DOI: 10.1101/474395Dec 2, 2018Paper

Neutrophil Elastase Activates Macrophage MMPs, Promotes Cell Adhesion And Cytokine Production Via Integrin-Src Kinases Pathway

BioRxiv : the Preprint Server for Biology
Karina KrotovaMark Brantly

Abstract

There are a number of diseases characterized by the presence of neutrophil elastase (NE) activity in tissues including cystic fibrosis and alpha-1-antitrypsin deficiency induced lung destruction. It is generally accepted that NE actively contributes to this pathological process, but the precise mechanisms has yet to be determined. We hypothesized that NE activates the macrophages (Mϕ) pro-inflammatory program. We demonstrate that following NE exposure, monocyte-derived Mϕ release proteolytic activity composed of several matrix metalloproteinases (MMPs) which could contribute to extracellular matrix (ECM) degradation. NE upregulates expression of Mϕ derived pro-inflammatory cytokines including TNFα, IL-1β, and IL-8. Thus, NE-activated Mϕ can contribute to tissue destruction through the proteolytic activity of metalloproteinases and by supporting chronic inflammation through expression of pro-inflammatory cytokines. We also demonstrate that NE increases Mϕ adhesion that is attenuated by antibodies specific to integrin subunits. We show that the effects of NE on Mϕ can be mediated through an activation of integrin pathways. In support of integrin involvement, we demonstrate that NE activates the Src kinase family, a hallmark of in...Continue Reading

Related Concepts

Tissue Adhesions
Alpha 1-Antitrypsin
Cell Adhesion
Cystic Fibrosis
Extracellular Matrix
Chronic Inflammation
Integrins
Interleukin-1 beta
Lung Diseases
Macrophage

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