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An IL-17-Ly6G+Polymorphonuclear Neutrophil (PMN) axis limits protective host responses against tuberculosis.

ABSTRACT: The protective correlates of Mycobacterium tuberculosis (Mtb) infection-elicited host immune responses are incompletely understood. Here we report pro-pathogenic crosstalk between IL-17, COX2, and Ly6G+Polymorphonuclear Neutrophils (PMNs). We show that most intracellular bacilli in the wild-type (WT) mice's lungs are Ly6G+PMN-resident. In BCG-vaccinated WT mice, Mtb continues to persist inside Ly6G+PMNs, which is sensitive to COX2 inhibition. Using a genetically susceptible IFNγ -/- mice model, we report that excessive neutrophil infiltration and corresponding bacteremia are dependent on Ly6G+PMN-derived IL-17. COX2 inhibition and IL-17 neutralization reverses Ly6G+PMN infiltration, associated pathology and death in IFNγ -/- mice. Inhibiting RORγT along with COX2 in Mtb-infected WT mice further demonstrates the pathological nature of the IL-17- Ly6G+PMN axis. Clinically, in a prospective cohort of pulmonary TB subjects, high neutrophil count and serum IL-17 levels precipitate adverse treatment outcomes. Therefore, targeting the pro-pathogenic IL-17- Ly6G+PMN axis could enhance TB prevention and therapy in normal and genetically vulnerable subjects.

ORGANISM(S): Mus musculus

PROVIDER: GSE238265 | GEO | 2025/10/31

REPOSITORIES: GEO

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Project description:Background: Community-associated methicillin-resistant staphylococcus aureus (CA-MRSA) is a drug-resistant bacterium prevalent in community settings, characterized by high pathogenicity and transmission potential. Polymorphonuclear neutrophils (PMNs) represent the first line of defense in innate immunity and are activated to phagocytose MRSA. However, MRSA, once phagocytosed by PMNs, induces necroptosis within the neutrophils, which is a key mechanism contributing to host damage.CA-MRSA releases virulence factors that enhance its pathogenicity by disrupting the host's innate immune response, particularly impairing the phagocytic function of PMNs. Steamed Panax notoginseng (S-PN) has demonstrated immune-regulatory and anti-inflammatory properties, showing promising therapeutic effects in alleviating the severe inflammatory responses induced by pathogenic microbial infections. Objective: This study aims to investigate the pharmacological effects and mechanisms of S-PN in attenuating CA-MRSA-induced necroptosis of PMNs, and to explore the impact of PMN necroptosis on the inflammatory response. Methods: A co-culture model of MRSA USA300 strain and PMNs isolated from healthy human blood was established to observe the changes in necroptosis marker HMGB1, PMNs counts, ROS, chemokine MCP-1 and pro-inflammatory cytokines IL-1β, IL-8, TNF-α. RNA-seq was employed to analyze the effects of S-PN on the transcriptional expression of pathogenesis-related genes of MRSA. RT-PCR was utilized to validate the expression of S-PN on MRSA virulence factors and PMNs necroptosis related genes. Results: S-PN significantly inhibited HMGB1, ROS, MCP-1, IL-1β and IL-8 in MRSA-PMN co-cultures, the PMN count in the S-PN group was higher than that in the model group. S-PN down-regulated MRSA pathogenic-associated Staphylococcus aureus infection and quorum sensing signaling pathways, and significantly reduced the virulence factors PSM and PVL. S-PN suppressed the expression of genes associated with necroptosis ripk1, ripk3, and mlkl in PMNs. Conclusion: S-PN inhibited CA-MRSA-induced necroptosis of PMNs, as well as the excessive inflammatory response and ROS accumulation accompanying this process. The mechanism involves the inhibition of the expression of MRSA virulence factor PSM and necroptosis pathway genes. These findings underscore the significant potential of S-PN in the treatment of CA-MRSA infections.

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An IL-17-Ly6G+Polymorphonuclear Neutrophil (PMN) axis limits protective host responses against tuberculosis.

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