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Role of mechanical signal in regulating neutrophil function

ABSTRACT: It is not understood, how mechanical signals influence the behavior and action of circulating cells in our body. Previous studies showed that the process of migration through narrow slits might enhance lifespan of polymorpho-nuclear cells (PMN / neutrophil). But it is unknown, how the mechanical signal is received, relayed, and translated into specific phenotype shift in PMN. Here we investigated whether compressional force affects defense system of circulating lymphocytes by increasing their killing ability during migration through narrow endothelial junctions. To decipher the receiving and transducing components of this mechanical signal relay process, we performed gene expression analysis between transmigrated and non-transmigrated neutrophils. Comparison of early gene-expression pattern of transmigrated and non-transmigrated neutrophils revealed a huge change in gene expression profile. Molecular and genetic analysis of the proteins revealed from gene-expression analysis led us to understand the mechanism of mechanical signal relay from the neutrophil membrane to bacterial-killing machinery. As neutrophils are most abundant and immediate-responding circulating immune cells in our body, our study advances the path for understanding the general process of mechano-transduction, and mechano-modulatory applications with mechanically enhanced neutrophils.

ORGANISM(S): Mus musculus

PROVIDER: GSE210111 | GEO | 2023/12/04

REPOSITORIES: GEO

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Project description:Neutrophil accumulation in crypt abscesses is a pathological hallmark of ulcerative colitis. Based on recent evidence that mucosal metabolic changes influence disease outcomes, we hypothesized that transmigrating neutrophils influence the transcriptional profile of intestinal epithelia. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by neutrophil-epithelial crosstalk. Real-time O2 sensing indicated that transmigrating neutrophils rapidly deplete microenvironmental O2 sufficient enough to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). Utilizing HIF reporter mice in a TNBS colitis model, we investigated the relative contribution of neutrophils and the respiratory burst to M-bM-^@M-^\inflammatory hypoxiaM-bM-^@M-^] in vivo. Gp91phox-null mice, which mirror human chronic granulomatous disease, developed accentuated colitis compared to control with exaggerated neutrophil infiltration and diminished inflammatory hypoxia. In conclusion, transcriptional imprinting of host tissue by infiltrating neutrophils modulates the host response to inflammation. Likewise, the respiratory burst contributes fundamentally to localized O2 depletion, resultant microenvironmental hypoxia and effective inflammatory resolution. Two models were employed, direct and indirect. The M-bM-^@M-^\DirectM-bM-^@M-^] migration model entailed establishing a chemotactic gradient (using fMLP) across monolayers of T84 intestinal epithelial cells grown on the underside of permeable supports (3um pore). Neutrophils (PMN) were induced to migrate in the physiologically relevant the physiologically relevant basolateral-to-apical direction. Following migration, T84s were rested in complete media and 2hrs later harvested for RNA isolation. In the Indirect model, PMN were applied to T84s as with the direct model. After migration, conditioned supernatants were collected, cells pelleted and supernatants filtered through 0.2um pore. Conditioned supernatants were transferred to naive T84 monolayers for 2hrs, followed by RNA harvest. Each model was exposed to neutrophils (PMN) or not. All monolayers contained chemotactic peptide fMLP on the apical side. Total of 12 samples, 4 conditions in triplicate: Direct migration without neutrophils (T84 +fMLP -PMN), Direct migration with neutrophils (T84 +fMLP +PMN), Indirect migration without neutrophils (T84 +fMLP -PMN), Indirect migration with neutrophils (T84 +fMLP +PMN)

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Role of mechanical signal in regulating neutrophil function

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