Inflammation Research最新文献

Introduction: Skin lesions in atopic dermatitis (AD) are characterized by elevated levels of both Th1 and Th2 cytokines, along with increased concentrations of inflammatory mediators such as cysteinyl leukotrienes (CysLTs). The enzymes 5-lipoxygenase (5-LO/ALOX5) and leukotriene-C4-synthase (LTC4S), which are essential in CysLT biosynthesis, are highly expressed by macrophages. We aimed to investigate the expression of 5-LO/ALOX5 and LTC4S mRNA in lesional AD skin at single cell level. Furthermore, we analyzed the regulatory effects of the Th1 cytokine interferon gamma (IFNγ) and the Th2 cytokines IL-4, IL-13 on 5-LO/ALOX5 and LTC4S expression in monocytes and macrophages derived from AD patients and healthy volunteers.

Methods: Single-cell RNA sequencing (scRNA-seq) data from lesional AD skin biopsies, as reported in a previously published study, were re-analyzed to evaluate 5-LO/ALOX5 and LTC4S mRNA expression. PBMCs from AD patients, healthy volunteers and anonymous donors were used to isolate monocytes. Macrophages were generated in the presence of GM-CSF or M-CSF for 10 days. Cells were stimulated with IFNγ, IL-4 or IL-13. 5-LO/ALOX5 and LTC4S mRNA expressions were quantified by q-PCR. Intracellular 5-LO/ALOX5 expression was assessed by immunocytochemistry.

Results: Re-analysis of scRNA-seq data revealed high levels of 5-LO/ALOX5 and LTC4S transcripts in monocytes and macrophages. In-vitro, IFNγ induced 5-LO/ALOX5 mRNA expression in blood derived monocytes and macrophages from AD patients, and protein levels in both monocytes and macrophages from anonymous donors, whereas IL-4 and IL-13 suppressed its expression. Vice versa LTC4S mRNA expression was downregulated by IFNγ but upregulated by IL-13. Higher baseline mRNA expressions of 5-LO/ALOX5 and LTC4S were observed in blood derived monocytes from AD patients compared to cells from healthy volunteers .

Conclusion: We demonstrate that IFNγ enhances the 5-LO/ALOX5-catalyzed stage of CysLT synthesis, whereas IL-13 promotes the LTC4S dependent pathway in human monocytes or macrophages. These findings suggest a potential role for these cells in driving CysLT production in acute and chronic AD lesions and may give rise for future therapeutic interventions targeting this pathway.

Background: Proinflammatory mediators including COX-2, IL-1β, IL-6, and TNF-α, play major roles in the initiation of postsurgical pain. Produced primarily by activated macrophages and microglia, these mediators drive hyperexcitation of nociceptors and promote peripheral and central pain sensitization. Post-transcriptional RNA regulation is a major control point for these mediators, centering around adenine- and uridine-rich elements (ARE) in the 3' untranslated regions of their mRNA transcripts. The ARE governs RNA stability and translational efficiency through an interaction with ARE-specific RNA binding proteins (AUBP). Tristetraprolin (TTP) is an AUBP that promotes RNA degradation and translational silencing of these mediators to suppress inflammatory responses.

Methods: Mice with myeloid-specific TTP knockout or TTP knock-in underwent paw incision and were assessed for mechanical allodynia and thermal sensitivity. Molecular and cellular inflammatory responses were monitored at the site of incision, dorsal root ganglia (DRG) and lumbar spinal cord (L-SC) by qPCR, ELISA, immunohistochemistry and/or flow cytometry.

Results: TTP deletion exacerbated post-incisional allodynic pain in parallel with increased edema at the site of injury and delayed wound healing but without significant effects on thermal sensitivity. There was an increase in infiltrating macrophages at the incisional site, particularly at the dermal-epidermal junction, in parallel with a robust increase in proinflammatory/pronociceptive mediators. An enhanced inflammatory response was also detected in the circulation, ipsilateral DRG and L-SC which persisted through post-incisional day 7. Conversely, TTP knock-in mice showed attenuation of allodynic pain and inflammatory responses in skin, DRG, L-SC, and circulation.

Conclusion: TTP plays a critical role in mitigating postsurgical pain by tamping down peripheral, central and systemic inflammatory responses, thus identifying a new target and mechanism for future development of pain therapeutics.

Introduction: Rosacea is a chronic inflammatory skin disorder characterized by symptoms like itching, redness, and impaired skin barrier function. Mast cell activation plays a crucial role in its pathogenesis. Recent evidence shows higher expression of mast cell receptor MRGPRX2/MRGPRB2 in rosacea patients' skin tissues and its potential as a novel drug target. We evaluated the therapeutic effect of a novel small-molecule MRGPRX2/MRGPRB2 antagonist in a mouse model of rosacea and itch.

Methods: The therapeutic effects of GE1111 were evaluated in vivo on wildtype and MRGPRB2 knock-out mice with LL-37-induced rosacea. Serum MCP-1 level and histochemistry measured inflammation and mast cell degranulation in skin tissue. Functional in vitro cell culture assays were developed using MRGPRX2/MRGPRB2 agonist LL-37, mast cells, keratinocytes, and macrophage cell lines.

Results: LL-37-treated mice showed redness, increased serum MCP-1, and epidermal thickness of skin tissue, while these changes were absent in LL-37-treated MRGPRB2 knock-out mice. Treatment with GE1111 reduced rosacea symptoms, epidermal thickness, and serum MCP-1 levels. GE1111 protected tight junction protein expression and reduced mast cell degranulation and inflammatory cytokine gene and protein expression in skin lesions. GE1111 treatment reduced the number and duration of itch in the compound 48/80 induced itch model. In vitro evidence showed GE1111's mechanism by inhibiting inflammatory interaction of mast cells with keratinocytes and macrophages.

Conclusion: GE1111 showed promising therapeutic effects in rosacea via targeting interactions between mast cells, keratinocytes, and macrophages and inhibiting inflammatory cytokines. These findings open possibilities for developing MRGPRX2/MRGPRB2 antagonists as novel treatments for rosacea.

Background: Pneumonia caused by Streptococcus pneumoniae remains a major global health concern, leading to significant morbidity and mortality. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide with known anti-inflammatory and pro-resolving properties, but its therapeutic potential in bacterial pneumonia is not fully understood.

Purpose: This study aimed to investigate whether Ang-(1-7) could reduce inflammation, improve bacterial clearance, and enhance survival in a murine model of pneumococcal pneumonia, alone or in combination with the antibiotic ceftriaxone.

Methods: A mouse model of S. pneumoniae pneumonia was used to evaluate the effects of Ang-(1-7). Mice received Ang-(1-7) treatment after infection, either alone or combined with ceftriaxone. Outcomes included leukocyte infiltration, pulmonary edema, lung tissue damage, cytokine production (TNF-α, IL-6, CXCL-1), bacterial load in bronchoalveolar lavage and blood, survival analysis, bone marrow-derived macrophage phagocytosis assays, and expression of lung barrier-associated genes.

Results: Ang-(1-7) reduced leukocyte infiltration, pulmonary edema, and lung tissue injury, and decreased pro-inflammatory cytokine levels. Treatment improved bacterial clearance in both lungs and bloodstream and increased survival in infected mice. Importantly, combining Ang-(1-7) with ceftriaxone further enhanced survival, even when treatment initiation was delayed. Mechanistically, Ang-(1-7) increased macrophage phagocytic activity and upregulated genes associated with lung barrier integrity.

Conclusion: Ang-(1-7) decreased inflammation, improved bacterial clearance, and enhanced survival in severe pneumococcal pneumonia. Its combination with ceftriaxone produced additive benefits, supporting Ang-(1-7) as a promising adjuvant therapeutic strategy in this infectious condition.

Background: Sepsis and heatstroke, although arising from microbial infection or environmental heat exposure, converge upon similar pathophysiological systemic inflammatory responses that include immune dysregulation, mitochondrial dysfunction, endothelial injury, and multiorgan failure. Despite this overlap, important mechanistic differences, especially in the initiating triggers and immune response dynamics, distinguish their clinical manifestations and therapeutic strategies.

Findings: Sepsis is initiated by pathogen-associated molecular patterns (PAMPs) recognized by pattern recognition receptors, whereas heatstroke stems from the release of damage-associated molecular patterns (DAMPs) in response to thermal injury. Both syndromes disrupt mitochondrial integrity, leading to impaired oxidative phosphorylation, an excess production of reactive oxygen species (ROS), and the release of mitochondrial DNA and cytochrome C, which further amplify inflammation and promote cell death. Leukocytes undergo diverse forms of death-including apoptosis, necroptosis, pyroptosis, and ferroptosis-compounding immune dysfunction. Coagulopathy and disseminated intravascular coagulation are prevalent in both conditions, driven by endothelial injury, platelet activation, and NET formation, although microbial toxins intensify this response in sepsis.

Conclusions: This review synthesizes current evidence to delineate the converging and diverging pathways of sepsis and heatstroke, with a focus on mitochondrial injury, immune paralysis, and thromboinflammation. We also explore emerging biomarkers and novel therapeutic targets, including mitochondrial stabilizers and modulators of cell death. A comprehensive understanding of these mechanisms can inform precision medicine strategies and improve outcomes in both syndromes.

Objective: Mitogen-activated protein kinase phosphatase-1 (MKP-1) is an anti-inflammatory enzyme whose expression is increased by glucocorticoids (GCs). MKP-1 dephosphorylates and thereby inactivates mitogen-activated protein kinases (MAP kinases) which are major signaling pathways mediating proinflammatory effects of various extracellular factors to gene expression. In this study, we examined the regulatory effects of the synthetic glucocorticoid dexamethasone on the expression of a panel of genes previously identified as the top 15 critical mediators in the pathogenesis of osteoarthritis (OA). Furthermore, we investigated the hypothesis that MKP-1 is involved in mediating these glucocorticoid-induced effects in chondrocytes.

Methods: The effects of dexamethasone on the interleukin-1β-induced expression of OA target genes were investigated with RNA-seq and quantitative RT-PCR in primary cultured chondrocytes from wild-type and MKP-1 deficient mice, and from OA patients undergoing joint replacement surgery.

Results: Under these conditions, dexamethasone was found to significantly alter the expression of seven out of the 15 OA-related genes including two cholesterol hydroxylases, namely cholesterol 25-hydroxylase (CH25H) and 25-hydroxycholesterol 7-hydroxylase (also known as cytochrome P450 family 7 subfamily B member 1, CYP7B1). Dexamethasone attenuated the interleukin-1β -induced expression of CH25H and CYP7B1 in primary chondrocytes of wild-type mice and in primary human OA chondrocytes, but the dexamethasone effect was absent (CYP7B1) or reduced (CH25H) in chondrocytes from MKP-1 deficient mice. Furthermore, the p38 MAP kinase inhibitor BIRB796 significantly inhibited CH25H expression while the JNK MAP kinase inhibitor SP600125 attenuated CYP7B1 expression in human OA chondrocytes.

Conclusions: In conjunction with previous findings, the current data substantiate the role of MKP-1 as a protective factor in chondrocytes and highlight its potential as a therapeutic target for the treatment of osteoarthritis, because increased levels of cholesterol and its metabolism by CH25H and CYP7B1 are involved in the pathogenesis of OA, particularly in its obesity-associated phenotype.

The OX40/OX40L co-stimulatory signaling pathway plays a crucial role in T cell activation, differentiation, expansion, and survival across various human tissues, including the skin and mucosal surfaces. Alterations in this pathway have been implicated in diverse immune-mediated skin conditions such as tumor microenvironments; atopic dermatitis, characterized by type 2 inflammation; psoriasis and hidradenitis suppurativa, associated with Th17 responses; vitiligo, involving dysregulated interferon-producing CD8⁺ T cells. The complex interplay between mast cells expressing OX40L and T cells expressing OX40, which in some contexts can inhibit regulatory T cell (Treg) function and promote Th17 differentiation, underscores the therapeutic potential of either antagonizing or agonizing this co-stimulatory pathway. In this review, we discuss selected dermatological diseases in which the OX40/OX40L axis appears relevant to their immunopathogenesis and may serve as a potential therapeutic target.

Objective: Colitis disrupts the intestinal barrier, leading to increased permeability and the translocation of harmful microbial components into the circulation and distant organs, including bone. Given that macrophages serve as both frontline immune defenders in tissues and key regulators of bone homeostasis, this study investigates molecular alterations in osteal macrophages (Omacs) and their contribution to bone loss in a murine model of colitis-induced osteoporosis.

Methods: Colitis-induced osteoporosis was established by administering DSS in drinking water for 5 days. Omacs were isolated from bone tissue and subjected to bulk RNA-seq analysis, phagocytosis assays and co-culture models with osteoblasts or osteoclast precursors.

Results: RNA-seq data of Omcas demonstrated a shift towards an inflammatory phenotype under colitis conditions, which was accompanied by bone loss in mice. The upregulated genes in these cells were most significantly enriched in IL-17, NF-κB, and TNF signaling pathways. Importantly, these cells exhibited decreased phagocytic activity and were able to disrupt osteoblast differentiation and promote osteoclast differentiation in vitro.

Conclusions: These results indicate that colitis triggers a significant inflammatory response in Omacs, which can contribute to bone metabolic dysfunction. Modulating the activation of inflammatory pathways may offer a potential therapeutic avenue for treating colitis-induced osteoporosis.

Objective: T cell immunoglobulin and mucin-domain containing-3 (TIM-3) plays a critical regulatory role in a variety of diseases. Human soluble TIM-3 (sTIM-3) is known to be generated through proteolytic cleavage of membrane-bound TIM-3 by the A disintegrin and metalloprotease, however its precise role in inflammation remains largely unclear. This study aims to define the specific function of sTIM-3.

Methods: In this study, the role of sTIM-3 was investigated using in vivo models of experimental autoimmune encephalomyelitis (EAE) and septic shock. Mechanistic insights were gained through biochemical analyses of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome pathway.

Results: We found that sTIM-3 alleviated disease severity in both EAE and septic shock. This protective effect was achieved through the inhibition of NLRP3 inflammasome activation. Mechanistically, sTIM-3 interacted with the adaptor protein Apoptosis-associated speck-like protein containing a CARD (ASC), thereby dampening its oligomerization and subsequent assembly of the active NLRP3 inflammasome complex.

Conclusion: Our findings establish sTIM-3 as a promising therapeutic candidate for mitigating inflammation caused by excessive NLRP3 inflammasome activation, providing novel insights into potential interventions for various inflammatory diseases.