Anterior cruciate ligament reconstruction (ACLR) is one of the most common orthopaedic procedures and one of the most well studied. Despite extensive research dedicated to ACLR, there is limited understanding of how chronic inflammatory systemic diseases (CIDs) such as rheumatoid arthritis and systemic lupus erythematosus affect outcomes.

To compare the outcomes of ACLR in cohorts of patients with and without CID.

Cohort study; Level of evidence, 3.

A retrospective query of a regional data set was conducted for all patients who underwent ACLR from 1990 to 2021 for traumatic ACL rupture. All patients with CID were identified and propensity matched to non-CID controls. Baseline characteristics and clinical outcomes were identified through retrospective chart review, and patients were contacted for subjective outcomes.

A total of 30 patients with ACLR and a diagnosis of CID were identified. These patients were propensity matched to 120 non-CID controls. Baseline demographic and surgical characteristics demonstrated no statistical differences. Follow-up duration was similar between the CID and non-CID groups (mean, 14.6 vs 14.2 years; P = .868). The CID cohort had a higher arthrofibrosis rate (16.7% vs 4.3%; P = .031), higher osteoarthritis rate (33.3% vs 16.7%; P = .041), higher total knee arthroplasty (TKA) rate (16.7% vs 3.3%; P = .016), and earlier time to TKA (14.7 vs 23.5 years; P = .032). Knee range of motion, infection rate, retear rate, time to retear, and time to osteoarthritis were not statistically different between the cohorts. The CID cohort had higher visual analog scale pain scores (mean, 2.00 vs 1.20; P = .043) but slightly higher satisfaction (mean, 3.92 vs 3.39; P = .043). There were no differences in preinjury Tegner, postoperative Tegner, change in Tegner, or IKDC score. In a univariate Cox regression model, the CID cohort had a retear hazard ratio of 1.43 (95% CI, 0.46-4.51; P = .537). Kaplan-Meier survival revealed no significant differences in retear-free survival between the CID and non-CID cohorts at 25 years (85.7% vs 87.3%; P = .53). The CID cohort had a TKA hazard ratio of 3.94 (95% CI, 1.05-14.8; P = .042). Kaplan-Meier survival demonstrated significantly decreased TKA-free survival at 25 years in the CID cohort (64.9% vs 91.2%; P = .029).

CID increases the incidence of arthrofibrosis, osteoarthritis, and TKA in those undergoing ACLR. Patients with CID also undergo TKA significantly sooner than non-CID counterparts. Notably, the majority of patient-reported outcome measures are no worse in patients who have a CID diagnosis. Thus, ACLR constructs themselves may not necessarily fare worse in patients with CID. Nonetheless, these patients need to be cautiously counseled on the clinical outlook after their ACLR.

Myofibroblasts, the primary producers of extracellular matrix, primarily originate from hepatic stellate cells (HSCs), and their activation plays a pivotal role in liver fibrosis. This study aimed to investigate the function of CXC motif ligand 14 (CXCL14) in the progression of liver fibrosis.

CXCL14 knockdown significantly reduced the extent of liver fibrosis. Using Ingenuity pathway analysis and qRT-PCR, activating transcription factor 3 (ATF3) was identified as a key upstream regulator of CXCL14 expression. Mechanistically, ATF3 was shown to bind to the CXCL14 promoter, promoting its transactivation by TGF-β in HSCs. Notably, both global CXCL14 deletion (CXCL14-/-) and HSC/myofibroblast-specific CXCL14 knockdown significantly attenuated liver fibrosis in mice. RNA-seq comparisons between CXCL14-/- and WT mice highlighted Jak2 as the most significantly downregulated gene, implicating its role in the antifibrotic effects of CXCL14 suppression on HSC inactivation. Moreover, Jak2 overexpression reversed the inhibition of liver fibrosis caused by CXCL14 knockdown in vivo.

These findings unveil a novel ATF3/CXCL14/Jak2 signalling axis in liver fibrosis, presenting potential therapeutic targets for the disease.

Chemokines, also known as chemotactic cytokines, stimulate the migration of immune cells. These molecules play a key role in the pathogenesis of inflammation leading to atherosclerosis, neurodegenerative disorders, rheumatoid arthritis, insulin-resistant diabetes, and cancer. Moreover, they take part in inflammatory bowel disease (IBD). The main objective of our research was to determine the activity of methyl-derivatives of flavanone, namely, 2'-methylflavanone (5B), 3'-methylflavanone (6B), 4'-methylflavanone (7B), and 6-methylflavanone (8B), on the releasing of selected cytokines by RAW264.7 macrophages activated by LPS. We determined the concentration of chemokines belonging to the CC chemokine family, namely, MCP-1, MIP-1β, RANTES, and eotaxin, using the Bio-Plex Magnetic Luminex Assay and the Bio-PlexTM 200 System. Among the tested compounds, only 5B and 6B had the strongest effect on inhibiting the examined chemokines' release by macrophages. Therefore, 5B and 6B appear to be potentially useful in the prevention of diseases associated with the inflammatory process.

Clinical drawback in checkpoint inhibitors immunotherapy (ICI) of metastatic melanoma (MM) is monitoring clinical benefit. Soluble forms of PD1(sPD1) and PD-L1(sPD-L1) and extracellular vesicles (EVs) expressing PD1 and PD-L1 have recently emerged as predictive biomarkers of response. As factors released in the blood, EVs and soluble forms could be relevant in monitoring treatment efficacy and adaptive resistance to ICI.

We used pre-therapy plasma samples of 110 MM patients and longitudinal samples of 46 patients. Elisa assay and flow cytometry (FCM) were used to measure sPD-L1 and sPD1 concentrations and the percentage of PD1+ EVs and PD-L1+ EVs, released from tumor and immune cells in patients subsets. Transwell assays were conducted to investigate the impact of EVs of each patient subset on MM cells invasion and interaction between tumor cells and macrophages or dendritic cells. Viability assays were performed to assess EVs effect on MM cells and organoids sensitivity to anti-PD1. FCM was used to investigate immunosuppressive markers in EVs and immune cells.

The concentrations of sPD1 and sPD-L1 in pre-treatment and longitudinal samples did not correlate with anti-PD1 response, instead only tumor-derived PD1+ EVs decreased in long responders while increased during disease progression in responders. Notably, we observed reduction of T cell derived EVs expressing LAG3+ and PD1+ in long responders and their increase in responders experiencing progression. By investigating the impact of EVs on disease progression, we found that those isolated from non-responders and from patients with progression disease accelerated tumor cells invasiveness and migration towards macrophages, while EVs of long responders reduced the metastatic potential of MM cells and neo-angiogenesis. Additionally, the EVs of non-responders and of progression disease patients subset reduced the sensitivity of MM cells and organoids of responder to anti-PD1 and the recruitment of dendritic cells, while the EVs of progression disease subset skewed macrophages to express higher level of PDL-1.

Collectively, we suggest that the detection of tumor-derived PD1 + EVs may represent a useful tool for monitoring the response to anti-PD1 and a role for EVs shed by tumor and immune cells in promoting tumor progression and immune dysfunction.

Intriguingly, liver regeneration after injury does not induce uncontrolled growth and the underlying mechanisms of such a "hepatostat" are still not clear. Endocan, a proteoglycan, was implicated in liver regeneration. It can support the function of hepatocyte growth factor/scatter factor in tissue repair after injury. Endostatin, a 20 kDa C-terminal fragment of collagen XVIII, may modulate the cessation of liver regeneration. eEF2K, a protein kinase that regulates protein synthesis, can regulate angiogenesis. Thus, we investigated the role of endocan, endostatin and eEF2K during normal liver regeneration.

Serum samples and regenerating remnant liver tissues were obtained on various days after partial hepatectomy in rats. mRNA expression levels of Vegf and Pcna were analyzed in addition to immunohistochemical evaluations. Liver tissue protein levels of endostatin, endocan and p-eEF2K/eEF2K were determined with Western blot. Serum levels of endostatin and endocan were assessed with ELISA.

Pcna expression level in residual liver tissues peaked on day-1, while Vegf expression reached its highest level on days 1-3 after partial hepatectomy (70%). Endocan activity declined gradually on days 1-7. The decrease in liver endocan expression was accompanied by an increase in serum endocan levels. Partial hepatectomy induced a rapid increase in liver endostatin levels. Following its surge on day-1, endostatin expression gradually declined, which was accompanied by a peak in serum endostatin. Finally, partial hepatectomy was shown to regulate eEF2K; thus, increasing protein translation.

We revealed possible mechanistic insights into liver regeneration by examining the associations of Pcna, Vegf, endocan, endostatin, eEF2K with hepatic regeneration after partial hepatectomy. Indeed, endocan might serve as a useful biomarker to monitor clinical prognosis in a plethora of conditions such as recovery of donor's remaining liver after living-donor liver transplant. Whether endocan might represent a strategy to optimize liver regeneration when given therapeutically needs to be investigated in future studies.

Patients undergoing anterior cruciate ligament (ACL) reconstruction have been shown to be at risk for postoperative arthrofibrosis. Diagnostic biomarkers associated with the development of postoperative stiffness are unknown.

Biomarkers found in the synovial fluid at the time of surgery are associated with the development of postoperative arthrofibrosis in a cohort of patients undergoing ACL reconstruction.

Case-control study; Level of evidence, 3.

Patients undergoing ACL reconstruction were prospectively enrolled. Synovial fluid was collected before surgical incision. A cohort of patients with postoperative stiffness requiring manipulation under anesthesia (MUA) and/or lysis of adhesions (LOA) was retrospectively identified. Matching of cases to controls was performed using a 1:2 pair matching algorithm. Risk factor-adjusted single-biomarker and multivariable models were used to assess the association of synovial fluid biomarkers with postoperative stiffness requiring MUA/LOA. Stepwise logistic regression controlling for clinical risk factors was used to identify biomarkers that are possible predictors of postoperative stiffness.

A total of 11 cases (3 male, 8 female) were identified and matched with 21 controls (6 male, 15 female) with no significant differences in age, sex, smoking history, or days from injury to surgery. Concentrations of the biomarker regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) were significantly higher in patients requiring MUA/LOA versus controls (694.20 pg/mL [interquartile range, 214.75-3428.79] vs 113.04 pg/mL [interquartile range, 32.81-517.91], respectively; P = .034). On single-biomarker models, RANTES (odds ratio, 2.28; 95% CI, 1.29-5.37; P = .019) and basic fibroblast growth factor (bFGF) (odds ratio, 1.91; 95% CI, 1.07-3.99; P = .047) were associated with increased risk of postoperative stiffness requiring MUA/LOA after ACL reconstruction. Stepwise logistic regression identified 3 biomarkers that are possible predictors of postoperative stiffness, which were included in the final model: Interleukin 1 receptor antagonist (IL-1RA) (P = .198), bFGF (P = .157), and RANTES (P = .046).

Higher concentrations of synovial fluid biomarkers bFGF and RANTES were associated with increased risk for stiffness requiring intervention after ACL reconstruction. Interleukin 6 (IL-6), vascular endothelial growth factor A (VEGF-A), tissue inhibitor of metalloproteinases 1 (TIMP-1), interleukin 1 receptor antagonist (IL-1RA), matrix metalloproteinase 3 (MMP-3), monocyte chemotactic protein 1 (MCP-1), and macrophage inflammatory protein 1B (MIP-1B) were not associated with the development of postoperative arthrofibrosis.

Hepatitis C virus (HCV) treatment in HIV/HCV co-infected individuals has renewed relevance given the ongoing opioid crisis and rise of new HIV and HCV infections associated with injection drug use. Patients co-infected with HIV and HCV demonstrate increased rates of hepatic fibrosis, progression to liver failure, and liver-related mortality. HIV co-infection does not impact outcomes of current HCV treatments, and patients should be treated the same as HCV mono-infected persons, though attention to drug:drug interactions is required. In this review, we discuss the mechanisms mediating injury to the liver in HIV mono-infection and HIV/HCV co-infection, and present the landmark trials of HCV treatment in HIV-infected individuals.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. Its severity ranges from simple steatosis to cirrhosis. C-C chemokine ligand type 5 or RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) plays an important role in the progression of hepatic inflammation and fibrosis. Our objective was to examine the preventive and therapeutic effects of maraviroc (MVC), a C-C chemokine receptor 5 antagonist, on liver pathology in an NAFLD mouse model. A total of 60 male C57BL/6 mice were randomly assigned to 1 of 4 groups: (1) high-fat diet (HFD) group or control group, (2) preventive group (HFD group plus MVC in drinking water since the beginning of the study), (3) early-therapeutic group (HFD group plus MVC in drinking starting at week 24 of the study), and (4) late-therapeutic group (HFD group plus MVC in drinking water starting at week 36 of the study). All mice were sacrificed at week 48. The hepatic triglyceride concentration in the HFD group was significantly higher than that in the groups treated with MVC at any time. Gene expression associated with lipogenesis (diacylglycerol acyltransferase 2 and proliferator-activated receptor-γ), insulin resistance (insulin receptor substrate-2), and β-oxidation (carnitine palmitoyltransferase 1A and acyl-CoA oxidase) was significantly reduced in all the groups treated with MVC. In summary, the beneficial effect of MVC on hepatic steatosis is maintained throughout the study.

We prospectively screened patients treated with direct-acting antivirals (DAA) in order to detect and analyze serum markers that are present prior to the development of drug-induced liver injury (DILI).

The levels of various serum markers among DILI, non-DILI and control groups were compared. The DILI group consisted of eight patients whose alanine aminotransferase (ALT) levels exceeded 32 IU/L during the DAA treatment. Eight patients without DILI were selected for the non-DILI group via a matched-group design based on age, sex and disease severity. Additionally, eight healthy volunteers were employed as the controls. Serum measurements of cytokines/chemokines, cytokeratin-18 fragment (CK-18F) and super oxidase dismutase-2 (SOD2) were evaluated on the date at which hepatitis C virus RNA was absent (baseline). For patients with DILI, serum measurements taken before treatment, 1 week before pronounced transaminase elevation (prominence-1 W) and on the date at which pronounced elevation of transaminase occurred (prominence) were also evaluated.

All patients treated with DAA had normalized transaminase levels at baseline. In patients with DILI, interferon-inducible protein-10 (IP-10) levels were higher at prominence-1 W than at baseline. Those patients also had significantly higher levels of SOD2 and CK-18F at prominence-1 W than at baseline.

Elevated IP-10 may be a preconditioning chemokine for DAA-induced liver injury, and damage markers associated with cell death and mitochondrial dysfunction are potential predictive serum markers for DILI.

There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis. Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis, complemented by other sources of matrix-producing cells, including portal fibroblasts, fibrocytes and bone marrow-derived myofibroblasts. These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury. Defining the interaction of different cell types, revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets. Moreover, the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies. This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies. The pathogenesis of liver fibrosis associated with alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.

Chronic hepatitis C virus (HCV) infection is an important cause of morbidity and mortality in people coinfected with human immunodeficiency virus (HIV). Several studies have shown that HIV infection promotes accelerated HCV hepatic fibrosis progression, even with HIV replication under full antiretroviral control. The pathogenesis of accelerated hepatic fibrosis among HIV/HCV coinfected individuals is complex and multifactorial. The most relevant mechanisms involved include direct viral effects, immune/cytokine dysregulation, altered levels of matrix metalloproteinases and fibrosis biomarkers, increased oxidative stress and hepatocyte apoptosis, HIV-associated gut depletion of CD4 cells, and microbial translocation. In addition, metabolic alterations, heavy alcohol use, as well drug use, may have a potential role in liver disease progression. Understanding the pathophysiology and regulation of liver fibrosis in HIV/HCV co-infection may lead to the development of therapeutic strategies for the management of all patients with ongoing liver disease. In this review, we therefore discuss the evidence and potential molecular mechanisms involved in the accelerated liver fibrosis seen in patients coinfected with HIV and HCV.

Overdose of acetaminophen (APAP) causes necrosis of centrilobular cells of the liver. Accumulating evidence suggests that innate immune system may contribute to APAP-induced hepatotoxicity. Interaction between RANTES and its receptor C-C chemokine receptor (CCR) 5 is related to recruitment of macrophages to sites of inflammation. In this study, we examined effects of CCR5 deficiency on APAP-mediated liver injury by employing CCR5 knockout (KO) mice. CCR5 wild-type (WT) and KO mice received intraperitoneal injection of APAP (300 mg/kg) and were killed 24 h after the injection. Hepatic injury was determined by using histological and biochemical analyses. Intraperitoneal APAP caused the hepatocytic necrosis, as evidenced by hematoxylin and eosin staining and an increase in alanine transaminase and aspartate transaminase levels in serum. Hepatic damage appeared to be larger in CCR5 WT animals compared with KO animals. There were no differences in cytochrome P450 2E1 between CCR5 WT and KO animals suggesting that the resistance of CCR5 KO mice did not come from alterations in APAP metabolism. Infiltration of macrophages into the liver was reduced in CCR5 KO mice, and this was accompanied decreased inflammatory responses. Inhibition of macrophage activity by pretreatment of gadolinium chloride significantly blocked APAP-caused hepatotoxicity. These results indicate that recruitment of macrophage into the inflammatory sites significantly contributes to APAP-mediated hepatocytic death and CCR5 gene deletion protects from APAP-induced liver injury by alleviating macrophage recruitment and inflammatory responses. This study represents a critical role of CCR5 in macrophage infiltration into the liver and subsequent hepatotoxicity upon challenge of APAP.

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the general population. The NAFLD spectrum ranges from simple steatosis to cirrhosis. The chemokine CCL5/RANTES plays an important role in the progression of hepatic inflammation and fibrosis. The objective of this study was to examine the effects of maraviroc, a CCR5 antagonist, on liver pathology in a NAFLD mouse model.

A total of 32 male C57BL/6 mice were randomly assigned to one of four groups: (i) control group (chow diet plus tap water); (ii) maraviroc group (chow diet plus maraviroc in drinking water); (iii) high-fat diet (HFD) group (HFD plus tap water); and (iv) maraviroc/HFD group (HFD plus maraviroc). All mice were sacrificed 16 weeks after the beginning of the experiment. Biochemical analyses and liver examinations were performed.

Mice in the HFD group showed a tendency towards increased body mass gain and liver damage compared with the maraviroc/HFD group. Moreover, liver weight in the HFD group was significantly higher than in the maraviroc/HFD group. Hepatic triglyceride concentration in the maraviroc/HFD group was significantly lower than in the HFD group. Interestingly, the maraviroc/HFD group exhibited a lower degree of steatosis. Furthermore, hepatic CCL5/RANTES expression was significantly lower in the maraviroc/HFD group than in the HFD group. Overall, no differences were observed between the control group and the maraviroc group.

Maraviroc ameliorates hepatic steatosis in an experimental model of NAFLD.

It is unknown what role Regulated Upon Activation Normal T-Cell Exposed and Secreted may play in retransplantation or T-cell memory-transfer models. The experiment observed the influence of the chemokine RANTES in a mouse model of acute cardiac allograft rejection induced by adoptive transfer of alloreactive CD4(+) memory T (Tm) cells.

Alloreactive CD4(+) Tm cells from spleens of skin-grafted C57BL/6 were adoptively transferred to naïve C57BL/6 recipients prior to heterotopic heart transplantation. We measured the median survival time of cardiac grafts and performed some tests.

Spleens from skin-grafted C57BL/6 contained 26.83% CD4(+) Tm cells. The median graft survival time of heterotopic heart transplantations (n = 6) was 5.17 ± 0.17 days for hosts receiving CD4(+) Tm cells compared with 7.76 ± 0.21 days among controls (n = 6; P < .001). The mean rejection activity in histological sections of cardiac allografts at day 5 postgrafting was 3.92 ± 0.08 in the CD4(+) Tm cell recipient group (n = 6) compared with 2.67 ± 0.14 in the controls (n = 6; P < .001). Gene expression of Ccl5, interferon (IFN)-γ and interleukin2 was significantly higher among CD4(+) Tm recipients compared with controls. Serum concentrations of RANTES and IFN-γ were higher in the heterotopic heart transplantation group receiving CD4(+) Tm compared with controls.

Alloreactive CD4(+) Tm cells contribute to increased expression and secretion of RANTES, and to the Tm and other inflammatory cells migration into the graft.

HCV infection is a global health problem that affects 170 million people worldwide. The severity of the disease varies from asymptomatic chronic infection to cirrhosis and hepatocellular carcinoma (HCC). Recently, the standard of care for genotype 1 patients has greatly improved with the addition of protease inhibitors (telaprevir or boceprevir) to pegylated interferon (PegIFN) and ribavirin (RBV). The prediction of fibrosis progression and the response to antiviral treatment are two major issues in the management of patients with chronic hepatitis C. Differential expression of mRNAs was first analyzed for both progression of fibrosis and treatment response. Specific polymorphisms, associated with either fibrosis or viral response, were identified thanks to major improvements in genome scanning technologies. Since 2009, several independent genome wide association studies (GWAS) have reported an association between genetic polymorphisms within the IL-28B promoter and both natural and treatment-induced clearance in genotype 1 infected patients. These different studies showed the strong association and the importance of IL-28B polymorphisms in the treatment response. Combining the different genetic factors could improve their predictive value and help identify patients at a high risk of progression of fibrosis as well as those with a lower chance of responding to treatment. The aim of this review was to discuss the genomic factors (mRNAs, miRNAs, and SNPs) and HCV infection with clinical implications for either progression of fibrosis or treatment response. Recent findings on the IL-28B polymorphism and its application in clinical practice will also be discussed.

The specific mechanisms that mediate CD4(+) T-cell-mediated liver injury have not been fully elucidated. CD4(+) invariant natural killer T (iNKT) cells are required for liver damage in some mouse models of hepatitis, while the chemokine receptors CXCR3 and CCR5 are considered dominant Th1 chemokine receptors involved in Th1 trafficking in inflammatory conditions. BALB/c-Tgfb1(-/-) mice spontaneously develop Th1 hepatitis. Here, we directly test the hypotheses that iNKT cells or the Th1-cell chemokine receptors CXCR3 and CCR5 are required for development of liver disease in Tgfb1(-/-) mice. Tgfb1(-/-) mouse livers exhibited significant increases in iNKT cells and in ligands for CXCR3 or CCR5. Tgfb1(-/-) mice were rendered deficient in iNKT cells, CXCR3, CCR5, or both CXCR3 and CCR5, by cross-breeding with appropriate knockout mice. Tgfb1(-/-) mice developed severe liver injury, even in the absence of functional CD1d/iNKT cells, CXCR3, CCR5, or both CXCR3 and CCR5. Liver CD4(+) T cells accumulated to high numbers, and spleen CD4(+) T-cell numbers declined, regardless of the functionality of the CXCR3/CCR5 response pathways. Similarly, dendritic cells and macrophages accumulated in Tgfb1(-/-) livers even when CXCR3 and CCR5 were knocked out. Th1-associated cytokines (IFN-γ, TNF-α, IL-2) and chemokines (CXCL9, CXCL10) were strongly overexpressed in Tgfb1(-/-) mice despite knockouts in CD1d, CXCR3, or CCR5. These studies indicate that the cellular and biochemical basis for CD4(+) T-cell-mediated injury in liver can be complex, with myriad pathways potentially involved.