OBJECTIVE

The aim of the article is to describe an immunological reaction to shunt infection in children with hydrocephalus. The main cause of shunt infection involves methicillin resistant Staphylococcus epidermidis (Bhatia et al. Indian J Med Microbiol 35:120-123, 2017; Hayhurst et al. Childs Nerv Syst 24:557-562, 2008; Martínez-Lage et al. Childs Nerv Syst 26: 1795-1798, 2010; Simon et al. PLoS One, 2014; Snowden et al. PLoS One 8:e84089, 2013; Turgut et al. Pediatr Neurosurg 41:131-136, 2005), a bacterial strain which is responsible for the formation of biofilm on contaminated catheters (Snowden et al. PLoS One 8:e84089, 2013; Stevens et al. Br J of Neurosurg 26: 792-797, 2012).

METHODS

The study group involved 30 children with congenital hydrocephalus after shunt system implantation, whose procedures were complicated by S. epidermidis implant infection. Thirty children with congenital hydrocephalus awaiting their first-time shunt implantation formed the control group. The level of eosinophils in peripheral blood was assessed in both groups. Cerebrospinal fluid (CSF) was examined for protein level, pleocytosis, interleukins, CCL26/Eotaxin-3, IL-5, IL-6, CCL11/Eotaxin-1, CCL3/MIP-1a, and MBP. Three measurements were performed in the study group. The first measurement was obtained at the time of shunt infection diagnosis, the second one at the time of the first sterile shunt, and the third one at the time of shunt reimplantation. In the control group, blood and CSF samples were taken once, at the time of shunt implantation.

RESULTS

In the clinical material, the highest values of eosinophils in peripheral blood and CSF pleocytosis were observed in the second measurement. It was accompanied by an increase in the majority of analyzed CSF interleukins.

CONCLUSIONS

CSF pleocytosis observed in the study group shortly after CSF sterilization is presumably related to an allergic reaction to Staphylococcus epidermidis, the causative agent of ventriculoperitoneal shunt infection.

CCL11 (also known as eotaxin) is a very potent and selective mediator of eosinophil migration which exerts its effects through its receptor, CCR3. In this study we report the cloning of an equine CCR3 cDNA sequence and investigation of the localization of CCR3 mRNA expression in horse tissues. Equine CCR3 displayed high levels of sequence identity with CCR3 sequences in other species. RT-PCR analysis revealed the expression of CCR3 in colon, lung and spleen of normal horses. In situ hybridisation experiments indicated that expression of CCR3 mRNA in colon was predominantly in eosinophils and to a lesser extent in mast cells, whereas CCR3 was seen mainly in lymphocytes of the lung and spleen. In view of the role of CCR3 in the recruitment of cells into sites of allergic inflammation, equine-specific CCR3 sequence data and information on tissue localization will be of potential benefit in the development of CCR3-targeted anti-inflammatory therapies in the horse.

Cytokines CCL11 (eotaxin) and HMGB1 (alarmin1) are molecular markers of ageing and neurological, cardiovascular and immune diseases. Created in St. Petersburg Institute of Bioregulation and Gerontology short peptides are known to regulate gene expression and protein synthesis. They promote the mortality decrease and slowdown the development of pathology in the elderly. The article presents the proposed role of dipeptide vilon (Lys-Glu) and tetrapeptide epitalon (Ala-Glu-Asp-Gly) in CCL11 and HMGB1 genes regulation as activators of their expression. Geroprotective action of vilon and epitalon probably realizes in suppression of these genes.

Degeneration of central neurons and fibers has been observed in postmortem brains of heroin dependent patients. However, there are no biomarkers to predict the severity of neurodegeneration related to heroin dependence. A correlation has been reported between inflammatory C-C motif chemokine ligand 11 (CCL11, or eotaxin-1) and neurodegeneration in Alzheimer's disease.

Three-hundred-forty-four heroin dependent, Taiwanese patients under methadone maintenance treatment (MMT) were included with clinical assessment and genomics information. Eighty-seven normal control subjects were also recruited for comparison.

Using receiver operating characteristics curve analyses, CCL11 showed the strongest sensitivity and specificity in correlation with age by a cut-off at 45 years (AUC = 0.69, P < 0.0001) in MMT patients, but not normal controls. Patients 45 years of age or older had significantly higher plasma levels of CCL11, fibroblast growth factor 2 (FGF-2), nicotine metabolite cotinine, and a longer duration of addiction. Plasma level of CCL11 was correlated with that of FGF-2 (partial r2 = 0.24, P < 0.0001). Carriers with the mutant allele of rs1129844, a functional single nucleotide polymorphism (Ala23Thr) in the CCL11 gene, showed a higher plasma level of Aß42, ratio of Aß42/Aß40, and insomnia side effect symptom score than the GG genotype carriers among MMT responders with morphine-negative urine results.

The results suggest possible novel mechanisms mediated through CCL11 involving neurotoxicity in heroin dependent patients.

Background: Identification of clinically useful biomarkers for Nasal Polyposis in chronic rhinosinusitis (CRSwNP) has proven dif-ficult. We analyzed gene expression profiling data to find explanations for this.

Methods: We analyzed mRNA expression profiling data, GSE36830, of six uncinate tissues from healthy controls and six NP from CRSwNP patients. We performed Ingenuity Pathway Analysis (IPA) of differentially expressed genes to identify pathways and predicted upstream regulators.

Results: We identified 1,608 differentially expressed genes and 177 significant pathways, of which Th1 and Th2 activation pathway and leukocyte extravasation signaling were most significant. We identified 75 upstream regulators whose activity was predicted to be upregulated. These included regulators of known pathogenic and therapeutic relevance, like IL-4. However, only seven of the 75 regulators were actually differentially expressed in NP, namely CSF1, TYROBP, CCL2, CCL11, SELP, ADORA3, ICAM1. Interes-tingly, these did not include IL-4, and four of the seven were receptors. This suggested a potential explanation for the discrepancy between the predicted and observed expression levels of the regulators, namely that the receptors, and not their ligands, were upregulated. Indeed, we found that 10 receptors of key predicted upstream regulators were upregulated, including IL4R.

Conclusion: Our findings indicate that the difficulties in finding specific biomarkers for CRSwNP depend on the complex underly-ing mechanisms, which include multiple pathways and regulators, each of which may be subdivided into multiple components such as ligands, soluble and membrane-bound receptors. This suggests that combinations of biomarkers may be needed for CRSwNP diagnostics.

Regulation of cellular death is central to nearly all physiological routines and is dysregulated in virtually all diseases. Cell death occurs by two major processes, necrosis which culminates in a pervasive inflammatory response and apoptosis which is largely immunologically inert. As necrosis has long been considered an accidental, unregulated form of cellular death that occurred in response to a harsh environmental stimulus, it was largely ignored as a clinical target. However, recent elegant studies suggest that certain forms of necrosis can be reprogrammed. However, scant little is known about the molecules and pathways that orchestrate calcium-overload-induced necrosis, a main mediator of ischemia/reperfusion (IR)-induced cardiomyocyte cell death. To rectify this critical gap in our knowledge, we performed a novel genome-wide siRNA screen to identify modulators of calcium-induced necrosis in human muscle cells. Our screen identified multiple molecular circuitries that either enhance or inhibit this process, including lysosomal calcium channel TPCN1, mitophagy mediatorTOMM7, Ran-binding protein RanBP9, Histone deacetylase HDAC2, chemokine CCL11, and the Arp2/3 complex regulator glia maturation factor-γ (GMFG). Notably, a number of druggable enzymes were identified, including the proteasome β5 subunit (encoded by PSMB5 gene), which controls the proteasomal chymotrypsin-like peptidase activity. Such findings open up the possibility for the discovery of pharmacological interventions that could provide therapeutic benefits to patients affected by myriad disorders characterized by excessive (or too little) necrotic cell loss, including but not limited to IR injury in the heart and kidney, chronic neurodegenerative disorders, muscular dystrophies, sepsis, and cancers.

Chitin is a structural biopolymer found in numerous organisms, including pathogenic fungi, and recognized as an immune-stimulating pathogen associated molecular pattern by pattern recognition molecules of the host immune system. However, programming and regulation of lung innate immunity to chitin inhalation in the context of inhalation of fungal pathogens such as Aspergillus fumigatus is complex and our understanding incomplete. Here we report that the systemic metabolism-regulating cytokine adiponectin is decreased in the lungs and serum of mice after chitin inhalation, with a concomitant decrease in surface expression of the adiponectin receptor AdipoR1 on lung leukocytes. Constitutive lung expression of acidic mammalian chitinase resulted in decreased inflammatory cytokine gene expression and neutrophil recruitment, but did not significantly affect lung adiponectin transcription. Exogenous recombinant adiponectin specifically dampened airway chitin-mediated eosinophil recruitment, while adiponectin deficiency resulted in increased airway eosinophils. The presence of adiponectin also resulted in decreased CCL11-mediated migration of bone marrow-derived eosinophils. In contrast to purified chitin, aspiration of viable conidia from the high chitin-expressing A. fumigatus isolate Af5517 resulted in increased neutrophil recruitment and inflammatory cytokine gene expression in adiponectin-deficient mice, while no significant changes were observed in response to the isolate Af293. Our results identify a novel role for the adiponectin pathway in inhibition of lung inflammatory responses to chitin and A. fumigatus inhalation.

OBJECTIVE

To assess the biological effects of purified recombinant equine CCL11 on equine eosinophil function.

METHODS

Following stimulation of eosinophils from normal horses, the polymerised form of actin was measured by flow cytometry using fluorescently labelled phalloidin. Migration was determined in a 96 well plate chemotaxis assay using 8 microm pore membranes, and adherence of eosinophils to serum-coated plastic was assessed using a colorimetric assay for eosinophil peroxidase. Superoxide generation was measured by the reduction of cytochrome C in a colorimetric assay.

RESULTS

Equine CCL11 induced significant (p < 0.001), concentration-dependent actin polymerisation and migration of equine eosinophils. Stimulation with CCL11 did not induce significant adherence to serum coated plastic, or superoxide production.

CONCLUSIONS

Equine CCL11 stimulates cytoskeletal reorganization and migration of equine eosinophils, suggesting that it may be involved in the regulation of eosinophil trafficking in horses.

In recent years commensal microorganisms are not just "passive occupants", but important element of homeostasis. There are numerous reports documenting the composition and role of the gut, skin or vagina microbiome but the role of commensal organisms living in the lungs is relatively unknown. Pulmonary microbiome impact on the immune response of the host organism and may indicate new therapeutic directions. Lung microbiome, by modulating the expression of innate immunity genes, causes an increase in the concentration of IL-5, IL-10, IFNγ and CCL11, affects the TLR4 dependent response of pulmonary macrophages and modulate the production of antibacterial peptides contained in the mucus. It is documented that disorders of the lung microbiome contribute to asthma or chronic obstructive pulmonary disease. However it is known that pulmonary dysbiosis also occurs in critically ill patients. It is possible, therefore, that microbiota-targeted therapy may constitute the future therapeutic direction in ICU.

Keywords: lung microbiom; lung-gut interaction; ICU.

Background and aim: Pre-clinical ulcerative colitis is poorly defined. We aimed to characterize the pre-clinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins.

Methods: We obtained plasma samples, biobanked from individuals who later in life developed ulcerative colitis (n=72), and matched healthy controls (n=140), within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biological relevance of these findings were validated in an inception cohort of ulcerative colitis patients (n=101), and healthy controls (n=50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of ulcerative colitis patients (n=41) and matched healthy controls (n=37) were explored.

Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP1) were upregulated (p<0.05) in pre-clinical ulcerative colitis compared to controls based on both univariate and mulativariable models. Ingenuity Pathway Analyses identified several potential key regulators, including IL-1b, TNF, IFN-gamma, OSM, NFĸB, IL-6 and IL-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve ulcerative colitis patients from controls with leave-one-out cross-validation (AUC=0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly upregulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis.

Conclusions: A set of inflammatory proteins are upregulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be upregulated already at exposure to genetic and environmental risk factors.

Keywords: CXCL9; Inflammatory Bowel Disease; MMP10; pre-clinical disease; proximity extension assay.

Purpose: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection.

Methods: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation.

Results: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1β (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1β (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels.

Conclusions: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.

Keywords: CCL11; Children; Cytokines; Epilepsy; HHV6; Inflammation; Seizures.

Background: Schizophrenia (SCZ) and treatment-resistant schizophrenia (TRS) are associated with aberrations in immune-inflammatory pathways. Increased high mobility group protein 1 (HMGB1), an inflammatory mediator, and Dickkopf-related protein (DKK1), a Wnt/β-catenin signaling antagonist, affect the blood-brain barrier and induce neurotoxic effects and neurocognitive deficits.

Aim: The present study aims to examine HMGB1 and DDK1 in nonresponders to treatments (NRTT) with antipsychotics (n = 60), partial RTT (PRTT, n = 55), and healthy controls (n = 43) in relation to established markers of SCZ, including interleukin (IL)-6, IL-10, and CCL11 (eotaxin), and to delineate whether these proteins are associated with the SCZ symptom subdomains and neurocognitive impairments.

Results: HMGB1, DKK1, IL-6, and CCL11 were significantly higher in SCZ patients than in controls. DKK1 and IL-6 were significantly higher in NRTT than in PRTT and controls, while IL-10 was higher in NRTT than in controls. Binary logistic regression analysis showed that SCZ was best predicted by increased DDK1 and HMGB1, while NRTT (vs PRTT) was best predicted by increased IL-6 and CCL11 levels. A large part of the variance in psychosis, hostility, excitation, mannerism, and negative (PHEMN) symptoms and formal thought disorders was explained by HMGB1, IL-6, and CCL11, while most neurocognitive functions were predicted by HMGB1, DDK1, and CCL11.

Conclusions: The neurotoxic effects of HMGB1, DKK1, IL-6, and CCL11 including the effects on the blood-brain barrier and the Wnt/β-catenin signaling pathway may cause impairments in executive functions and working, episodic, and semantic memory and explain, in part, PHEMN symptoms and a nonresponse to treatment with antipsychotic drugs.

Keywords: cytokines; inflammation; neuro-immune; neurocognition; schizophrenia; treatment resistance.

Berberine is an isoquinoline alkaloid isolated from various Chinese herbs that has potential of anti-inflammatory, anti-lipidemic, anti-neoplastic, and anti-diabetic activity. In this study, we evaluated the anti-inflammatory efficacy of berberine on allergic airway inflammation by targeting epithelial cells. Allergic airway inflammation driven by T helper 2 (Th2)-type immunity is characterized by airway hyperresponsiveness, elevated IgE production, and eosinophilic infiltration. For eosinophil recruitment, major chemoattractant CCL11 (eotaxin-1) was secreted by lung epithelial cells. BEAS-2B cells, a human bronchial epithelial cell line, were pre-treated with berberine and then activated by IL-4 plus TNF-α. The viability of BEAS-2B cells was assessed. Expression levels of IL-6 and CCL11 were determined using ELISA and real-time PCR. The signaling pathways of MAP kinases, NF-κB, and STAT6 were analyzed by western blot. Berberine treatment (≤1 μM) didn't significantly affect the viability of BEAS-2B cells with or without IL-4 plus TNF-stimulation. Berberine significantly inhibited the secretion of IL-6 and CCL11 from pro-inflammatory cytokine-activated BEAS-2B cells. NF-κB and MAP kinase pathways were seemingly unaffected in BEAS-2B cells with berberine treatment. Significant reduction of nuclear STAT6 protein expression in activated BEAS-2B cells with berberine treatment was observed. Current study reveals that berberine has inhibitory effect in pro-inflammatory cytokine-activated BEAS-2B cells through reducing IL-6 and CCL11 production, which is possibly modulated by suppressing STAT6 signaling pathway.

Keywords: Berberine; asthma; cytokines; eotaxin; epithelial cell.

Introduction: Dysregulation of NLRP3 inflammasome complex formation can promote chronic inflammation by increased release of IL-1β. However, the effect of NLRP3 complex formation on tumor progression remains controversial. Therefore, we sought to determine the effect of NLRP3 modulation on the growth of the different types of cancer cells, derived from lung, breast, and prostate cancers as well as neuroblastoma and glioblastoma in-vitro.

Method: The effect of Caspase 1 inhibitor (VX765) and combination of LPS/Nigericin on NLRP3 inflammasome activity was analyzed in A549 (lung cancer), MCF-7 (breast cancer), PC3 (prostate cancer), SH-SY5Y (neuroblastoma), and U138MG (glioblastoma) cells. Human fibroblasts were used as control cells. The effect of VX765 and LPS/Nigericin on NLRP3 expression was analyzed using western blot, while IL-1β and IL-18 secretion was detected by ELISA. Tumor cell viability and progression were determined using Annexin V, cell proliferation assay, LDH assay, sphere formation assay, transmission electron microscopy, and a multiplex cytokine assay. Also, angiogenesis was investigated by a tube formation assay. VEGF and MMPs secretion were detected by ELISA and a multiplex assay, respectively. Statistical analysis was done using one-way ANOVA with Tukey's analyses and Kruskal-Wallis one-way analysis of variance.

Results: LPS/Nigericin increased NRLP3 protein expression as well as IL-1β and IL-18 secretion in PC3 and U138MG cells compared to A549, MCF7, SH-SY5Y cells, and fibroblasts. In contrast, MIF expression was commonly found upregulated in A549, PC3, SH-SY5Y, and U138MG cells and fibroblasts after Nigericin treatment. Nigericin and a combination of LPS/Nigericin decreased the cell viability and proliferation. Also, LPS/Nigericin significantly increased tumorsphere size in PC3 and U138MG cells. In contrast, the sphere size was reduced in MCF7 and SH-SY5Y cells treated with LPS/Nigericin, while no effect was detected in A549 cells. VX765 increased secretion of CCL24 in A549, MCF7, PC3, and fibroblasts as well as CCL11 and CCL26 in SH-SY5Y cells. Also, VX765 significantly increased the production of VEGF and MMPs and stimulated angiogenesis in all tumor cell lines.

Discussion: Our data suggest that NLRP3 activation using Nigericin could be a novel therapeutic approach to control the growth of tumors producing a low level of IL-1β and IL-18.

Keywords: IL-1β; NLRP3; cancer; inflammasome; nigericin.

The paper presents the latest literature data on the structure and functions of «protein of juvenility» - CCL11 and «protein of senility» - GDF11. Chemokine CCL11 injected to young animals has been shown to lead to degenerative changes in the central nervous system (CNS), disturb cognitive functions and impede tissue regeneration. CCL11 concentration increases dramatically in schizophrenia, Alzheimer's disease, neuro-inflammatory disorders, cerebral malaria, drug addiction, as well as in atherosclerosis, periodontal disease, macular degeneration, cancer and other pathologies. In contrast to CCL11, differentiation growth factor 11 (GDF11), being administered to old mice, eliminates age-associated hypertrophy of the heart, improves muscle tone and prevents degenerative changes in the CNS, improves cognitive functions and enhances tissue regeneration. Its concentration decreases in cardiovascular disease, osteoporosis, and other «diseases of old age». At the same time, the higher the GDF11 level in the blood, the milder myocardial infarction, stroke and other age-related diseases of the cardiovascular system.

Purpose: To evaluate the levels and regulation of tear film inflammatory proteins in contact lens-related dry eye (CLDE).

Methods: One hundred healthy, daily wear (non-overnight), experienced soft contact lens wearers were classified into normal (n = 50) and CLDE (n = 50) groups based on Contact Lens and Dry Eye Questionnaire scores, tear break-up times, and comfort (a two-hour difference between total and comfortable daily lens wear hours). Tear samples (up to 5 μL) were collected by capillary extraction from the inferior meniscus of each eye, and pooled tear samples (10 per group) were tested using a customized Quantibody array. Mann Whitney tests with the Benjamini-Hochberg procedure with a 5% false discovery rate were used to compare the normal and CLDE groups.

Results: Relative to the normal group, the CLDE group showed a significantly increased tear concentration of several inflammatory mediators, including interleukin (IL)-7 (p = 0.001), IL-8 (p = 0.001), IL-13 (p = 0.001), IL-15 (p = 0.001), IL-12 p70 (p = 0.002), growth-related oncogene-alpha/ chemokine (CXC motif) ligand 1 (p = 0.003), granulocyte-colony stimulating factor (p = 0.005), IL-11 (p = 0.008), epidermal growth factor receptor (p = 0.01), IL-1 receptor antagonist (RA) (p = 0.013), macrophage colony-stimulating factor (p = 0.013), Eotaxin/CC motif chemokine ligand 11 (CCL11) (p = 0.016), and IL-2 (p = 0.016). The following cytokines were increased three-fold or more in the CLDE group: IL-13 (p = 0.001), Eotaxin/CCL11 (p = 0.016), and IL-1RA (p = 0.013).

Conclusions: Several inflammatory markers, including interleukins, were increased in tears of subjects with CLDE. These results support a growing body of evidence that suggests a potential role of inflammation in CLDE.

Keywords: Contact lens; Dry eye disease; Inflammation; Inflammatory proteins; Tear film.

Opioid use disorder is a leading cause of morbidity and mortality in the United States. Increasing pre-clinical and clinical evidence demonstrates sex differences in opioid use and dependence. However, the underlying molecular mechanisms contributing to these effects, including neuroinflammation, are still obscure. Therefore, in this study, we investigated the effect of oxycodone exposure and withdrawal on sex- and region-specific neuroimmune response. Real-time PCR and multiplex cytokine array analysis demonstrated elevated neuroinflammation with increased pro-inflammatory cytokine levels, and aberrant oligodendroglial response in reward neurocircuitry, following withdrawal from chronic oxycodone treatment. Chronic oxycodone and withdrawal treated male mice had lower mRNA expression of TMEM119 along with elevated protein levels of pro-inflammatory cytokines/chemokines and growth factors (IL-1β, IL-2, IL-7, IL-9, IL-12, IL-15, IL17, M-CSF, VEGF) in the prefrontal cortex (PFC) as compared to their female counterparts. In contrast, reduced levels of pro-inflammatory cytokines/chemokines (IL-1β, IL-6, IL-9, IL-12, CCL11) was observed in the nucleus accumbens (NAc) of oxycodone and withdrawal-treated males as compared to female mice. No treatment specific effects were observed on the mRNA expression of putative microglial activation markers (Iba1, CD68), but an overall sex specific decrease in the mRNA expression of Iba1 and CD68 was found in the PFC and NAc of male mice as compared to females. Moreover, a sex and region-specific increase in the mRNA levels of oligodendrocyte lineage markers (NG2, Sox10) was also observed in oxycodone and withdrawal treated animals. These findings may open a new avenue for development of sex-specific therapeutics for opioid dependence by targeting region-specific neuroimmune signaling.

Keywords: Glia; Neuroinflammation; Opioid; Oxycodone; Sex differences; Withdrawal.

The pathogenesis involving non-alcoholic fatty liver disease (NAFLD) in the context of chronic HBV (CHB) virus infection requires to be understood for developing improved modalities of diagnosis and treatment. We retrospectively investigated the association between NAFLD and CHB virus infection in the context of liver fibrosis. Among the 522 consecutive CHB patients who underwent transient elastography between years 2013 and 2016, we studied 455 subjects in the current investigation. Controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) scores were generally higher in patients with steatosis and fibrosis or cirrhosis. Antiviral treatment had significantly reduced the hepatitis B virus (HBV) viral load. Other liver function markers showed a significant positive correlation with both CAP and LSM scores. Plasma IL-13 was independently associated with increased CAP score where every increase of 1 unit of IL-13 was associated with an increase in CAP score by 0.98 unit. CCL11 was independently associated with LSM with every increase of CCL11 by a unit that, in turn, was associated with an increase of LSM score. We found that there was a high concurrence of NAFLD among patients with CHB virus infection. The presence of metabolic syndrome and chronic inflammation in CHB virus-infected patients were two independent factors that led to the progression of liver cirrhosis, with IL-13 playing the key role in linking the metabolic with the inflammatory components.

Keywords: CCL11; Fibrosis; HBV; IL-13; metabolic syndrome.

There are different case definitions of premenstrual syndrome, one proposed by the American College of Obstetricians and Gynecologists (ACOG) and another based on the Daily Record of Severity of Problems (DRSP) scores. Here we review our recent findings indicating that the gold-standard methods to assess PMS, including ACOG, induce a high degree of false-negative findings. We propose a new case definition of the menstrual cycle-associated syndrome (MCAS), which is characterized by increased DRSP scores during the menstrual cycle and by symptom increases the week prior to the menses. The MCAS case definition was externally validated by diverse biomarkers including plasma levels of progesterone and estradiol, chemokines (e.g. CCL2, CCL5 and CCL11), epidermal growth factor, hydroperoxides, paraoxonase 1 activity and complement C4. These biomarkers as well as IgA responses to Gram-negative bacteria are significantly associated with the DRSP and its subdomains including depression, anxiety, and physiosomatic (fatigue, pain) symptoms. In conclusion, we propose, to a) use the MCAS diagnosis as an indicant of menstrual cycle-related symptoms; and b) examine the associations of the time series in the DRSP and its subdomains and those in biomarkers including distributed lag models. Aberrations in the uterine-chemokine-brain-axis underpin the pathophysiology of MCAS whereby suboptimal pre-ovulatory follicular development coupled with a relative corpus luteum insufficiency may drive increased chemokine production, lowered antioxidant defenses, neuro-oxidative stress pathways, and increased bacterial translocation. As such, we have delineated new drug targets for the treatment of MCAS. This opinion paper reviews new possible treatments that should be trialed in MCAS.

Keywords: Fatigue; antioxidants; biomarkers.; depression; inflammation; neuroimmune; oxidative stress.

Allergic asthma is a chronic inflammatory airway disease characterized by dysregulated type 2 immune responses, including degranulating airway eosinophils that induce tissue damage and airway hyperresponsiveness (AHR). The type 2 cytokines interleukin 5 (IL-5) and IL-13 and the eosinophil-specific chemokine CCL11/CCL24/CCL26 axis recruit, activate, and regulate eosinophils in the airways. In this issue of the JCI, Karcz et al. identified a mechanism involving the nucleotide sugar UDP-glucose (UDP-G) and the purinergic receptor P2Y14R in amplifying eosinophil accumulation in the lung. During type 2 inflammation, UDP-G activates P2Y14R on eosinophils, inducing the cells to move and migrate into the lung. Pharmacologically or genetically inhibiting P2Y14R on eosinophils attenuated eosinophil infiltration and AHR. Future experiments, including identifying additional type 2 factors regulating P2Y14R expression on lung eosinophils, are necessary to ascertain the impact of targeting P2Y14R as an alternative or adjunctive therapy to current type 2 biologics for the treatment of asthma.

Treatment of autoimmune and inflammatory diseases typically involves immune suppression. In an opposite strategy, we show that administration of the highly inflammatory erythrocyte-specific antibody Ter119 into mice remodels the monocyte cellular landscape, leading to resolution of inflammatory disease. Ter119 with intact Fc function was unexpectedly therapeutic in the K/BxN serum transfer model of arthritis. Similarly, it rapidly reversed clinical disease progression in collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis and completely corrected CAIA-induced increase in monocyte Fcγ receptor II/III expression. Ter119 dose-dependently induced plasma chemokines CCL2, CCL5, CXCL9, CXCL10, and CCL11 with corresponding alterations in monocyte percentages in the blood and liver within 24 hours. Ter119 attenuated chemokine production from the synovial fluid and prevented the accumulation of inflammatory cells and complement components in the synovium. Ter119 could also accelerate the resolution of hypothermia and pulmonary edema in an acute lung injury model. We conclude that this inflammatory anti-erythrocyte antibody simultaneously triggers a highly efficient anti-inflammatory effect with broad therapeutic potential.