Cytokine & Growth Factor Reviews最新文献

Psoriatic arthritis (PsA) is part of the psoriatic disease spectrum and is characterized by a chronic inflammatory process that affects entheses, tendons and joints. Cytokines produced by immune and non-immune cells play a central role in the pathogenesis of PsA by orchestrating key aspects of the inflammatory response. Pro-inflammatory cytokines such as TNF, IL-23 and IL-17 have been shown to regulate the initiation and progression of PsA, ultimately leading to the destruction of the architecture of the local tissues such as soft tissue, cartilage and bone. The important role of cytokines in PsA has been underscored by the clinical success of antibodies that neutralize their function. In addition to biologic agents targeting individual pro-inflammatory cytokines, signaling inhibitors that block multiple cytokines simultaneously such as JAK inhibitors have been approved for PsA therapy. In this review, we will focus on our current understanding of the role of cytokines in the disease process of PsA and discuss potential new treatment options based on modulation of cytokine function.

Preterm birth is a major public health concern, requiring a deeper understanding of its underlying inflammatory mechanisms and to develop effective therapeutic strategies. This review explores the complex interaction between inflammation and preterm labor, highlighting the pivotal role of the dysregulation of inflammation in triggering premature delivery. The immunological environment of pregnancy, characterized by a fragile balance of immune tolerance and resistance, is disrupted in preterm labor, leading to a pathological inflammatory response. Feto-maternal infections, among other pro-inflammatory stimuli, trigger the activation of toll-like receptors and the production of pro-inflammatory mediators, promoting uterine contractility and cervical ripening. Emerging anti-inflammatory therapeutics offer promising approaches for the prevention of preterm birth by targeting key inflammatory pathways. From TLR-4 antagonists to chemokine and interleukin receptor antagonists, these interventions aim to modulate the inflammatory environment and prevent adverse pregnancy outcomes. In conclusion, a comprehensive understanding of the inflammatory mechanisms leading to preterm labor is crucial for the development of targeted interventions in hope of reducing the incidence of preterm birth and improving neonatal health outcomes.

Stimulator of Interferon Genes (STING) serves as a pivotal mediator in the innate immune signaling pathway, transducing signals from various DNA receptors and playing a crucial role in natural immune processes. During cellular quiescence, STING protein resides in the endoplasmic reticulum (ER), and its activation typically occurs through the cGAS-STING signaling pathway. Upon activation, STING protein is transported to the Golgi apparatus, thereby initiating downstream signaling cascades. Vesicular transport serves as the primary mechanism for STING protein trafficking between the ER and Golgi apparatus, with COPII mediating anterograde transport from the ER to Golgi apparatus, while COPI is responsible for retrograde transport. Numerous factors influence these transport processes, thereby exerting either promoting or inhibitory effects on STING protein expression. Upon reaching the Golgi apparatus, to prevent over-activation, STING protein is transported to post-Golgi compartments for degradation. In addition to the conventional lysosomal degradation pathway, ESCRT has also been identified as one of the degradation pathways for STING protein. This review summarizes the recent findings on the membrane trafficking pathways of STING, highlighting their contributions to the regulation of cytokine production, the activation of immune cells, and the coordination of immune signaling pathways.

Cytokines are small signaling proteins that regulate the immune responses to infection and tissue damage. Surface charges of cytokines determine their in vivo fate in immune regulation, e.g., half-life and distribution. The overall negative charges in the extracellular microenvironment and the acidosis during inflammation and infection may differentially impact cytokines with different surface charges for fine-tuned immune regulation via controlling tissue residential properties. However, the trend and role of cytokine surface charges has yet to be elucidated in the literature. Interestingly, we have observed that most pro-inflammatory cytokines have a negative charge, while most anti-inflammatory cytokines and chemokines have a positive charge. In this review, we extensively examined the surface charges of all cytokines and chemokines, summarized the pharmacokinetics and tissue adhesion of major cytokines, and analyzed the link of surface charge with cytokine biodistribution, activation, and function in immune regulation. Additionally, we identified that the general trend of charge disparity between pro- and anti-inflammatory cytokines represents a unique opportunity to develop precise immune modulation approaches, which can be applied to many inflammation-associated diseases including solid tumors, chronic wounds, infection, and sepsis.

G protein-coupled receptors (GPCRs) are well-studied and the most traceable cell surface receptors for drug discovery. One of the intriguing members of this family is G protein-coupled receptors 35 (GPR35), which belongs to the class A rhodopsin-like family of GPCRs identified over two decades ago. GPR35 presents interesting features such as ubiquitous expression and distinct isoforms. Moreover, functional and genome-wide association studies on its widespread expression have linked GPR35 with pathophysiological disease progression. Various pieces of evidence have been accumulated regarding the independent or endogenous ligand-dependent role of GPR35 in cancer progression and metastasis. In the current scenario, the relationship of this versatile receptor and its putative endogenous ligands for the activation of oncogenic signal transduction pathways at the cellular level is an active area of research. These intriguing features offered by GPR35 make it an oncological target, justifying its uniqueness at the physiological and pathophysiological levels concerning other GPCRs. For pharmacologically targeting receptor-induced signaling, few potential competitive antagonists have been discovered that offer high selectivity at a human level. In addition to its fascinating features, targeting GPR35 at rodent and human orthologue levels is distinct, thus contributing to the sub-species selectivity. Strategies to modulate these issues will help us understand and truly target GPR35 at the therapeutic level. In this article, we have provided prospects on each topic mentioned above and suggestions to overcome the challenges. This review discusses the molecular mechanism and signal transduction pathways activated by endogenous ligands or spontaneous auto-activation of GPR35 that contributes towards disease progression. Furthermore, we have highlighted the GPR35 structure, ubiquitous expression, its role in immunomodulation, and at the pathophysiological level, especially in cancer, indicating its status as a versatile receptor. Subsequently, we discussed the various proposed ligands and their mechanism of interaction with GPR35. Additionally, we have summarized the GPR35 antagonist that provides insights into the opportunities for therapeutically targeting this receptor.

Macrophage migration inhibitory factor (MIF) is a cytokine in the immune system, participated in both innate and adaptive immune responses. Except from immune cells, MIF is also secreted by a variety of non-immune cells, including hematopoietic cells, endothelial cells (ECs), and neurons. MIF plays a crucial role in various diseases, such as sepsis, rheumatoid arthritis, acute kidney injury, and neurodegenerative diseases. The role of MIF in the neuropathogenesis of cognitive impairment disorders is emphasized, as it recruits multiple inflammatory mediators, leading to activating microglia or astrocyte-derived neuroinflammation. Furthermore, it contributes to the cell death of neurons and ECs with the binding of apoptosis-inducing factor (AIF) through parthanatos-associated apoptosis-inducing factor nuclease (PAAN) / MIF pathway. This review comprehensively delves into the relationship between MIF and the neuropathogenesis of cognitive impairment disorders, providing a series of emerging MIF-targeted pharmaceuticals as potential treatments for cognitive impairment disorders.

Innate immunity is not only the first line of host defense against microbial infections but is also crucial for the host responses against a variety of noxious stimuli. Z-DNA binding protein 1 (ZBP1) is a cytosolic nucleic acid sensor that can induce inflammatory cell death in both immune and nonimmune cells upon sensing of incursive virus-derived Z-form nucleic acids and self-nucleic acids via its Zα domain. Mechanistically, aberrantly expressed or activated ZBP1 induced by pathogens or noxious stimuli enables recruitment of TANK binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 to drive type I interferon (IFN-I) responses and activation of nuclear factor kappa B (NF-κB) signaling. Meanwhile, ZBP1 promotes the assembly of ZBP1- and absent in melanoma 2 (AIM2)-PANoptosome, which ultimately triggers PANoptosis through caspase 3-mediated apoptosis, mixed lineage kinase domain like pseudokinase (MLKL)-mediated necroptosis, and gasdermin D (GSDMD)-mediated pyroptosis. In response to damaged mitochondrial DNA, ZBP1 can interact with cyclic GMP-AMP synthase to augment IFN-I responses but inhibits toll like receptor 9-mediated inflammatory responses. This review summarizes the structure and expression pattern of ZBP1, discusses its roles in human diseases through immune-dependent (e.g., the production of IFN-I and pro-inflammatory cytokines) and -independent (e.g., the activation of cell death) functions, and highlights the attractive prospect of manipulating ZBP1 as a promising therapeutic target in diseases.

Atopic dermatitis (AD) is an inflammatory skin disease characterized by intense pruritus. AD is harmful to both children and adults, but its pathogenic mechanism has yet to be fully elucidated. The development of mouse models for AD has greatly contributed to its study and treatment. Among these models, the exogenous drug-induced mouse model has shown promising results and significant advantages. Until now, a large amount of AD-related research has utilized exogenous drug-induced mouse models, leading to notable advancements in research. This indicates the crucial significance of applying such models in AD research. These models exhibit diverse characteristics and are highly complex. They involve the use of various strains of mice, diverse types of inducers, and different modeling effects. However, there is currently a lack of comprehensive comparative studies on exogenous drug-induced AD mouse models, which hinders researchers' ability to choose among these models. This paper provides a comprehensive review of the features and mechanisms associated with various exogenous drug-induced mouse models, including the important role of each cytokine in AD development. It aims to assist researchers in quickly understanding models and selecting the most suitable one for further investigation.

Pyroptosis, a programmed cell death process, is vital for the immune response against microbial infections and internal danger signals. Recent studies have highlighted the importance of protein palmitoylation, a modification that involves attaching palmitate to cysteine residues, in regulating key proteins involved in pyroptosis. Palmitoylation of cGAS at residue C474 by ZDHHC18 affects its enzymatic activity and DNA binding ability. Similarly, ZDHHC9 promotes cGAS activity through palmitoylation at residues C404/405. NLRP3 palmitoylation at residue C844, mediated by ZDHHC12, impacts its stability and interactions with other proteins, crucial for activating the NLRP3 inflammasome and triggering inflammation. However, the role of ZDHHC5 in NLRP3 palmitoylation remains uncertain due to conflicting findings. Palmitoylation at C88/91 is essential for STING activation and induction of type I interferons. It modulates the formation of multimeric complexes and downstream signaling pathways. GSDMD palmitoylation at C191 is necessary for pore formation and membrane translocation, while GSDME palmitoylation at C407/408 is associated with drug-induced pyroptosis. Moreover, palmitoylation of NOD1 and NOD2 influences their membrane recruitment and immune signaling pathways in response to bacterial peptidoglycans, acting as upstream regulators of pyroptosis. This review summarizes the important roles for palmitoylation in regulating the function of key pyroptosis-related proteins, shedding light on the intricate mechanisms governing immune responses and inflammation.