Atypical chemokine receptor 3 (ACKR3) (formerly CXCR7) regulates various biological processes through its ligands and is closely associated with numerous diseases, including inflammation, cancer, cardiovascular diseases (CVDs), pain, and neurological disorders. Therefore, ACKR3 has emerged as a potential target for disease treatment.

This review summarizes the ACKR3 modulators published in patents from 2019 to 2024 using data from Google Patents, the European Patent Office, and the World Intellectual Property Organization's online databases. This includes information on their chemical structures, syntheses, activities, and developmental stages.

ACKR3 agonists gained traction as a treatment for cardiovascular and pain conditions. WW-12, which was derived from the chemical modifications of conolidine, became a novel small-molecule pain modulator by activating ACKR3, which in turn boosted endogenous opioid peptides for the classical opioid receptors.ACKR3 antagonist ACT-1004-1239 from Idorsia Pharmaceuticals Ltd. has demonstrated the ability to treat cancer, acute lung injury/ARDS, and autoimmune diseases, including multiple sclerosis. The outcomes of these clinical trials will direct the development and indications of future ACKR3 modulators.

Despite the promise of the human chemokine receptor 7 (CCR7) as drug target for the treatment of cancer metastasis and autoimmune diseases, there are no potent and selective CCR7 antagonists known in literature. In this work, a 1,2,5-thiadiazole 1,1-dioxide with low μM activity as a CXCR2 and CCR7 antagonist was selected as starting point for a structure-activity relationship study. The replacement of the central thiadiazole dioxide motif with squaramide led to low nanomolar CCR7 antagonism. Additional systematic structural variations afforded various squaramide analogues that displayed potent CCR7 antagonism in a calcium mobilization assay with IC50 values in the low nM range. Unfortunately, the same compounds also displayed potent CXCR2 antagonistic activity and should therefore be considered as dual CCR7/CXCR2 antagonists.

Chemokine receptors are critically involved in multiple physiological and pathophysiological processes related to immune response mechanisms. Most chemokine receptors are prototypical GPCRs although some also exhibit naturally-encoded signaling-bias toward β-arrestins (βarrs). C-X-C type chemokine receptors, namely CXCR3 and CXCR7, constitute a pair wherein the former is a prototypical GPCR while the latter exhibits selective coupling to βarrs despite sharing a common natural agonist: CXCL11. Moreover, CXCR3 and CXCR7 also recognize small molecule agonists suggesting a modular orthosteric ligand binding pocket. Here, we determine cryo-EM structures of CXCR3 in an Apo-state and in complex with small molecule agonists biased toward G-proteins or βarrs. These structural snapshots uncover an allosteric network bridging the ligand-binding pocket to intracellular side, driving the transducer-coupling bias at this receptor. Furthermore, structural topology of the orthosteric binding pocket also allows us to discover and validate that selected small molecule agonists of CXCR3 display robust agonism at CXCR7. Collectively, our study offers molecular insights into signaling-bias and dual agonism in the CXCR3-CXCR7 system with therapeutic implications.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, largely because of its ability to reshape the tumor microenvironment and evade immune surveillance.

CX3CL1 expression in HCC tumor tissues was assessed via immunohistochemistry, while plasma levels were quantified using enzyme-linked immunosorbent assays (ELISAs). CX3CR1-positive immune cell infiltration was analyzed by immunofluorescence. The associations among CX3CL1 expression, CX3CR1-positive cell infiltration, and patient prognosis were examined. Additionally, cell-based assays were conducted to evaluate the impact of CX3CL1 amplification on the expression of myeloid-derived suppressor cell (MDSC)-recruiting factors.

Elevated CX3CL1 levels were significantly correlated with increased MDSC infiltration in the tumor microenvironment and poorer patient prognosis. CX3CL1 amplification led to the upregulation of MDSC-recruiting factors, suggesting a potential mechanism for immune evasion.

These findings highlight the possible involvement of CX3CL1 in HCC progression via MDSC recruitment, suggesting that it is a promising therapeutic target for promoting antitumor immunity. Further studies are needed to confirm these findings and explore potential therapeutic strategies.

Histological transformation (HT) into aggressive lymphoma is a turning point in a significant fraction of patients affected by indolent lymphoproliferative neoplasms, namely, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphomas (MZLs), and lymphoplasmacytic lymphoma (LPL) [...].

Selectivity of natural agonists for their cognate receptors is a hallmark of G-protein-coupled receptors (GPCRs); however, this selectivity often breaks down at the chemokine receptors. Chemokines often display promiscuous binding to chemokine receptors, but the underlying molecular determinants remain mostly elusive. Here, we perform a comprehensive transducer-coupling analysis, testing all known C-X-C chemokines on every C-X-C type chemokine receptor to generate a global fingerprint of the selectivity and promiscuity encoded within this system. Taking lead from this, we determine cryoelectron microscopy (cryo-EM) structures of the most promiscuous receptor, C-X-C chemokine receptor 2 (CXCR2), in complex with several chemokines. These structural snapshots elucidate the details of ligand-receptor interactions, including structural motifs, which are validated using mutagenesis and functional experiments. We also observe that most chemokines position themselves on CXCR2 as a dimer while CXCL6 exhibits a monomeric binding pose. Taken together, our findings provide the molecular basis of chemokine promiscuity at CXCR2 with potential implications for developing therapeutic molecules.

Atherosclerosis is a systemic disease involving multiple blood vessels and a major cause of cardiovascular disease. Current treatment methods (eg, statins) for atherosclerosis can reduce the risk of cardiovascular diseases effectively, but they are insufficient to completely reverse existing atherosclerosis. Macrophages play a central role in development of atherosclerosis. Chemokines, the main mediators of macrophage chemotaxis, are important in immune and inflammatory responses. The effects of chemokines on mechanisms involved in atherosclerosis are unknown. This study preliminarily investigated these effects and mechanisms via bioinformatics methods.

In this study, data on chemokine ligands and receptors were obtained by mining public databases (the National Center of Biotechnology Information-Gene Expression Omnibus [NCBI-GEO] database, ArrayExpress database, and single-cell RNA sequencing [scRNA-seq] database), and an extensive literature search was performed. The expression levels of chemokines in mouse tissues were analyzed via Metascape software for signalling pathway enrichment, scRNA-seq data for chemokine expression in atherosclerotic plaque progression and regression, and GEO2R data for chemokine expression during macrophage polarization. Ingenuity Pathway Analysis (IPA) software was used to analyze regulatory factors such as transcription factors and microRNAs that are significantly differentially expressed upstream of chemokines in macrophage polarization. Finally, a model of the chemokine regulation of atherosclerosis was established on the basis of these results.

There are 5 main findings: (1) In atherosclerosis, chemokines are regulated by transcription factors and microRNAs. (2) The transcription factor STAT1 promotes the polarization of dormant (M0) macrophages into classically activated (M1) macrophages and alternative activated (M2) macrophages by regulating chemokines. The transcription factors STAT1, IRF7 and IRF1 regulate the polarization of M0 macrophages into M2a and M2b macrophages via different chemokines. For example, some transcription factors promote M1 polarization of M0 macrophages through CCL4, but M2 macrophage polarization is regulated via CCL19, CCL5 and CCR7. (3) Transcription factors can promote and inhibit, whereas miRNAs can only inhibit atherosclerosis. (4) CCL4 existed in all 5 different chemokine-regulated macrophage models, whereas CXCL3 only existed in the M2b macrophage transcriptional regulation model, indicating that CXCL3 may promote the M2b type macrophages polarization of M0 macrophages. (5) CCL5 and CCR7 can promote the M2a macrophages and M2b macrophages polarization of M0 macrophages.

Atherosclerosis can be treated by regulating chemokines and regulating the polarization of macrophages. The chemokines CCL4, CCL5, CCL8, CCL19, CXCL3, CXCL10, CXCL13, and CCR7 may play key roles in the progression and regression of atherosclerosis.

Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1-/- mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1-/- animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng-/- mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1-/- animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection.

Intrinsically disordered proteins or regions (IDPs/IDRs) adopt diverse binding modes with different partners, ranging from ordered to multivalent to fuzzy conformations in the bound state. Characterizing IDR interfaces is challenging experimentally and computationally. Alphafold-multimer and Alphafold3, the state-of-the-art structure prediction methods, are less accurate at predicting IDR binding sites at their benchmarked confidence cutoffs. Their performance improves upon lowering the confidence cutoffs. Here, we developed Disobind, a deep-learning method that predicts inter-protein contact maps and interface residues for an IDR and a partner protein, given their sequences. It outperforms AlphaFold-multimer and AlphaFold3 at multiple confidence cutoffs. Combining the Disobind and AlphaFold-multimer predictions further improves the performance. In contrast to most current methods, Disobind considers the context of the binding partner and does not depend on structures and multiple sequence alignments. Its predictions can be used to localize IDRs in integrative structures of large assemblies and characterize and modulate IDR-mediated interactions.

The prognosis for many pediatric brain tumors, including cerebellar medulloblastoma (MB), remains dismal but there is promise in new therapies. We have previously generated a mouse model developing spontaneous MB at high frequency, Ptch1+/-/Tis21-/-. In this model, reproducing human tumorigenesis, we identified the decline of the Cxcl3 chemokine in cerebellar granule cell precursors (GCPs) as responsible for a migration defect, which causes GCPs to stay longer in the proliferative area rather than differentiate and migrate internally, making them targets of transforming insults. We demonstrated that 4-week Cxcl3 infusion in cerebella of 1-month-old mice, at the initial stage of MB formation, forces preneoplastic GCPs (pGCPs) to leave lesions and differentiate, with a complete suppression of MB development. In this study, we sought to verify the effect of 4-week Cxcl3 treatment in 3-month-old Ptch1+/-/Tis21-/- mice, when MB lesions are at an advanced, irreversible stage. We found that Cxcl3 treatment reduces tumor volumes by sevenfold and stimulates the migration and differentiation of pGCPs from the lesion to the internal cerebellar layers. We also tested whether the pro-migratory action of Cxcl3 favors metastases formation, by xenografting DAOY human MB cells in the cerebellum of immunosuppressed mice. We showed that DAOY cells express the Cxcl3 receptor, Cxcr2, and that Cxcl3 triggers their migration. However, Cxcl3 did not significantly affect the frequency of metastases or the growth of DAOY-generated MBs. Finally, we mapped the expression of the Cxcr2 receptor in human MBs, by evaluating a well-characterized series of 52 human MBs belonging to different MB molecular subgroups. We found that Cxcr2 was variably expressed in all MB subgroups, suggesting that Cxcl3 could be used for therapy of different MBs.

Background/Objectives: Pterygium is a nonneoplastic elastotic degeneration characterized by subepithelial growth. It manifests as an ocular lesion originating from the bulbar conjunctiva, extending to the corneal surface, and reaching the visual axis in some cases. Although the exact cause is unknown, prolonged exposure to ultraviolet radiation is considered the most significant contributing factor. Chronic irritation and actinic damage are likely responsible for the typical fibrovascular reactions observed in pterygium. Additionally, growth factors, cytokines, and matrix metalloproteinases play roles in the pathogenesis of pterygium. This study compared recurrent and primary pterygium cases at the molecular level to gain new insights into the etiology of pterygium. Methods: Total protein was extracted from surgical samples of patients with primary and recurrent pterygium, and the levels of transforming growth factor beta 1 (TGF-β1), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), IL-8, and IL-10 were analyzed using the enzyme-linked immunosorbent assay technique. Target gene expression levels were analyzed using the ΔΔCt method after cDNA synthesis from isolated RNA, with normalization to GAPDH and quantification performed with SYBR Green PCR Master Mix. Results: Among the studied cytokines, IL-10 levels were higher in primary pterygium than in recurrent pterygium (722.0 ± 600.9/421.4 ± 266.8) (p = 0.0054). Other cytokines (IL-6, IL-8, IL-1β, and TGF-β1) were detected at similar levels in both primary and recurrent pterygium (p = 0.2986). Additionally, the TGF-β1 gene expression was found to be significantly upregulated in recurrent pterygium tissue compared to primary pterygium tissue (p = 0.034). Conclusions: This increase suggests that TGF-β1 may contribute to the recurrence mechanisms of pterygium through processes such as fibroblast activation and tissue remodeling. The higher levels of IL-10 in primary pterygium compared to recurrent pterygium indicate an enhanced early protective response aimed at limiting pterygium progression and controlling the inflammatory process.

Chemokine receptor 4 (CXCR4) is a subtype receptor protein of the GPCR family with a seven-transmembrane structure widely distributed in human tissues. CXCR4 is involved in diseases (e.g., HIV-1 infection), cancer proliferation and metastasis, inflammation signaling pathways, and leukemia, making it a promising drug target. Clinical trials on CXCR4 antagonists mainly focused on peptides and antibodies, with a few small molecule compounds, such as AMD11070 (2) and MSX-122 (3), showing promise in cancer treatment. This perspective discusses the structure-activity relationship (SAR) of CXCR4 and its role in diseases, mainly focusing on the SAR of CXCR4 antagonists. It also explores the standard structural features and target interactions of CXCR4 binding in different disease categories. Furthermore, it investigates various modification strategies to propose potential improvements in the effectiveness of CXCR4 drugs.

A wide variety of inflammatory mediators, mainly cytokines and chemokines, are induced during SARS CoV-2 infection. Among these proinflammatory mediators, chemokines tend to play a pivotal role in virus-mediated immunopathology. The C-C chemokine ligand 2 (CCL2), also known as monocyte chemoattractant protein-1 (MCP-1) is a potent proinflammatory cytokine and strong chemoattractant of monocytes, macrophages and CD4+ T cells bearing C-C chemokine receptor type-2 (CCR2). Besides controlling immune cell trafficking, CCL2 is also involved in multiple pathophysiological processes including systemic hyperinflammation associated cytokine release syndrome (CRS), organ fibrosis and blood coagulation. These pathological features are commonly manifested in severe and fatal cases of COVID-19. Given the crucial role of CCL2 in COVID-19 pathogenesis, the CCL2:CCR2 axis may constitute a potential therapeutic target to control virus-induced hyperinflammation and multi-organ dysfunction. Herein we describe recent advances on elucidating the role of CCL2 in COVID-19 pathogenesis, prognosis, and a potential target of anti-inflammatory interventions.

The appearance of brain metastasis is the most serious complication of breast cancer with mostly fatal outcomes. To reach the brain, tumor cells need to pass the blood-brain barrier (BBB). The molecular mechanisms underlying penetration of the BBB are largely unknown. Previously we found that tumor-infiltrating T lymphocytes enhance the development of brain metastasis of estrogen receptor-negative (ER-) breast cancer. In the current study, we investigate the contribution of T lymphocytes and the IFN-γ pathway in enabling breast cancer cells to pass the in vitro BBB. CD8+ cells display the strongest stimulatory effect on breast cancer cell passage. We show that inhibition of the IFN-γ receptor in MDA-MB-231 breast cancer cells, or neutralization of soluble IFN-γ, impairs the in vitro trespassing of breast cancer cells. Importantly, we validated our findings using gene expression data of breast cancer patients. The CXCL-9,-10,-11/CXCR3 axis, dependent on IFN-γ signaling activity, was overexpressed in primary breast cancer samples of patients who developed brain metastasis. The data support a role for T-lymphocytes and the IFN-γ pathway in the formation of brain metastasis of ER-breast cancer, and offer targets to design future therapies for preventing breast cancer cells to cross the BBB.

Breast cancer is the most diagnosed cancer in the world, and it is the primary cause of cancer death for women. The risk of breast cancer is increased by endogenous factors like hormones and exogenous factors like radiation exposure that causes damage to the mammary epithelial cells leading to an inflammatory response. Chronic inflammation creates a microenvironment composed of, among other factors, chemokines, and interleukins, which promote cancer. The gene expression of the interleukin 1 receptor type 1, the interleukin 1 receptor antagonist, the Interleukin 1 Receptor Accessory Protein, the interleukin 6 cytokine family signal transducer, the C-X-C motif chemokine ligand 3, the C-X-C motif chemokine ligand 5, and the C-X-C motif chemokine ligand 6 were analyzed in an estrogen and radiation experimental breast cancer model. Furthermore, the expression of these genes was correlated with immune cell infiltration, estrogen receptor expression, and their clinical relevance in breast cancer patients based on data provided by The Cancer Genome Atlas database online. Results given by the experimental breast cancer model showed that all genes related to inflammation respond to ionizing radiation alone or in combination with estrogen. On the other hand, the immune response depended on the breast cancer type and on the expression of the gene that encoded the estrogen receptor. Finally, the importance of the expression of these genes in breast cancer is such that high IL1R1 or IL1RAP is strongly related to patient survival. These findings may help to improve the understanding of the role of immune molecules in carcinogenesis and enhance therapeutic approaches.

Chemokines and their receptors are a family of chemotactic cytokines with important functions in the immune response in both health and disease. Their known physiological roles such as the regulation of leukocyte trafficking and the development of immune organs generated great interest when it was found that they were also related to the control of early and late inflammatory stages in the tumor microenvironment. In fact, in breast cancer, an imbalance in the synthesis of chemokines and/or in the expression of their receptors was attributed to be involved in the regulation of disease progression, including invasion and metastasis. Research in this area is progressing rapidly and the development of new agents based on chemokine and chemokine receptor antagonists are emerging as attractive alternative strategies. This chapter provides a snapshot of the different functions reported for chemokines and their receptors with respect to the potential to regulate breast cancer progression.

Mpox is a zoonotic disease that was once endemic in Africa countries caused by mpox virus. However, cases recently have been confirmed in many non-endemic countries outside of Africa. The rapidly increasing number of confirmed mpox cases poses a threat to the international community. In-depth studies of key viral factors are urgently needed, which will inform the design of multiple antiviral agents. Mpox virus A41L gene encodes a secreted protein, A41, that is nonessential for viral replication, but could affect the host response to infection via interacting with chemokines. Here, mpox virus A41 protein was expressed in Sf9 cells, and purified by affinity chromatography followed by gel filtration. Surface plasmon resonance spectroscopy showed that purified A41 binds a certain human chemokine CXCL8 with the equilibrium dissociation constant (KD) being 1.22 × 10-6 M. The crystal structure of mpox virus A41 protein was solved at 1.92 Å. Structural analysis and comparison revealed that mpox virus A41 protein adopts a characteristic β-sheet topology, showing minor differences with that of vaccinia virus. These preliminary structural and functional studies of A41 protein from mpox virus will help us better understand its role in chemokine subversion, and contributing to the knowledge to viral chemokine binding proteins.

Major depressive disorder (MDD) and bipolar disorder (BD) are highly disabling illnesses defined by different psychopathological, neuroimaging, and cognitive profiles. In the last decades, immune dysregulation has received increasing attention as a central factor in the pathophysiology of these disorders. Several aspects of immune dysregulations have been investigated, including, low-grade inflammation cytokines, chemokines, cell populations, gene expression, and markers of both peripheral and central immune activation. Understanding the distinct immune profiles characterizing the two disorders is indeed of crucial importance for differential diagnosis and the implementation of personalized treatment strategies. In this paper, we reviewed the current literature on the dysregulation of the immune response system focusing our attention on studies using inflammatory markers to discriminate between MDD and BD. High heterogeneity characterized the available literature, reflecting the heterogeneity of the disorders. Common alterations in the immune response system include high pro-inflammatory cytokines such as IL-6 and TNF-α. On the contrary, a greater involvement of chemokines and markers associated with innate immunity has been reported in BD together with dynamic changes in T cells with differentiation defects during childhood which normalize in adulthood, whereas classic mediators of immune responses such as IL-4 and IL-10 are present in MDD together with signs of immune-senescence.

Pregnancy is intricately regulated by the interactions between various bioactive substances secreted by the conceptus, uterus, and corpus luteum (CL). Interferon-τ, synthesized and secreted by the conceptus, plays a central role in the interaction mechanism of maternal recognition in cows. Chemokines, chemotaxis mediators that are primarily secreted by immune cells, regulate various reproductive responses in various species. Although there are scattered reports on the potential roles of chemokines in the bovine CL and the uterus during the estrous cycle, there is little information on chemokines in these organs during pregnancy. Therefore, in this review, we discuss the possible physiological roles of chemokines in the CL and uterus of pregnant cows, focusing on our recent findings on chemokines and changes in their receptor expression in the CL and endometrium of cows at some stages of pregnancy.

Prostate cancer (PCa) stands as a significant global health concern, ranking among the leading causes of cancer deaths in men. While there are several treatment modalities for localized PCa, metastatic castration-resistant PCa (mCRPC) remains incurable. Despite therapeutic advancements showing promise in mCRPC, their impact on overall survival has been limited. This chapter explores the process by which tumors form, reviews our current understanding of PCa progression to mCRPC, and addresses the challenges of boosting anti-tumor immune responses in these tumors. It specifically discusses how chemotactic signaling affects the tumor microenvironment and its role in immune evasion and cancer progression. The chapter further examines the rationale of directly or indirectly targeting these pathways as adjuvant therapies for mCRPC, highlighting recent pre-clinical and clinical studies currently underway. The discussion emphasizes the potential of targeting specific chemokines and chemokine receptors as combination therapies with mainstream treatments for PCa and mCRPC to maximize long-term survival for this deadly disease.

Casein (CN) is the primary allergenic protein in cow's milk, contributing to the worldwide escalating prevalence of food allergies. However, there remains limited knowledge regarding the effect of structural modifications on CN allergenicity. Herein, we prepared three modified CNs (mCN), including sodium dodecyl sulfate and dithiothreitol-induced linear CN (LCN), transglutaminase-cross-linked CN (TCN), and glucose-glycated CN (GCN). The electrophoresis results indicated widespread protein aggregation among mCN, causing variations in their molecular weights. The unique internal and external structural characteristics of mCN were substantiated by disparities in surface microstructure, alterations in the secondary structure, variations in free amino acid contents, and modifications in functional molecular groups. Despite the lower digestibility of TCN and GCN compared to LCN, they significantly suppressed IL-8 production in Caco-2 cells without significantly promoting their proliferation. Moreover, GCN showed the weakest capacity to induce LAD2 cell degranulation. Despite the therapeutic effect of TCN, GCN-treated mice displayed the most prominent attenuation of allergic reactions and a remarkably restored Th1/Th2 imbalance, while LCN administration resulted in severe allergic phenotypes and endotypes in both cellular and murine models. This study highlighted the detrimental effect of linear modifications and underscored the significance of glycation in relation to CN allergenicity.

Intramuscular fat (IMF) refers to the lipid stored in skeletal muscle tissue. The number and size of intramuscular adipocytes are the primary factors that regulate IMF content. Intramuscular adipocytes can be derived from either in situ or ectopic migration. In this study, it was discovered that the regulation of IMF levels is achieved through the chemokine (C-C motif) ligand 5 (CCL5)/chemokine (C-C motif) receptor 5 (CCR5) pathway by modulating adipocyte migration. In coculture experiments, C2C12 myotubes were more effective in promoting the migration of 3T3-L1 preadipocytes than C2C12 myoblasts, along with increasing CCL5. Correspondingly, overexpressing the CCR5, one of the receptors of CCL5, in 3T3-L1 preadipocytes facilitated their migration. Conversely, the application of the CCL5/CCR5 inhibitor, MARAVIROC (MVC), reduced this migration. In vivo, transplanted experiments of subcutaneous adipose tissue (SCAT) from transgenic mice expressing green fluorescent protein (GFP) provided evidence that injecting recombinant CCL5 (rCCL5) into skeletal muscle promotes the migration of subcutaneous adipocytes to the skeletal muscle. The level of CCL5 in skeletal muscle increased with obesity. Blocking the CCL5/CCR5 axis by MVC inhibited IMF deposition, whereas elevated skeletal muscle CCL5 promoted IMF deposition in obese mice. These results establish a link between the IMF and the CCL5/CCR5 pathway, which could have a potential application for modulating IMF through adipocyte migration.NEW & NOTEWORTHY C2C12 myotubes attract 3T3-L1 preadipocyte migration regulated by the chemokine (C-C motif) ligand 5 (CCL5)/ chemokine (C-C motif) receptor 5 (CCR5) axis. High levels of skeletal muscle-specific CCL5 promote the migration of subcutaneous adipocytes to skeletal muscle and induce the intramuscular fat (IMF) content.

Acute restraint stress (RS) is routinely used to study the effects of psychological and/or physiological stress. We evaluated the impact of RS on cervical lymph nodes in rats at molecular and cellular levels. Male Sprague-Dawley rats were subjected to stress by immobilization for 30, 60, and 120 min (RS30, RS60, and RS120, respectively) and compared with rats of a no-stress control (C) group. The expression of genes encoding chemokines CXCL1/CXCL2 (Cxcl1 and Cxcl2) and their receptor CXCR2 (Cxcr2) was analyzed using reverse transcription-quantitative PCR (RT-qPCR) and microarray analyses. Immunohistochemistry and in situ hybridization were performed to determine the expression of these proteins and the macrophage biomarker CD68. Microarray analysis revealed that the expression of 514 and 496 genes was upregulated and downregulated, respectively, in the RS30 group. Compared with the C group, the RS30 group exhibited a 23.0-, 13.0-, and 1.6-fold increase in Cxcl1, Cxcl2, and Cxcr2 expression. Gene Ontology analysis revealed the involvement of these three upregulated genes in the cytokine network, inflammation, and leukocyte chemotaxis and migration. RT-qPCR analysis indicated that the mRNA levels of Cxcl1 and Cxcl2 were significantly increased in the RS30 group but were reverted to normal levels in the RS60 and RS120 groups. Cxcr2 mRNA level was significantly increased in the RS30 and RS120 groups compared with that in the C group. RS-induced CXCL1-immunopositive cells corresponded to B/plasma cells, whereas CXCL2-immunopositive cells corresponded to endothelial cells of the high endothelial venules. Stress-induced CXCR2-immunopositive cells corresponded to macrophages. Psychological and/or physiological stress induces an acute stress response and formation of an immunoreactive microenvironment in cervical lymph nodes, with the CXCL1/CXCL2-CXCR2 axis being pivotal in the acute stress response.

Chimeric antigen receptor (CAR)-engineered natural killer (NK) cells are a promising immunotherapy for solid cancers; however, their effectiveness against pancreatic cancer is limited by the immunosuppressive tumor microenvironment. In particular, low NK cell infiltration poses a major obstacle that reduces cytotoxicity. The current study aimed to enhance the tumor-homing capacity of CAR-NK cells by targeting the chemokine-chemokine receptor axis between NK and pancreatic cancer cells. To this end, data from a chemokine array and The Cancer Genome Atlas pan-cancer cohort were analyzed. Pancreatic cancer cells were found to secrete high levels of ligands for C-X-C motif receptor 1 (CXCR1) and CXCR2. Subsequently, we generated anti-mesothelin CAR-NK cells incorporating CXCR1 or CXCR2 and evaluated their tumor-killing abilities in 2D cancer cell co-culture and 3D tumor-mimetic organoid models. CAR-NK cells engineered with CXCR2 demonstrated enhanced tumor killing and strong infiltration of tumor sites. Collectively, these findings highlight the potential of CXCR2-augmented CAR-NK cells as a clinically relevant modality for effective pancreatic cancer treatment. By improving their infiltration and tumor-killing capabilities, these CXCR2-augmented CAR-NK cells have the potential to overcome the challenges posed by the immunosuppressive tumor microenvironment, providing improved therapeutic outcomes.

Historically, KRAS has been considered 'undruggable' inspite of being one of the most frequently altered oncogenic proteins in solid tumors, primarily due to the paucity of pharmacologically 'druggable' pockets within the mutant isoforms. However, pioneering developments in drug design capable of targeting the mutant KRAS isoforms especially KRASG12C-mutant cancers, have opened the doors for emergence of combination therapies comprising of a plethora of inhibitors targeting different signaling pathways. SHP2 signaling pathway, primarily known for activation of intracellular signaling pathways such as KRAS has come up as a potential target for such combination therapies as it emerged to be the signaling protein connecting KRAS and the immune signaling pathways and providing the link for understanding the overlapping regions of RAS/ERK/MAPK signaling cascade. Thus, SHP2 inhibitors having potent tumoricidal activity as well as role in immunomodulation have generated keen interest in researchers to explore its potential as combination therapy in KRAS mutant solid tumors. However, the excitement with these combination therapies need to overcome challenges thrown up by drug resistance and enhanced toxicity. In this review, we will discuss KRAS and SHP2 signaling pathways and their roles in immunomodulation and regulation of tumor microenvironment and also analyze the positive effects and drawbacks of the different combination therapies targeted at these signaling pathways along with their present and future potential to treat solid tumors.

Chemokines are small molecules that function as chemotactic factors which regulate the migration, infiltration, and accumulation of immune cells. Here, we comprehensively assess the structural and functional role of chemokines, examine the effects of chemokines that are present in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME), specifically those produced by cancer cells and stromal components, and evaluate their impact on immune cell trafficking, both in promoting and suppressing anti-tumor responses. We further explore the impact of chemokines on patient outcomes in PDAC and their role in the context of immunotherapy treatments, and review clinical trials that have targeted chemokine receptors and ligands in the treatment of PDAC. Lastly, we highlight potential strategies that can be utilized to harness chemokines in order to increase cytotoxic immune cell infiltration and the anti-tumor effects of immunotherapy.

Salmonids are affected by the economically significant whirling disease (WD) caused by the myxozoan parasite Myxobolus cerebralis. In the past, it was endemic to Eurasia, but it has now spread to different regions of North America, Europe, New Zealand, and South Africa. Among salmonids, rainbow trout is considered the most highly susceptible host. Upon entering to the host's body, the parasite invades the spine and cranium, resulting in whirling behaviour, a blackened tail, and destruction of cartilage. The disease is characterized by the infiltration of numerous inflammatory cells, primarily lymphocytes and macrophages, with the onset of fibrous tissue infiltration. Several efforts have been undertaken to investigate the role of various immune modulatory molecules and immune regulatory genes using advanced molecular methods including flow cytometry and transcriptional techniques. Investigation of the molecular and cellular responses, the role of STAT3 in Th17 cell differentiation, and the inhibitory actions of suppressors of cytokine signaling (SOCS) on interferons and interleukins, as well as the role of natural resistance-associated macrophage proteins (Nramp) in WD have significantly contributed to our understanding of the immune regulation mechanism in salmonids against M. cerebralis. This review thoroughly highlights previous research and discusses potential future directions for understanding the molecular immune response of salmonids and the possible development of prophylactic approaches against WD.

Parkinson's disease (PD) and chronic periodontitis (CP) are both inflammatory diseases; a correlation between the two diseases has been reported, but the underlying mechanisms of this association have not been investigated. We investigated the common molecular mechanisms between PD and CP and the role of immune cells in the pathogenesis of them using bioinformatics analyses to elucidate the association between the two diseases.

We obtained gene expression data from the Gene Expression Omnibus (GEO) database: GSE10334, GSE16134, and GSE23586 for CP gingival samples and GSE20146 for PD brain samples. Subsequently, we conducted an enrichment analysis of the differentially expressed genes (DEGs) using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses. Moreover, all DEGs were analysed for protein-transcription factor interactions and protein-immune cell co-expression. We constructed protein-transcription factor, protein-protein interaction (PPI), and protein-immune cell co-expression networks using the Cytoscape software. Moreover, we identified the hub genes and investigated them for potential diagnostic value.

We identified 99 DEGs in the three CP datasets, 520 DEGs in the PD dataset and found five common DEGs in the CP and PD datasets, namely CXCR4, CXCL8, CD19, RPTN, and SLC16A9. These common DEGs identified in our study may have a potential impact on disease pathogenesis through the involvement of CXCR4-CXCL8-CD19 protein-complexes in dendritic cells. Therefore, CD19, LCP2, CXCR4, and LYN could be used as target molecules for the clinical diagnosis of both diseases.

Sodium (Na+) concentration in solid tumours of different origin is highly dysregulated, and this corresponds to the aberrant expression of Na+ transporters. In particular, the α subunits of voltage gated Na+ channels (VGSCs) raise intracellular Na+ concentration ([Na+]i) in malignant cells, which influences the progression of solid tumours, predominantly driving cancer cells towards a more aggressive and metastatic phenotype. Conversely, re-expression of VGSC β subunits in cancer cells can either enhance tumour progression or promote anti-tumourigenic properties. Metastasis is the leading cause of cancer-related mortality, highlighting an important area of research which urgently requires improved therapeutic interventions. Here, we review the extent to which VGSC subunits are dysregulated in solid tumours, and consider the implications of such dysregulation on solid tumour progression. We discuss current understanding of VGSC-dependent mechanisms underlying increased invasive and metastatic potential of solid tumours, and how the complex relationship between the tumour microenvironment (TME) and VGSC expression may further drive tumour progression, in part due to the interplay of infiltrating immune cells, cancer-associated fibroblasts (CAFs) and insufficient supply of oxygen (hypoxia). Finally, we explore past and present clinical trials that investigate utilising existing VGSC modulators as potential pharmacological options to support adjuvant chemotherapies to prevent cancer recurrence. Such research demonstrates an exciting opportunity to repurpose therapeutics in order to improve the disease-free survival of patients with aggressive solid tumours.

Chemokine receptor 5 (CCR5) is one of the main co-receptors of HIV-1, and has been found to be a potential therapeutic target for stroke. Maraviroc is a classic CCR5 antagonist, which is undergoing clinical trials against stroke. As maraviroc shows poor blood-brain barrier (BBB) permeability, it is of interest to find novel CCR5 antagonists suitable for neurological medication. In this study we characterized the therapeutic potential of a novel CCR5 antagonist A14 in treating ischemic stroke mice. A14 was discovered in screening millions compounds in the Chemdiv library based on the molecular docking diagram of CCR5 and maraviroc. We found that A14 dose-dependently inhibited the CCR5 activity with an IC50 value of 4.29 μM. Pharmacodynamic studies showed that A14 treatment exerted protective effects against neuronal ischemic injury both in vitro and vivo. In a SH-SY5Y cell line overexpressing CCR5, A14 (0.1, 1 μM) significantly alleviated OGD/R-induced cell injury. We found that the expression of CCR5 and its ligand CKLF1 was significantly upregulated during both acute and recovery period in focal cortical stroke mice; oral administration of A14 (20 mg·kg-1·d-1, for 1 week) produced sustained protective effect against motor impairment. A14 treatment had earlier onset time, lower onset dosage and much better BBB permeability compared to maraviroc. MRI analysis also showed that A14 treatment significantly reduced the infarction volume after 1 week of treatment. We further revealed that A14 treatment blocked the protein-protein interaction between CCR5 and CKLF1, increasing the activity of CREB signaling pathway in neurons, thereby improving axonal sprouting and synaptic density after stroke. In addition, A14 treatment remarkably inhibited the reactive proliferation of glial cells after stroke and reduced the infiltration of peripheral immune cells. These results demonstrate that A14 is a promising novel CCR5 antagonist for promoting neuronal repair after ischemic stroke. A14 blocked the protein-protein interaction between CKLF1 and CCR5 after stroke by binding with CCR5 stably, improved the infarct area and promoted motor recovery through reversing the CREB/pCREB signaling which was inhibited by activated CCR5 Gαi pathway, and benefited to the dendritic spines and axons sprouting.

Interleukin 8 (IL8) is vital in promoting inflammation and is a crucial mediator in various physiopathological processes while influencing immunological function. The effect of IL8 on the immunological response to acute bacterial infections in Nile tilapia (Oreochromis niloticus) remains unknown. This work found an IL8 gene from Nile tilapia (On-IL8). It includes a 285 bp open reading frame and codes for 94 amino acids. The transcript levels of On-IL8 were highest in the head-kidney tissue and sharply induced by Streptococcus agalactiae and Aeromonas hydrophila. Besides, in vitro experiments revealed that On-IL8 regulated a variety of immunological processes and promoted inflammatory responses. Moreover, On-IL8 suppressed the NF-κB signaling pathway, consistent with in vitro results. These significant findings serve as the basis for further investigation into how IL8 confers protection to bony fish in opposition to bacterial infections.

Acute-on-chronic liver failure (ACLF) is an acute decompensated syndrome based on chronic liver disease, while neutrophil recruitment is the most critical early step. C-X-C motif chemokine ligand 1 (CXCL1), a cytokine that recruits neutrophils, was significantly upregulated in both ACLF mice and patients with ACLF. This present study aims to explore the role of CXCL1 in the pathogenesis of ACLF.

We established an ACLF mouse model induced by carbon tetrachloride, lipopolysaccharide, and D-galactosamine, and used adeno-associated virus to achieve overexpression and knockdown of Cxcl1. We employed mass cytometry, flow cytometry, multiplex cytokine and chemokine analysis, Western blot, and reactive oxygen species (ROS) detection in mice blood and liver. ACLF patients (n = 10) and healthy controls (n = 5) were included, and their liver samples were stained using multiplex immunohistochemistry techniques.

CXCL1 was significantly elevated in both ACLF mice and patients. CXCL1 recruits neutrophils by binding to the C-X-C motif chemokine receptor 2 on the surface of neutrophils, affects ACLF prognosis by generating ROS and mitochondrial depolarization and modulating caspase3-related apoptotic pathways. We found that the knockdown of CXCL1 attenuated the infiltration of neutrophils in the mouse liver, reduced the expression of inflammatory cytokines, and also significantly downregulated ROS production and caspase3-related hepatocyte apoptosis, thereby ameliorating the liver injury of ACLF.

CXCL1 is a core player in the mobilization of neutrophils in ACLF, and the knockdown of Cxcl1 improves neutrophil infiltration, reduces ROS levels, and reduces hepatocyte apoptosis, thereby attenuating inflammation and liver injury in ACLF. Our results revealed a previously unknown link between CXCL1-induced neutrophil recruitment and ACLF, providing evidencing for potential therapies targeting ACLF.

Obesity is known to have important roles in driving prostate cancer aggressiveness and increased mortality. Multiple mechanisms have been postulated for these clinical observations, including effects of diet and lifestyle, systemic changes in energy balance and hormonal regulation and activation of signalling by growth factors and cytokines and other components of the immune system. Over the past decade, research on obesity has shifted towards investigating the role of peri-prostatic white adipose tissue as an important source of locally produced factors that stimulate prostate cancer progression. Cells that comprise white adipose tissue, the adipocytes and their progenitor adipose stromal cells (ASCs), which proliferate to accommodate white adipose tissue expansion in obesity, have been identified as important drivers of obesity-associated cancer progression. Accumulating evidence suggests that adipocytes are a source of lipids that are used by adjacent prostate cancer cells. However, results of preclinical studies indicate that ASCs promote tumour growth by remodelling extracellular matrix and supporting neovascularization, contributing to the recruitment of immunosuppressive cells, and inducing epithelial-mesenchymal transition through paracrine signalling. Because epithelial-mesenchymal transition is associated with cancer chemotherapy resistance and metastasis, ASCs are considered to be potential targets of therapies that could be developed to suppress cancer aggressiveness in patients with obesity.

We investigate the physicochemical effects of pyroglutamination on the QHALTSV-NH2 peptide, a segment of cytosolic helix 8 of the human C-X-C chemokine G-protein-coupled receptor type 4 (CXCR4). This modification, resulting from the spontaneous conversion of glutamine to pyroglutamic acid, has significant impacts on the physicochemical features of peptides. Using a static approach, we compared the transformation in different conditions and experimentally found that the rate of product formation increases with temperature, underscoring the need for caution during laboratory experiments to prevent glutamine cyclization. Circular dichroism experiments revealed that the QHALTSV-NH2 segment plays a minor role in the structuration of H8 CXCR4; however, its pyroglutaminated analogue interacts differently with its chemical environment, showing increased susceptibility to solvent variations compared to the native form. The pyroglutaminated analogue exhibits altered behavior when interacting with lipid models, suggesting a significant impact on its interaction with cell membranes. A unique combination of atomic force microscopy and infrared nanospectroscopy revealed that pyroglutamination affects supramolecular self-assembly, leading to highly packed molecular arrangements and a crystalline structure. Moreover, the presence of pyroglumatic acid has been found to favor the formation of amyloidogenic aggregates. Our findings emphasize the importance of considering pyroglutamination in peptide synthesis and proteomics and its potential significance in amyloidosis.

The efficacy of acupuncture in treating pain diseases has been recognized in clinical practice, and its mechanism of action has been a hot topic in academic acupuncture research. Previous basic research on acupuncture analgesia has focused mostly on the nervous system, with few studies addressing the immune system as a potential pathway of acupuncture analgesia. In this study, we investigated the effect of electroacupuncture (EA) on the β-endorphins (β-END) content, END-containing leukocyte type and number, sympathetic neurotransmitter norepinephrine (NE), and chemokine gene expression in inflamed tissues. To induce inflammatory pain, about 200 µL of complete Frester adjuvant (CFA) was injected into the unilateral medial femoral muscle of adult Wistar rats. Electroacupuncture treatment was performed for 3 days beginning on day 4 after CFA injection, with parameters of 2/100 Hz, 2 mA, and 30 minutes per treatment. The weight-bearing experiment and enzyme-linked immunosorbent assay showed that EA treatment significantly relieved spontaneous pain-like behaviors and increased the level of β-END in inflamed tissue. Injection of anti-END antibody in inflamed tissue blocked this analgesic effect. Flow cytometry and immunofluorescence staining revealed that the EA-induced increase in β-END was derived from opioid-containing ICAM-1 + /CD11b + immune cells in inflamed tissue. In addition, EA treatment increased the NE content and expression of β2 adrenergic receptor (ADR-β2) in inflammatory tissues and upregulated Cxcl1 and Cxcl6 gene expression levels. These findings provide new evidence for the peripheral analgesic effect of acupuncture treatment by recruiting β-END-containing ICAM-1 + /CD11b + immune cells and increasing the β-END content at the site of inflammation.

Chemokines are a family of signaling proteins that play a crucial role in cell-cell communication, cell migration, and cell trafficking, particularly leukocytes, under both normal and pathological conditions. The oligomerization state of chemokines influences their biological activity. The heterooligomerization occurs when multiple chemokines spatially and temporally co-localize, and it can significantly affect cellular responses. Recently, obligate heterodimers have emerged as tools to investigate the activities and molecular mechanisms of chemokine heterodimers, providing valuable insights into their functional roles. This review focuses on the latest progress in understanding the roles of chemokine heterodimers and their contribution to the functioning of the chemokine network.

Patients with chronic Chagas disease present marked clinical and immunological heterogeneity. During the disease, multiple immune mechanisms are activated to fight the parasite. The purpose of this study was to investigate the expression patterns of genes involved in relevant immunological processes throughout the disease in patients with chronic Chagas disease.

High-throughput RT-qPCR with QuantStudio 12K Flex real-time PCR system was used to evaluate the expression of 106 immune-related genes in PBMC from a cohort of cardiac Chagas disease patients (CCC I), asymptomatic patients (IND) and healthy donors (HD) after being stimulated with T. cruzi soluble antigens. Principal component analysis (PCA), cluster analysis and volcano plots were used to identify differentially expressed genes. In addition, gene set enrichment analysis (GSEA) was employed to identify the enriched immunological pathways in which these genes are involved. PCA revealed the existence of a statistically divergent expression profile of the 36 genes correlated with PC1 between CCC I patients and HD (p < 0.0001). Differential gene expression analysis revealed upregulation of 41 genes (expression fold-change > 1.5) and downregulation of 14 genes (expression fold-change < 0.66) (p = 8.4x10-13 to p = 0.007) in CCC I patients versus HD. Furthermore, significant differences in the expression level of specific genes have been identified between CCC I and IND patients (8 up and 1 downregulated). GSEA showed that several upregulated genes in CCC I patients participate in immunological pathways such as antigen-dependent B cell activation, stress induction of HSP regulation, NO2-dependent IL12 pathway in NK cells, cytokines-inflammatory response and IL-10 anti-inflammatory signaling.

Cardiac Chagas disease patients show an antigen-specific differential gene expression profile in which several relevant immunological pathways seem to be activated. Assessment of gene expression profiles reveal unique insights into the immune response that occurs along chronic Chagas disease.

An 18-year-old woman with intermittent fever, pancytopenia, abnormal liver function, and enlarged lymph nodes and hepatosplenomegaly was clinically suspected as hemophagocytic lymphohistiocytosis. 18F-FDG PET/CT showed increased metabolism in multiple lymph nodes, which were highly suggestive of lymphoma. No increased CXCR4 expression in lymph nodes was demonstrated on 68Ga-pentixafor PET/CT. Subsequent right neck lymph node biopsy pathology revealed EBV-associated lymphoproliferative disorders. Our case shows that 68Ga-pentixafor PET/CT may have potential value in differentiating EBV-associated lymphoproliferative disorders from lymphomas.

Acute respiratory viral infections (ARVI) are the most common illnesses worldwide. In some instances, mild cases of ARVI progress to hyperinflammatory responses, which are damaging to pulmonary tissue and requiring intensive care. Here we summarize available information on preclinical and clinical effects of XC221GI (1-[2-(1-methyl imidazole-4-yl)-ethyl]perhydroazin-2,6-dione), an oral drug with a favorable safety profile that has been tested in animal models of influenza, respiratory syncytial virus, highly pathogenic coronavirus strains and other acute viral upper respiratory infections. XC221GI is capable of controlling IFN-gamma-driven inflammation as it is evident from the suppression of the production of soluble cytokines and chemokines, including IL-6, IL-8, CXCL10, CXCL9 and CXCL11 as well as a decrease in migration of neutrophils into the pulmonary tissue. An excellent safety profile of XC221GI, which is not metabolized by the liver, and its significant anti-inflammatory effects indicate utility of this compound in abating conversion of ambulatory cases of respiratory infections into the cases with aggravated presentation that require hospitalization. This drug is especially useful when rapid molecular assays determining viral species are impractical, or when direct antiviral drugs are not available. Moreover, XC221GI may be combined with direct antiviral drugs to enhance their therapeutic effects.

We aimed to explore diagnostic biomarks and immune cell infiltration characteristics in ulcerative colitis (UC). We used the dataset GSE38713 as the training set and dataset GSE94648 as the test set. A total of 402 differentially expressed genes (DEGs) were obtained from GSE38713. Annotating, visualizing, and integrating discovery of these differential genes was performed using Gene Ontology (GO), Kyoto Gene and Genome Encyclopedia Pathway (KEGG), and Gene Set Enrichment Analysis (GSEA). Protein-protein interaction networks were constructed from the STRING database, and protein functional modules were identified using the CytoHubba plugin of Cytoscape. Random forest and LASSO regression were used to screen for UC-related diagnostic markers, and ROC curves were generated to validate their diagnostic value. The composition of 22 immune cells was analyzed, and the immune cell infiltration in UC was analyzed using CIBERSORT. Results: Seven diagnostic markers associated with UC were identified: TLCD3A, KLF9, EFNA1, NAAA,WDR4, CKAP4, and CHRNA1. Immune cell infiltration assessment revealed that macrophages M1, activated dendritic cells, and neutrophil cells infiltrated relatively more compared to normal control samples. Our results suggest a new functional feature of UC and suggest potential biomarkers for UC through comprehensive analysis of integrated gene expression data.

Colorectal cancer (CRC) represents the second leading cause of cancer-related deaths worldwide. The pathogenesis of CRC is a complex multistep process. Among other factors, inflammation and oxidative stress (OS) have been reported to be involved in the initiation and development of CRC. Although OS plays a vital part in the life of all organisms, its long-term effects on the human body may be involved in the development of different chronic diseases, including cancer diseases. Chronic OS can lead to the oxidation of biomolecules (nucleic acids, lipids and proteins) or the activation of inflammatory signaling pathways, resulting in the activation of several transcription factors or the dysregulation of gene and protein expression followed by tumor initiation or cancer cell survival. In addition, it is well known that chronic intestinal diseases such as inflammatory bowel disease (IBD) are associated with an increased risk of cancer, and a link between OS and IBD initiation and progression has been reported. This review focuses on the role of oxidative stress as a causative agent of inflammation in colorectal cancer.

This study aimed to assess the post-effort transcriptional changes of selected genes encoding receptors for chemokines and interleukins in young, physically active men to better understand the immunomodulatory effect of physical activity. The participants, aged 16-21 years, performed physical exercise tasks of either a maximal multistage 20 m shuttle-run test (beep test) or a repeated speed ability test. The expression of selected genes encoding receptors for chemokines and interleukins in nucleated peripheral blood cells was determined using RT-qPCR. Aerobic endurance activity was a positive stimulant that induced increased expression of CCR1 and CCR2 genes following lactate recovery, while the maximum expression of CCR5 was found immediately post-effort. The increase in the expression of inflammation-related genes encoding chemokine receptors triggered by aerobic effort strengthens the theory that physical effort induces sterile inflammation. Different profiles of studied chemokine receptor gene expression induced by short-term anaerobic effort suggest that not all types of physical effort activate the same immunological pathways. A significant increase in IL17RA gene expression after the beep test confirmed the hypothesis that cells expressing this receptor, including Th17 lymphocyte subsets, can be involved in the creation of an immune response after endurance efforts.

We demonstrate that CD193, the eotaxin receptor, is highly expressed on circulating B cells in paediatric schistosomiasis mansoni. CD193 plays a role in directing granulocytes into sites of allergic-like inflammation in the mucosa, but little is known about its functional significance on human B cells. We sought to characterize CD193 expression and its relationship with S. mansoni infection. We found that CD193+ B cells increased with the intensity of schistosome infection. In addition, a significant negative association was observed between CD193 expression by B cells and IgE production. Decreased IgE levels are generally associated with susceptibility to re-infection. B cell stimulation with eotaxin-1 increased CD193 levels whereas IL-4 led to a reduction. This was supported by plasma levels of eotaxin-1 correlating with CD193 levels on B cells and other cells. In contrast, CD193 expression was induced on naive B cells with a combination of IL-10 and schistosome antigens. Whereas T cells had a modest increase in CD193 expression, only B cell CD193 appeared functionally chemotactic to eotaxin-1. Thus, CD193+ B cells, which co-express CXCR5, may be enroute to sites with allergic-like inflammation, such as gastrointestinal follicles, or even to Th2 granulomas, which develop around parasite eggs. Overall, our results suggest that schistosome infection may promote CD193 expression and suppress IgE via IL-10 and other undefined mechanisms related to B cell trafficking. This study adds to our understanding of why young children may have poor immunity. Nonetheless, praziquantel treatment was shown to reduce percentages of circulating CD193+ B cells lending hope for future vaccine efforts.

Substance abuse is one of the significant problems in social and public health worldwide. Vast numbers of evidence illustrate that motivational and reinforcing impacts of addictive drugs are primarily attributed to their ability to change dopamine signaling in the reward circuit. However, the roles of classic neurotransmitters, especially dopamine and neuromodulators, monoamines, and neuropeptides, in reinforcing characteristics of abused drugs have been extensively investigated. It has recently been revealed that central immune signaling includes cascades of chemokines and proinflammatory cytokines released by neurons and glia via downstream intracellular signaling pathways that play a crucial role in mediating rewarding behavioral effects of drugs. More interestingly, inflammatory responses in the central nervous system modulate the mesolimbic dopamine signaling and glutamate-dependent currents induced by addictive drugs. This review summarized researches in the alterations of inflammatory responses accompanied by rewarding and reinforcing properties of addictive drugs, including cocaine, methamphetamine, and opioids that were evaluated by conditioned place preference and self-administration procedures as highly common behavioral tests to investigate the motivational and reinforcing impacts of addictive drugs. The neuroinflammatory responses affect the rewarding properties of psychostimulants and opioids.