T-bet Transcription Factor Promotes Antibody-Secreting Cell Differentiation by Limiting the Inflammatory Effects of IFN-γ on B Cells.

Although viral infections elicit robust interferon-γ (IFN-γ) and long-lived antibody-secreting cell (ASC) responses, the roles for IFN-γ and IFN-γ-induced transcription factors (TFs) in ASC development are unclear. We showed that B cell intrinsic expression of IFN-γR and the IFN-γ-induced TF T-bet were required for T-helper 1 cell-induced differentiation of B cells into ASCs. IFN-γR signaling induced Blimp1 expression in B cells but also initiated an inflammatory gene program that, if not restrained, prevented ASC formation. T-bet did not affect Blimp1 upregulation in IFN-γ-activated B cells but instead regulated chromatin accessibility within the Ifng and Ifngr2 loci and repressed the IFN-γ-induced inflammatory gene program. Consistent with this, B cell intrinsic T-bet was required for formation of long-lived ASCs and secondary ASCs following viral, but not nematode, infection. Therefore, T-bet facilitates differentiation of IFN-γ-activated inflammatory effector B cells into ASCs in the setting of IFN-γ-, but not IL-4-, induced inflammatory responses.

Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis.

Dysfunction and loss of insulin-producing pancreatic beta cells represent hallmarks of diabetes mellitus. Here, we show that mice lacking the mitogen-activated protein kinase (MAPK) p38delta display improved glucose tolerance due to enhanced insulin secretion from pancreatic beta cells. Deletion of p38delta results in pronounced activation of protein kinase D (PKD), the latter of which we have identified as a pivotal regulator of stimulated insulin exocytosis. p38delta catalyzes an inhibitory phosphorylation of PKD1, thereby attenuating stimulated insulin secretion. In addition, p38delta null mice are protected against high-fat-feeding-induced insulin resistance and oxidative stress-mediated beta cell failure. Inhibition of PKD1 reverses enhanced insulin secretion from p38delta-deficient islets and glucose tolerance in p38delta null mice as well as their susceptibility to oxidative stress. In conclusion, the p38delta-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic beta cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus.

Dissociable neural after-effects of cognitive and physical effort expenditure during reward evaluation.

The reward after-effect of effort expenditure refers to the phenomenon that previous effort investment changes the subjective value of rewards when obtained. However, the neural mechanisms underlying the after-effects of effort exertion are still not fully understood. We investigated the modulation of reward after-effects by effort type (cognitive vs. physical) through the lens of neural dynamics. Thirty-two participants performed a physically or cognitively demanding task during an effort phase and then played a simple gambling game during a subsequent reward phase to earn monetary rewards while their electroencephalogram (EEG) was recorded. We found that previous effort expenditure decreased electrocortical activity during feedback evaluation. Importantly, this effort effect occurred in a domain-general manner during the early stage (as indexed by the reward positivity) but in a domain-specific manner during the later and more elaborative stage (as indexed by the P3 and delta oscillation) of reward evaluation. Additionally, effort expenditure enhanced P3 sensitivity to feedback valence regardless of effort type. Our findings suggest that cognitive and physical effort, although bearing some surface resemblance to each other, may have dissociable neural influences on the reward after-effects.

Reduced 2,4-dienoyl-CoA reductase 1 is served as an unfavorable biomarker and is related to immune infiltration in cervical cancer.

BACKGROUND: Worldwide, cervical cancer (CC) remains the most prevalent malignancy of the female reproductive system, posing a threat to women's life and health, and increasing the medical and economic burden on society. Therefore, the search for tumor biomarkers for CC remains an important research direction. Immunotherapy has significantly improved patient outcomes, and genes related to tumor immune infiltration have been clinically relevant and highly reproducible biomarkers that affect the prognosis and response to treatment of CC. 2,4-dienoyl-CoA reductase 1 (DECR1) was considered to be an oncogene in a previous study, but relationship between DECR1 and immune infiltration was not mentioned. Our study aimed to reveal the clinical value of DECR1 in CC and to investigate its relationship with immune infiltration. METHODS: Human Protein Atlas was used to identify the localization of DECR1. The Ualcan database, TCGA, and IHC were used to assess the prognostic value of DECR1. GSEA was used to assess the possible signaling pathways of DECR1 in CC. The TIMER database was applied to reveal the relevance between DECR1 and immune infiltration. GEPIA was conducted to detect the co-relationship among DECR1, immune markers, and typical molecules of apoptosis. RESULTS: DECR1 was mainly distributed in the cytoplasm and overlapped with the endoplasmic reticulum. DECR1 was downregulated in CC compared to adjacent tissue. Survival analysis showed that patients with lower expression of DECR1 have a worse prognosis in CC. GSEA suggested that DECR1 was closely related to apoptosis signaling. TIMER showed that DECR1 was positively correlated with CD8+ T cell and CD4+ T cell but not with B cell in CC. CONCLUSION: DECR1 may be a potential cancer suppressor in CC and may be involved in apoptotic pathways and associated with immune infiltration.

Design of an ultra-broadband optical filter based on a local micro-structured long period fiber grating near PMTP.

This paper presents a local micro-structured long period fiber grating (LMS-LPFG) ultra-broadband optical filter based on the wide bandwidth near the phase-matching turning point (PMTP). The structure of LMS-LPFG is obtained by dividing a LPFG into two parts of equal length and reducing the cladding radius of the second LPFG. At this time, the LMS-LPFG can be regarded as a cascade of two equal-length LPFGs with different resonance wavelengths. The cladding mode and grating period are determined to make the first LPFG work in the double-peak resonance state, and the second LPFG operates near PMTP. It is found that the transmission spectra of the two LPFGs can be superimposed to form a wide loss bandwidth. Then the cladding radii of the second LPFG and grating structure parameters are designed based on coupled-mode theory. First, the grating period corresponding to the operating wavelength is determined from the phase-matching curve of LMS-LPFG. Then, the radius of the second LPFG with a designated grating period is selected to make LPFG 2 work in PMTP by reducing its cladding radius. In addition, the grating lengths of the two LPFGs are determined by maximizing the loss of the LMS-LPFG's transmission spectrum. Finally, the two LPFGs are cascaded into a LMS-LPFG, and the optical transmission spectrum of the LMS-LPFG is calculated by the transfer matrix method. Simulation results show that the bandwidth of the transmission spectrum can reach 380 nm. In addition, the flexibility of design for the operating wave band is discussed and confirmed, and can meet different actual requirements of optical communication.

Long Non-coding RNA GAS5/miR-520-3p/SOCS3 Axis Regulates Inflammatory Response in Lipopolysaccharide-Induced Macrophages.

Sepsis is mainly caused by infection, and inflammation plays a vital role in the progression of sepsis. Increasing evidence shows the regulatory mechanism of long non-coding RNA growth arrest-specific 5 (GAS5) in inflammatory response. However, the potential role of GAS5 in sepsis was not really clear. Here, we set to investigate the role and mechanism of GAS5 in the inflammatory response of lipopolysaccharide (LPS)-induced macrophages in vitro. Levels of GAS5, microRNA-520-3p, suppressor of cytokine signaling 3 (SOCS3) and inflammatory cytokines tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and IL-1ß were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Nitric oxide (NO) release was measured through flow cytometry. The levels of TNF-α, IL-6, and IL-1ß were also detected using ELISA. Dual-luciferase reporter and RNA pull-down assays were performed to clarify the relationship between miR-520-3p and GAS5 or SOCS3. Western blot was carried out to assess SOCS3 protein expression in macrophages. GAS5 level was remarkably decreased in sepsis serum and it was inversely related to the severity of sepsis. Upregulation of GAS5 repressed inflammatory response in LPS-induced macrophages, and the inhibitory effect was returned by miR-520-3p mimics. Moreover, miR-520-3p inhibitor downregulated the levels of inflammatory factors of TNF-α, IL-6, and IL-1ß, as well as suppressed NO release. Mechanically, GAS5 functioned as a sponge of miR-520-3p and miR-520-3p directly targeted SOCS3. GAS5 regulated inflammatory response by the miR-520-3p/SOCS3 axis in LPS-induced macrophages, which furnished a novel therapeutic idea in clinical treatment of inflammation-induced sepsis.

Galectin-3 in septic acute kidney injury: a translational study.

BACKGROUND: Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3's role and its potential utility as a therapeutic target in S-AKI. METHODS: In 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and development of AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, Interleukin-6 (IL-6), and creatinine were examined at 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group). RESULTS: Among 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1-1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1-2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both P-MCP groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP groups (400 mg: p = 0.007; 1200 mg: p = 0.007). CONCLUSIONS: This translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.

An evolving assessment model for environmental carrying capacity: A case study of coral reef islands.

Environmental carrying capacity (ECC) provides an insight into measuring sustainability of the vulnerable coral reef islands. However, an integrated assessment of ECC on the social-ecological system of reef islands is rarely existence. And conventional approaches miss addressing the difference of social development, which would lead to a misinterpretation of sustainable development of reef island system. This study develops an evolving model of RI-ECC which incorporates five specific development phases, and the assessment involves (1) identification and measurement of carrying components, (2) supply/demand surplus analysis of indicators and (3) ECC states determination. A case study is conducted in Zhaoshu Island of China, indicating the efficiency of RI-ECC model and serving as a reference for adaptive management.

Cumulative sojourn time in longitudinal studies: a sequential imputation method to handle missing health state data due to dropout.

Missing data are ubiquitous in longitudinal studies. In this paper, we propose an imputation procedure to handle dropouts in longitudinal studies. By taking advantage of the monotone missing pattern resulting from dropouts, our imputation procedure can be carried out sequentially, which substantially reduces the computation complexity. In addition, at each step of the sequential imputation, we set up a model selection mechanism that chooses between a parametric model and a nonparametric model to impute eachmissing observation. Unlike usual model selection procedures that aim at finding a single model fitting the entire data set well, our model selection procedure is customized to find a suitable model for the prediction of each missing observation.

Effort Expenditure Increases Risk-Taking for Improbable Rewards.

Previous studies have found that exerting effort can lead people to engage in risk-taking behaviors. While effort can be either cognitive or physical, risk-taking can take place in either a risky context with known outcome probabilities or an ambiguous context with unknown outcome probabilities. The goal of the current research is to investigate how effort type and decision context influence risk-taking after effort exertion. Across three experiments, we find evidence that investing effort increases risk-taking at a short timescale. Importantly, this effect is particularly noticeable when the chance of winning is low, rather than when it is uncertain. Furthermore, the increase in risk-taking happens regardless of whether the effort is cognitive or physical. These findings suggest the existence of a cost-invariant but decision context-variant mechanism for the risk-taking after-effect of effort expenditure, which helps to bring the negative emotions caused by effort exertion back to a state of emotional homeostasis.

Concentration of polychlorinated biphenyls and risk assessment in finless porpoises from the East China Sea.

Polychlorinated biphenyls (PCBs) are bioaccumulative persistent organic pollutants with a great impact on cetaceans. To examine the content of PCBs and their risks to finless porpoises, this study determined the concentrations of seven typical PCB congeners in 56 tissue samples of East Asian finless porpoises (EAFPs) sampled in 2009-2012 from Ningbo (29.8835° N, 122.0644° E), Pingtan (25.5133° N, 119.8172° E) and Lvsi (32.1035° N, 121.6078° E). PCB138, PCB153 and PCB101 were the predominant congeners, accounting for 31.15%, 18.59% and 15.75%, respectively, of all PCBs detected. The content of PCBs increased with age in males but decreased from juveniles to adults in females due to transfer to calves by reproduction and lactation. EAFPs in Ningbo and Pingtan accumulated more PCBs than those in Lvsi Port. The trophic positions of EAFPs from Lvsi, Pingtan and Ningbo were 9.41, 8.95 and 9.43, respectively. PCB concentrations did not accumulate significantly with increasing trophic levels. The risk quotient index indicated that the risk of trichlorobiphenyl (3-PCB), tetrachlorobiphenyl (4-PCB), pentachlorobiphenyls (5-PCB), and hexachlorobiphenyls (6-PCB) to EAFPs in the East China Sea was generally low and within safe limits thus far. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00221-0.

Comparison of transoral vestibular robotic thyroidectomy with traditional low-collar incision thyroidectomy.

Transoral vestibular robotic thyroidectomy can really make the patient's body surface free of scar. This study aimed to compare the surgical and patient-related outcomes between the transoral vestibular robotic thyroidectomy and traditional low-collar incision thyroidectomy. The clinical data of 120 patients underwent transoral vestibular robotic thyroidectomy (TOVRT) or traditional low-collar incision thyroidectomy (TLCIT) were collected from May 2020 to October 2021. Propensity score matching analysis was used to minimize selection bias. All these patients were diagnosed with papillary thyroid carcinoma (PTC) through ultrasound-guided fine-needle aspiration prior to surgical intervention and surgical plan was tailored for each patient. An intraoperative recurrent laryngeal nerve (RLN) detection system was used in all patients, whose RLNs were identified and protected. We performed transoral vestibular robotic thyroidectomy with three intraoral incisions. Additional right axillary fold incisions were adopted occasionally to enhance fine reverse traction of tissue for radical tumor dissection. Clinical data including gender, age, tumor size, BMI, operation time, postoperative drainage volume and time, pain score, postoperative length of stay (LOS),number of lymph nodes removed, complications, and medical expense were observed and analyzed. Propensity score matching was used for 1:1 matching between the TOVRT group and the TLCIT group. All these patients accepted total thyroidectomy(or lobectomy) plus central lymph node dissection and all suffered from PTC confirmed by postoperative pathology. No conversion to open surgery happened in TOVRT group. The operative time of TOVRT group was longer than that of TLCIT group (P < 0.05). The postoperative drainage volume of TOVRT group was more than that of TLCIT group (P < 0.05). The drainage tube placement time of TOVRT group were longer than that of TLCIT group (P < 0.05). Significant differences were also found in intraoperative bleeding volume, pain score and medical expense between the two groups (P < 0.05). The incidence of perioperative common complications such as hypoparathyroidism and vocal cord paralysis in the two groups was almost identical (P > 0.05). However, there were some specific complications such as surgical area infection (one case), skin burn (one case), oral tear (two cases), and paresthesia of the lower lip and the chin (two cases) were found in TOVRT group. Obviously, the postoperative cosmetic effect of the TOVRT group was better than TLCIT group (P < 0.05). TOVRT is safe and feasible for low to moderate-risk PTC patients and is a potential alternative for patients who require no scar on their neck. Patients accepted TOVRT can get more satisfaction and have less psychologic injury caused by surgery.

Evaluation of phosphatidylinositol-4-kinase IIIα as a hepatitis C virus drug target.

Phosphatidylinositol-4-kinase IIIα (PI4KIIIα) is an essential host cell factor for hepatitis C virus (HCV) replication. An N-terminally truncated 130-kDa form was used to reconstitute an in vitro biochemical lipid kinase assay that was optimized for small-molecule compound screening and identified potent and specific inhibitors. Cell culture studies with PI4KIIIα inhibitors demonstrated that the kinase activity was essential for HCV RNA replication. Two PI4KIIIα inhibitors were used to select cell lines harboring HCV replicon mutants with a 20-fold loss in sensitivity to the compounds. Reverse genetic mapping isolated an NS4B-NS5A segment that rescued HCV RNA replication in PIK4IIIα-deficient cells. HCV RNA replication occurs on specialized membranous webs, and this study with PIK4IIIα inhibitor-resistant mutants provides a genetic link between NS4B/NS5A functions and PI4-phosphate lipid metabolism. A comprehensive assessment of PI4KIIIα as a drug target included its evaluation for pharmacologic intervention in vivo through conditional transgenic murine lines that mimic target-specific inhibition in adult mice. Homozygotes that induce a knockout of the kinase domain or knock in a single amino acid substitution, kinase-defective PI4KIIIα, displayed a lethal phenotype with a fairly widespread mucosal epithelial degeneration of the gastrointestinal tract. This essential host physiologic role raises doubt about the pursuit of PI4KIIIα inhibitors for treatment of chronic HCV infection.

Nurse managers' experience during the COVID-19 pandemic in China: A qualitative study.

AIMS: The aim of the study was to explore the experiences of female new nurse managers during the COVID-19 pandemic. DESIGN: This was a phenomenological study, and qualitative descriptive analysis was used. METHODS: New nurse managers were defined as new nurse managers with less than 3 years of management experience in this study. During November and December of 2021, 18 female new nurse managers were interviewed face-to-face with a semi-structured interview guide in three municipal hospitals. The study followed the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines for evaluating qualitative research reports. Data analysis was performed using Colaizzi's seven-step method. RESULTS: Four main themes and 10 sub-themes were extracted from the collected data. The four major themes were as follows: (1) a shift in stress; (2) work-related physical and psychological discomfort; (3) reflection on the cause; (4) coping and struggles. CONCLUSIONS: New nurse managers were experiencing great stress and exhaustion in their roles. It is important that they are helped to handle situations. Providing them with readily accessible support, addressing their psychosocial needs and addressing exhaustion is necessary. Considering their short management time, the hospital should provide adequate support in human, financial and material areas and provide training to help new nurse managers better adapt to their new roles. In addition, nurse directors should create a culture of mutual respect, identify workplace bullying and create a harmonious and cooperation-oriented work environment for new nurse managers. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Contextual valence influences the neural dynamics of time and magnitude representation during feedback evaluation.

Contextual valence is an important dimension during value-based decision-making. Previous research has revealed behavioral and neural asymmetries between the gain context and the loss context. The present event-related potential study investigated the effects of contextual valence on neural dynamics underlying magnitude and time, two important reward dimensions, during feedback evaluation. Forty-two participants performed a simple guessing task in which they experienced both a gain context wherein high or low rewards were delivered immediately or six months later, and a loss context wherein high or low losses were delivered in the same way. Results showed that in the gain context, time and magnitude information were processed in a parallel way during the time windows of the reward positivity (RewP) and the P3. In the loss context, however, time and magnitude information were processed in a serial way such that time information was encoded during the RewP and P3 periods, whereas magnitude information was not tracked until the time window of the late positive potential. Our findings suggest that the neural dynamics underlying time and magnitude information are distinct between the gain and loss contexts, thus providing a novel perspective for the well-known gain-loss asymmetry.

Urban-rural disparities of carbon storage dynamics in China's human settlements driven by population and economic growth.

China has experienced a rapid expansion of human settlement in both urban and rural areas over the past three decades. Regarding the impacts on carbon storage, previous studies that only focus on certain ecosystems cannot reflect urban-rural disparities, resulting in the carbon storage changes in human settlement remaining unknown. In this study, we aimed to explore China's urban-rural disparities in human settlement expansion and direct impacts on carbon storage by using the big Earth data technology. The results showed that from 1990 to 2018, the total amount of China's human settlement expansion reached 175,703.80 km2, and the inner-city, peri-urban, and rural components accounted for 21.00 %, 20.18 %, and 58.82 %, respectively. Along with the general tendency of impervious surface area (ISA) growth, there was more soil organic carbon (SOC) (1254.33 TgC) being sealed beneath ISA (0-100 cm depth), compared to a huge reduction in vegetation biomass carbon (VBC) (91.44 TgC) during the study period. The results further indicated that the change density of either VBC or SOC presented a slightly rising trend along the urban-rural gradient, due to the increasingly common encroachment on vegetation and soil types with higher carbon content. We also found that socioeconomic drivers had a greater influence in urban areas than rural areas, and the related correlation exhibited a descending trajectory in both urban and rural areas. There is thus an urgent need to preserve lands with abundant carbon storage and contain the waste of land resources in rural areas. All stakeholders should pay more attention to concerted and targeted regulation policies for well-planned and eco-friendly human settlement expansion such as enhancing rural land use efficiency and promoting large-scale afforestation and continuous urban greening, which will be critical not only for guiding sustainable urbanization all over China but also for mitigating climate change for the entire world.

Tertiary lymphoid structures in gynecological cancers: prognostic role, methods for evaluating, antitumor immunity, and induction for therapy.

Tertiary lymphoid structures (TLSs), referred to as tertiary lymphoid organs and lymphoid tissue neogenesis, are aggregates of immune cells that occur in nonlymphoid tissues. In recent years, it has been found that TLSs within the tumor microenvironment have been associated with local adaptive immune immunity against cancer and favorable prognosis in several human solid tumors, including gynecological cancers. The issue of the prognosis of gynecological cancers, including endometrial, cervical, and ovarian cancer, is an enormous challenge that many clinical doctors and researchers are now facing. Concerning the predictive prognostic role of TLSs, effective evaluation, and quantification of TLSs in human tissues may be used to assist gynecologists in assessing the clinical outcome of gynecological cancer patients. This review summarizes the current knowledge of TLSs in gynecological cancers, mainly focusing on the potential mechanism of TLS neogenesis, methods for evaluating TLSs, their prognostic value, and their role in antitumor immune immunity. This review also discusses the new therapeutic methods currently being explored in gynecological cancers to induce the formation of TLSs.

Vaccination with platelet-derived growth factor B kinoids inhibits CCl4-induced hepatic fibrosis in mice.

Platelet-derived growth factor B (PDGF-B) plays an essential role in hepatic fibrosis. Inhibition of the PDGF-B signaling in chronically injured livers might represent a potential therapeutic measure for hepatic fibrosis. In this study, we assessed the effects of vaccination against PDGF-B on CCl4-induced liver fibrosis in BALB/c mice. The PDGF-B kinoid immunogens were prepared by cross-linking two PDGF-B-derived B-cell epitope peptides [PDGF-B¹6-(23-38) and PDGF-B¹6-(72-83)] to ovalbumin and keyhole limpet hemocyanin, respectively. Enzyme-linked immunosorbent assay, Western blotting, and NIH3T3 cell proliferation assay verified that immunization with the PDGF-B kinoids elicited the production of high levels of neutralizing anti-PDGF-B autoantibodies. The vaccination markedly alleviated CCl4-induced hepatic fibrosis, as indicated by the lessened morphological alternations and reduced hydroxyproline contents in the mouse livers. Moreover, immunohistochemical staining for proliferating cell nuclear antigen, α-smooth muscle actin, and desmin demonstrated that neutralization of PDGF-B inhibited both the proliferation and the activation of hepatic stellate cells in the fibrotic mouse livers. Taken together, this study demonstrated that vaccination with PDGF-B kinoids significantly suppressed CCl4-induced hepatic fibrosis in mice. Our results suggest that vaccination against PDGF-B might be developed into an effective, convenient, and safe therapeutic measure for the treatment of hepatic fibrosis.

Collagen-induced arthritis is exacerbated in C-reactive protein-deficient mice.

OBJECTIVE: Blood C-reactive protein (CRP) is routinely measured to gauge inflammation. In rheumatoid arthritis (RA), a heightened CRP level is predictive of a poor outcome, while a lowered CRP level is indicative of a positive response to therapy. CRP interacts with the innate and adaptive immune systems in ways that suggest it may be causal in RA and, although this is not proven, it is widely assumed that CRP makes a detrimental contribution to the disease process. Paradoxically, results from animal studies have indicated that CRP might be beneficial in RA. This study was undertaken to study the role of CRP in a mouse model of RA, the collagen-induced arthritis (CIA) model. METHODS: We compared the impact of CRP deficiency with that of transgenic overexpression of CRP on inflammatory and immune responses in mice, using CRP-deficient (Crp-/-) and human CRP-transgenic (CRP-Tg) mice, respectively. Susceptibility to CIA, a disease that resembles RA in humans, was compared between wild-type, Crp-/-, and CRP-Tg mice. RESULTS: CRP deficiency significantly altered the inflammatory cytokine response evoked by challenge with endotoxin or anti-CD3 antibody, and heightened some immune responses. Compared to that in wild-type mice, CIA in Crp-/- mice progressed more rapidly and was more severe, whereas CIA in CRP-Tg mice was dramatically attenuated. Despite these disparate clinical outcomes, anticollagen autoantibody responses during CIA did not differ among the genotypes. CONCLUSION: CRP exerts an early and beneficial effect in mice with CIA. The mechanism of this effect remains unknown but does not involve improvement of the autoantibody profile. In humans, the presumed detrimental role of a heightened blood CRP level during active RA might be balanced by a beneficial effect of the baseline CRP (i.e., levels manifest during the preclinical stages of disease).

Inhibitor of NF-kappa B kinases alpha and beta are both essential for high mobility group box 1-mediated chemotaxis [corrected].

Inhibitor of NF-kappaB kinases beta (IKKbeta) and alpha (IKKalpha) activate distinct NF-kappaB signaling modules. The IKKbeta/canonical NF-kappaB pathway rapidly responds to stress-like conditions, whereas the IKKalpha/noncanonical pathway controls adaptive immunity. Moreover, IKKalpha can attenuate IKKbeta-initiated inflammatory responses. High mobility group box 1 (HMGB1), a chromatin protein, is an extracellular signal of tissue damage-attracting cells in inflammation, tissue regeneration, and scar formation. We show that IKKalpha and IKKbeta are each critically important for HMGB1-elicited chemotaxis of fibroblasts, macrophages, and neutrophils in vitro and neutrophils in vivo. By time-lapse microscopy we dissected different parameters of the HMGB1 migration response and found that IKKalpha and IKKbeta are each essential to polarize cells toward HMGB1 and that each kinase also differentially affects cellular velocity in a time-dependent manner. In addition, HMGB1 modestly induces noncanonical IKKalpha-dependent p52 nuclear translocation and p52/RelB target gene expression. Akin to IKKalpha and IKKbeta, p52 and RelB are also required for HMGB1 chemotaxis, and p52 is essential for cellular orientation toward an HMGB1 gradient. RAGE, a ubiquitously expressed HMGB1 receptor, is required for HMGB1 chemotaxis. Moreover, IKKbeta, but not IKKalpha, is required for HMGB1 to induce RAGE mRNA, suggesting that RAGE is at least one IKKbeta target involved in HMGB1 migration responses, and in accord with these results enforced RAGE expression rescues the HMGB1 migration defect of IKKbeta, but not IKKalpha, null cells. Thus, proinflammatory HMGB1 chemotactic responses mechanistically require the differential collaboration of both IKK-dependent NF-kappaB signaling pathways.