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The role of b2-integrins for the effector functions of polymorphonuclear granulocytes

ABSTRACT: Background: b2-integrins are heterodimeric surface receptors that are expressed specifically by leukocytes and consist of a variable a (CD11a-d) and a common b-subunit (CD18). Functional impairment of CD18, which causes leukocyte adhesion deficiency type-1 results in an immunocompromised state characterized by severe infections, such as invasive pulmonary aspergillosis (IPA). The underlying immune defects have largely been attributed to an impaired migratory and phagocytic activity of polymorphonuclear granulocytes (PMN). However, the exact contribution of b2-integrins for PMN functions in-vivo has not been elucidated yet, since the mouse models available so far display a constitutive CD18 knockout (CD18-/- or CD18hypo). To determine the PMN-specific role of b2-integrins for innate effector functions and pathogen control, we generated a mouse line with a Ly6G-specific knockdown of the common b-subunit (CD18DLy6G). Methods: We analyzed expression levels of genes implicated in b2-integrin signaling for treated and untreated PMN derived from CD18DLy6G mice and CD18fl/fl mice using RNA-Sequencing. To determine the most up- or downregulated genes, genes were sorted on the basis of log2 [fold change] maximum-likelihood estimation, and the P-value cut-off was set to 0.05. Results were illustrated using the pheatmap package. Functional interaction networks were visualized using the STRING package in the open-source platform Cytoscape. Results: Our results revealed a downregulation of b2-integrins , while genes implicated in NFkB singaling were upregulated. With regard to PMN effector function, we observed a downregulation of genes implicated in PMN chemotaxis and microbicidal functions such as Defb40.

ORGANISM(S): Mus musculus

PROVIDER: GSE195444 | GEO | 2022/06/02

REPOSITORIES: GEO

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Project description:We have established that human cytomegalovirus (HCMV) infection modulates the biology of target primary blood monocytes, allowing HCMV to use monocytes as 'vehicles' for its systemic spread. HCMV infection of monocytes results in rapid induction of PI(3)K and NF-kB activity. Integrins, which are upstream of the PI(3)K and NF-kB pathways, were shown to be involved in HCMV binding to and entry into fibroblasts, suggesting that receptor-ligand-mediated signaling following viral binding to integrins on monocytes could trigger the functional changes seen in infected monocytes. We now show that integrin engagement and the activation of the integrin/Src-signaling pathway is essential for the induction of HCMV-infected monocyte motility. To investigate how integrin engagement by HCMV triggers monocyte motility, we examined the infected monocyte transcriptome and found that the integrin/Src-signaling pathway regulates the expression of paxillin, which is an important signal transducer in the regulation of actin rearrangement during cell adhesion and movement. Functionally, we observed that paxillin is activated via the integrin/Src-signaling pathway and is required for monocyte motility. Because motility is intimately connected to cellular cytoskeletal organization, a process that is also important in viral entry, we investigated the role paxillin regulation plays in the process of viral entry of monocytes. New results confirmed that HCMV`s ability to enter target monocytes is significantly inhibited in cells deficient in paxillin expression or that had their integrin/Src/paxillin signaling pathway blocked. From our data, HCMV-cell interactions emerge as an essential trigger for the cellular changes that allow for HCMV entry and hematogenous dissemination. Monocytes were mock-infected, HCMV-infected, or pretreated with PP2 inhibitor prior to HCMV infection. There were three samples analyzed per individual replicate. Three replicates are included. comparative studies with a use of the specific Src kinase activity inhibitor

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The role of b2-integrins for the effector functions of polymorphonuclear granulocytes

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