Neutrophil elastase promotes macrophage cell adhesion and cytokine production through the integrin-Src kinases pathway.

ABSTRACT: There are a number of respiratory diseases characterized by the presence of excess neutrophil elastase (NE) activity in tissues, including cystic fibrosis and chronic obstructive pulmonary disease (COPD). NE is considered a primary contributor to disease development, but the precise mechanism has yet to be fully determined. We hypothesized that NE alters the function of macrophages (M?) which play a critical role in many physiological processes in healthy lungs. We demonstrate that monocyte-derived M? exposed to NE releases active matrix metalloproteinases (MMPs), increase expression of pro-inflammatory cytokines TNF?, IL-1?, and IL-8, and reduce capacity to phagocytose bacteria. Changes in M? function following NE treatment were accompanied by increased adhesion and cytoskeleton re-arrangement, indicating the possibility of integrin involvement. To support this observation, we demonstrate that NE induces phosphorylation of kinases from the Src kinase family, a hallmark of integrin signaling activation. Moreover, pretreatment of M? with a specific Src kinase inhibitor, PP2 completely prevents NE-induced pro-inflammatory cytokine production. Taken together these findings indicate that NE participates in lung destruction not only through direct proteolytic degradation of matrix proteins, but also through activation of M? inflammatory and proteolytic functions.

SUBMITTER: Krotova K 

PROVIDER: S-EPMC7522083 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature