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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:Myeloid-derived suppressor cells (MDSCs) are key players in immune evasion, tumor progression and metastasis. MDSCs accumulate under various pathological states, and fall into two functionally and phenotypically distinct subsets: polymorphonuclear (PMN)-MDSCs and monocytic (M)-MDSCs. These subsets have been studied extensively in humans and mice, yet to date no study has identified MDSC subsets in dogs with spontaneous tumors. As dogs are an excellent model for human tumor development and progression, we set out to identify PMN-MDSCs and M-MDSCs in clinical canine oncology patients. We identified MDSCs as hypodense MHC class II-CD5-CD21-CD11b+ cells and show for the first time that they can also be subdivided into polymorphonuclear (CADO48A+CD14-) and monocytic (CADO48A-CD14+) subsets. The transcriptomic signatures of PMN-MDSCs and M-MDSCs are distinct from each other and from those of conventional polymorphonuclear (PMN) and monocytic cells, respectively. Notably, bioinformatic analyses reveal a statistically significant similarity between canine and previously published human MDSC gene expression patterns. As in humans, peripheral blood frequencies of canine PMN-MDSCs and M-MDSCs are significantly different in dogs with cancer compared to healthy control dogs (PMN-MDSCs: p < .001; M-MDSCs: p < .01). Furthermore, a comparison of our canine MDSC RNA-seq data with transcriptomic results previously published for human and murine MDSCs highlights five commonly upregulated genes in PMN-MDSCs in all species, suggesting that these genes are evolutionarily conserved and functionally important. Interestingly, one gene has previously been implicated in PMN-MDSC function (MMP8), but four genes (LTF, LCN2, CAMP, EBP41L3) are novel in the context of PMN-MDSCs. Our findings therefore demonstrate for the first time that dogs have two distinct populations of MDSCs, characterized by specific phenotypic and transcriptomic signatures that share key features of human MDSC subsets. Importantly, by leveraging the power of evolution, we have identified additional conserved genes in PMN-MDSCs of multiple species which may play a role in MDSC function. Our findings therefore validate the dog as a model for studying MDSCs in the context of cancer.

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

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