUR and the ISCIII-EDRF.