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Macropinocytosis, a type of large-scale endocytosis process, is induced in macrophages by extracellular stimuli, including lipopolysaccharide (LPS). In addition to uptake function, emerging evidence supports a link between macropinocytosis and LPS-induced signal transduction. Following LPS stimulation, membrane ruffles are induced to form cup-like structures known as macropinocytic cups, a necessary precursory step for macropinocytosis. We have recently shown that Akt is activated at the cups and is an upstream regulator of the Iκ-B/NF-κB pathway implicated in the production of IL-1α and IL-6. Here, we further investigated the molecular mechanisms and show that the macropinocytic cups also regulated the Ras/Mek/Erk/c-Fos pathway to modulate IL-1β expression independently of the Akt pathway. In addition, we observed that the cup-dependent Akt pathway downregulated the expression of IL-10, in which the activation of the Erk pathway was critical. Taken together, we propose that macropinocytic cups separately modulate the Akt and Erk pathways in cytokine expression.Key words: macropinocytosis, Erk, IL-1β, IL-10

Success with B cell depletion using rituximab has proven the concept that B lineage cells represent a valid target for the treatment of autoimmune diseases, and has promoted the development of other B cell targeting agents. Present data confirm that B cell depletion is beneficial in various autoimmune disorders and also show that it can worsen the disease course in some patients. These findings suggest that B lineage cells not only produce pathogenic autoantibodies, but also significantly contribute to the regulation of inflammation. In this review, we will discuss the multiple pro- and anti-inflammatory roles of B lineage cells play in autoimmune diseases, in the context of recent findings using B lineage targeting therapies.

Interleukin-10 (IL-10) is emerging as a promising cancer immunotherapy due to its ability to boost exhausted immune cells (CD8[sup.+] T cells), helping them fight tumors more effectively while also reducing harmful inflammation. However, despite encouraging early research, clinical trials of IL-10-based treatments, such as pegilodecakin, have faced challenges like side effects and inconsistent results, highlighting the need for better dosing and delivery methods. To overcome these obstacles, scientists have developed engineered IL-10 variants, fusion proteins, and bispecific constructs, which improve stability and extend IL-10’s activity, enhancing its effects when used with immune checkpoint inhibitors. As research continues to refine IL-10 therapies, innovative delivery systems and combination treatments could unlock its full potential in precision cancer care, making IL-10 a key player in the future of immunotherapy.

Our prior studies have shown that protein misfolding and aggregation in the placenta are linked to the development of preeclampsia, a severe pregnancy complication. We identified transthyretin (TTR) as a key component of the aggregated protein complex. However, the regulation of native TTR in normal pregnancy remains unclear. In this study, we found that pregnant mice exhibited a remarkable and progressive decline in serum TTR levels through gestational day (gd) 12–14, followed by an increase in late pregnancy and postpartum. Meanwhile, serum albumin levels showed a modest but statistically significant increase throughout gestation. TTR protein and mRNA levels in the liver, a primary source of circulating TTR, mirrored the changes observed in serum TTR levels during gestation. Intriguingly, a similar pattern of TTR alteration was also observed in the serum of pregnant women and pregnant interleukin-10-knockout (IL-10−/−) mice with high inflammation background. In non-pregnant IL-10−/− mice, serum TTR levels were significantly lower than those in age-matched wild-type mice. Administration of IL-10 to non-pregnant IL-10−/− mice restored their serum TTR levels. Notably, dysregulation of TTR resulted in fewer implantation units, lower fetal weight, and smaller litter sizes in human TTR-overexpressing transgenic mice. Thus, TTR may play a pivotal role as a crucial regulator in normal pregnancy, and inflammation during pregnancy may contribute to the downregulation of serum TTR presence.

Interleukin-10 (IL-10) is a pleiotropic cytokine that has a fundamental role in modulating inflammation and in maintaining cell homeostasis. It primarily acts as an anti-inflammatory cytokine, protecting the body from an uncontrolled immune response, mostly through the Jak1/Tyk2 and STAT3 signaling pathway. On the other hand, IL-10 can also have immunostimulating functions under certain conditions. Given the pivotal role of IL-10 in immune modulation, this cytokine could have relevant implications in pathologies characterized by hyperinflammatory state, such as cancer, or infectious diseases as in the case of COVID-19 and Post-COVID-19 syndrome. Recent evidence proposed IL-10 as a predictor of severity and mortality for patients with acute or post-acute SARS-CoV-2 infection. In this context, IL-10 can act as an endogenous danger signal, released by tissues undergoing damage in an attempt to protect the organism from harmful hyperinflammation. Pharmacological strategies aimed to potentiate or restore IL-10 immunomodulatory action may represent novel promising avenues to counteract cytokine storm arising from hyperinflammation and effectively mitigate severe complications. Natural bioactive compounds, derived from terrestrial or marine photosynthetic organisms and able to increase IL-10 expression, could represent a useful prevention strategy to curb inflammation through IL-10 elevation and will be discussed here. However, the multifaceted nature of IL-10 has to be taken into account in the attempts to modulate its levels.

Interleukin-10 (IL-10) signaling genes are attractive inflammatory bowel disease (IBD) candidate genes as IL-10 restricts intestinal inflammation, IL-10 polymorphisms have been associated with IBD in genome-wide association studies, and mutations in IL-10 and IL-10 receptor (IL-10R) genes have been reported in immunodeficient children with severe infantile-onset IBD. Our objective was to determine if IL-10R polymorphisms were associated with early-onset IBD (EO-IBD) and very-early-onset IBD (VEO-IBD).MethodsCandidate-gene analysis of IL10RA and IL10RB was performed after initial sequencing of an infantile onset-IBD patient identified a novel homozygous mutation. The discovery cohort included 188 EO-IBD subjects and 188 healthy subjects. Polymorphisms associated with IBD in the discovery cohort were genotyped in an independent validation cohort of 422 EO-IBD subjects and 480 healthy subjects.ResultsWe identified a homozygous, splice-site point mutation in IL10RA in an infantile-onset IBD patient causing a premature stop codon (P206X) and IL-10 insensitivity. IL10RA and IL10RB sequencing in the discovery cohort identified five IL10RA polymorphisms associated with ulcerative colitis (UC) and two IL10RB polymorphisms associated with Crohn's disease (CD). Of these polymorphisms, two IL10RA single nucleotide polymorphisms, rs2228054 and rs2228055, were associated with VEO-UC in the discovery cohort and replicated in an independent validation cohort (odds ratio [OR] 3.08, combined P = 2 x 10−4; and OR 2.93, P = 6 x 10−4, respectively).ConclusionsWe identified IL10RA polymorphisms that confer risk for developing VEO-UC. Additionally, we identified the first splice site mutation in IL10RA resulting in infantile-onset IBD. This study expands the phenotype of IL10RA polymorphisms to include both severe arthritis and VEO-UC.

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

With the ability to induce T cell activation and elicit humoral responses, B cells are generally considered as effectors of the immune system. However, the emergence of regulatory B cells (Bregs) has given new insight into the role of B cells in immune responses. Bregs exhibit immunosuppressive functions via diverse mechanisms, including the secretion of anti-inflammatory cytokines and direct cell contact. The balance between Bregs and effector B cells is important for the immune tolerance. In this review, we focus on recent advances in the characteristics of Bregs and their functional roles in autoimmunity.

The results of recent studies have shown that granulocytic-myeloid derived suppressor cells (G-MDSCs) can secrete exosomes that transport various biologically active molecules with regulatory effects on immune cells. However, their roles in autoimmune diseases such as rheumatoid arthritis remain to be further elucidated. In the present study, we investigated the influence of exosomes from G-MDSCs on the humoral immune response in murine collagen-induced arthritis (CIA). G-MDSCs exosomes-treated mice showed lower arthritis index values and decreased inflammatory cell infiltration. Treatment with G-MDSCs exosomes promoted splenic B cells to secrete IL-10 both in vivo and in vitro . In addition, a decrease in the proportion of plasma cells and follicular helper T cells was observed in drainage lymph nodes from G-MDSCs exosomes-treated mice. Moreover, lower serum levels of IgG were detected in G-MDSCs exosomes-treated mice, indicating an alteration of the humoral environment. Mechanistic studies showed that exosomal prostaglandin E2 (PGE2) produced by G-MDSCs upregulated the phosphorylation levels of GSK-3β and CREB, which play a key role in the production of IL-10 + B cells. Taken together, our findings demonstrated that G-MDSC exosomal PGE2 attenuates CIA in mice by promoting the generation of IL-10 + Breg cells.

Lei Li, Yang Chen, Guojun He, Yang Gao, Yongqing Cheng, Jin Chen, Dingming Sun, Mingyu Shi Department of Neurology, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, Jiangsu, 224005, People’s Republic of ChinaCorrespondence: Mingyu Shi, The Yancheng Clinical College of Xuzhou Medical University, The First People’s Hospital of Yancheng, Yancheng, Jiangsu, 224005, People’s Republic of China, Email xzmcashi@126.comBackground: Chronic inflammation and the imbalance of M1/M2 phenotype of microglia contribute to the onset and progression of cerebral small vessel disease (CSVD). Currently, no effective biomarkers for diagnosing CSVD are found. Our research aims to explore the efficacy of IL-6/IL-10 ratio in the diagnosis of CSVD and assessment of its severity, establishing IL-6/IL-10 as an independent predictive biomarker.Patients and Methods: A total of 155 participants admitted to the First People’s Hospital of Yancheng City from February 2022 to September 2024 were grouped based on MRI and CSVD imaging scoring. Clinical and laboratory data were collected and analyzed.Results: Compared with the healthy control group, the CSVD group showed significant increases of IL-6/IL-10 ratio in peripheral blood (P=0.001); while compared with the CSVD (score 0– 1) group, IL-6/IL-10 ratio was statistically significant elevation in the CSVD (score 2– 4) group (P=0.002). The area under the curve (AUC) of IL-6/IL-10 ratio in the diagnosis of CSVD was 0.816, the sensitivity and specificity were 67.9% and 85.7%. Besides, the AUC of IL-6/IL-10 ratio in evaluating the severity of CSVD was 0.687.Conclusion: IL-6/IL-10 ratio is a potential circulating biomarker for diagnosing CSVD, with good diagnostic efficacy and has the ability to distinguish the severity of the disease to a certain degree.Keywords: cerebral small vessel disease, neuroinflammation, biomarker, microglia polarization, IL-6/IL-10