Background: Perturbation of macrophage homeostasis is one of the key mechanisms of airway inflammation in asthma. However, the exact mechanisms remain poorly understood.

Background: Antibiotic exposure can occur in medical settings and from environmental sources. Long-term effects of brief antibiotic exposure in early life are largely unknown. Results: Post a short-term treatment by ceftriaxone to C57BL/6 mice in early life, a 14-month observation was performed using 16S rRNA gene-sequencing technique, metabolomics analysis, and metagenomics analysis on the effects of ceftriaxone exposure. Firstly, the results showed that antibiotic pre-treatment significantly disturbed gut microbial α and β diversities (P < 0.05). Both Chao1 indices and Shannon indices manifested recovery trends over time, but they didn’t entirely recover to the baseline of control throughout the experiment. Secondly, antibiotic pre-treatment reduced the complexity of gut molecular ecological networks (MENs). Various network parameters were affected and manifested recovery trends over time with different degrees, such as nodes (P < 0.001, R² = 0.6563), links (P < 0.01, R² = 0.4543), number of modules (P = 0.0672, R² = 0.2523), relative modularity (P = 0.6714, R² = 0.0155), number of keystones (P = 0.1003, R² = 0.2090), robustness_random (P = 0.79, R² = 0.0063), and vulnerability (P = 0.0528, R² = 0.28). The network parameters didn't entirely recover. Antibiotic exposure obviously reduced the number of key species in gut MENs. Interestingly, new keystones appeared during the recovery process of network complexity. Changes in network stability might be caused by variations in network complexity, which supports the ecological theory that complexity begets stability. Besides, the metabolism profiles of the antibiotic group and control were significantly different. Correlation analysis showed that antibiotic-induced differences in gut microbial metabolism were related to MEN changes. Antibiotic exposure also caused long-term effects on gut microbial functional networks in mice. Conclusions: These results suggest that short-term antibiotic exposure in early life will cause long-term negative impacts on gut microbial diversity, MENs, and microbial metabolism. Therefore, great concern should be raised about children’s brief exposure to antibiotics if the results observed in mice are applicable to humans.

Previous studies have indicated that the monocyte chemo-attractant protein 1 (MCP-1), also referred to as C-C motif chemokine ligand 2 (CCL2), plays a significant role in the pathogenesis of sepsis, and this study investigated the clinical relevance of two MCP-1 gene polymorphisms on sepsis onset and progression. The Multiplex SNaPshot genotyping method was used to detect MCP-1 gene polymorphisms in the Chinese Han population (403 sepsis patients and 400 controls). MCP-1 mRNA expression levels were measured using real-time quantitative PCR, and enzyme-linked immunosorbent assays were used to analyze MCP-1, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and interleukin-1 beta (IL-1β) plasma concentrations. The rs1024611 polymorphism analysis showed lower frequencies of minor homozygous genotype (AA) and allele (A) in sepsis patients compared to the healthy controls (19.4% vs. 31.5%, P = 0.0001 and 45.9% vs. 54.8%, P = 0.0004, respectively). And the frequencies of GG genotype and G allele were lower in sepsis patients compared to the controls (19.6% vs. 31.3%, P = 0.0002 and 46.0% vs. 54.5%, P = 0.0007, respectively). The rs1024611 AG/GG and rs2857656 GC/CC genotypes were both overrepresented in patients with severe sepsis (both P = 0.0005) and septic shock (P = 0.010 and P = 0.015, respectively) compared to the patients with mild sepsis. Moreover, among sepsis patients, the rs1024611 AG/GG and rs2857656 GC/CC carriers exhibited significant increases in expression levels of MCP-1 (P = 0.025), TNF-α (P = 0.034) and IL-6 (P = 0.043) compared with the rs1024611 AA or rs2857656 GG carriers. This study provides valuable clinical evidence that the MCP-1/CCL2 polymorphisms rs1024611 and rs2857656 are associated with sepsis susceptibility and development. We conclude that MCP-1/CCL2 plays a significant role in the pathogenesis of sepsis, which has potentially important therapeutic implications.

Introduction: Although genetic variants of the A disintegrin and metalloproteinase 10 (ADAM10) gene have been shown to be associated with susceptibility to several inflammatory-related diseases, to date little is known about the clinical relationship in the development of sepsis.Methods: Two genetic variants in the promoter of ADAM10 were selected to analyze the potential association with the risk of sepsis. A total of 440 sepsis patients and 450 matched healthy individuals in two independent Chinese Han population were enrolled. Pyrosequencing and polymerase chain reaction-length polymorphism was used to determine the genotypes of the rs514049 and rs653765. A real-time qPCR method was used to detect the mRNA level of ADAM10. Enzyme-linked immunosorbent assay was used to measure the expression levels of substrates CX3CL1, interleukin (IL)-6R, tumor necrosis factor alpha (TNF-α), and the pro-inflammatory cytokines IL-1β and IL-6. Luciferase assay was used to analyze the activities of the promoter haplotypes of ADAM10.Results: No statistically significant differences between sepsis cases and controls in the genotype or allele frequencies were observed, suggesting that ADAM10 single nucleotide polymorphisms (SNPs) may not be risk factors for the occurrence of sepsis. A significant difference in the genotype and allele frequencies of the rs653765 SNP between patients with sepsis subtype and severe sepsis (P = 0.0014) or severe sepsis/sepsis shock (P = 0.0037) were observed. Moreover, the rs653765 CC genotype in severe sepsis showed a higher ADAM10 level compared to healthy groups, and the rs653765 CC polymorphism had a strong impact on the production of the ADAM10 substrates CX3CL1, IL-6R and TNF-α. Furthermore, the functional assay showed that ADAM10 C-A haplotype carriers exhibited significantly higher reporter activity compared with the T-A carriers and T-C carriers in human acute monocytic leukemia cell line.Conclusions: Our data initially indicated the ADAM10 rs653765 polymorphism was associated with the development of severe sepsis; the risk CC genotype could functionally affect the expression level of ADAM10 mRNA and was accompanied by the up-regulation of its substrates. Thus, ADAM10 might be clinically important and play a critical role in the pathogenesis of the development of sepsis, with potentially important therapeutic implications.

Pathogens exploit cellular stress responses to drive infection and evade immune responses, posing a persistent global health threat. Stress granules (SGs), dynamic mRNA hubs formed under stress, and regulated cell death (RCD) pathways collectively orchestrate host-pathogen dynamics. While SGs regulate mRNA translation to aid adaptation, RCD mechanisms—including apoptosis, pyroptosis, and necroptosis—eliminate infected cells to curb pathogen spread. However, pathogens subvert these systems through immune evasion strategies, such as disrupting SGs assembly or hijacking cell death signaling, to enhance replication and persistence. This review integrates molecular insights into SGs biogenesis and RCD regulation, dissecting their bidirectional interplay during infection. We highlight pathogen-specific tactics, such as viral proteases cleaving G3BP1 or bacterial effectors halting translation, to manipulate SGs dynamics and cell death pathways. Furthermore, we explore therapeutic opportunities targeting SGs assembly (e.g., eIF2α phosphorylation modulators, G3BP1 inhibitors) and RCD modulation (e.g., PANoptosis suppression, ferroptosis inducers) to restore host defense and mitigate immunopathology. By bridging molecular mechanisms with clinical applications, this analysis charts a course toward precision therapies leveraging the SGs-RCD axis to combat infectious diseases.

Previous studies have identified critical roles of IL-27 in the pathological mechanisms of sepsis, and blockade of IL-27 may be a promising alternative therapy for sepsis. The purpose of this study was to evaluate the clinical relevance of IL-27 genetic polymorphisms in sepsis and to further characterize their effect on IL-27 expression and inflammatory processes following sepsis. A total of 885 septic patients and 1101 healthy controls were enrolled and genotyped for IL-27 genetic variants (rs153109/−964A > G and rs17855750/2905 T > G). Quantitative real-time PCR and enzyme-linked immunosorbent assays were performed to detect IL-27 expression and cytokine production. The effect of the rs153109 polymorphism on IL-27 promoter activity was evaluated using a luciferase reporter assay, and THP-1 cell apoptosis was calculated using an annexin V apoptosis assay. No significant differences in the genotype/allele frequencies were observed between patients with sepsis and healthy controls, suggesting that these two IL-27 polymorphisms may not influence susceptibility to sepsis. The -964AA genotype was overrepresented in patients with severe sepsis/septic shock relative to patients with the sepsis subtype, and the A allele was significantly associated with 28-mortality in sepsis. Patients carrying the -964AA genotype exhibited significantly higher expression levels of IL-27 than the GA/GG genotype carriers. The results of an in vitro (lipopolysaccharide (LPS))-stimulated experiment showed that this sepsis-associated high-risk AA genotype significantly increased IL-27 levels and enhanced TNF-α and IL-1β production in the peripheral blood mononuclear cells (PBMCs) upon exposure to LPS in vitro. Furthermore, luciferase reporter assays indicated that the high-risk -964A allele resulted in increased promoter activities compared to the non-risk allele in THP-1 and 293 T cells. Additionally, IL-27 treatment significantly enhanced TNF-α and IL-6 secretion and apoptosis of THP-1 cells upon LPS stimulation. These results provided evidence that the IL-27 -964A > G polymorphism functionally enhanced IL-27 expression and promoted sepsis-induced inflammatory responses, which ultimately resulted in promoting the progression of sepsis and poor prognosis.