Neutrophil elastase activates MMPs in macrophages and promotes adhesion and cytokine expression through the integrin – Srk pathway.

Abstract

Abstract There are a number of diseases characterized by the presence of neutrophil elastase (NE) activity in tissues. It is generally accepted that presence of NE actively contributes to a pathological process, but the precise mechanism remains to be elucidated. We hypothesize that one NE action is activation of an inflammatory response in macrophages (Mφ). First, we show that in response to free NE exposure, Mφ release profound proteolytic activity composed of several MMPs which could contribute to extracellular matrix (ECM) degradation. Second, NE treatment also upregulated inflammatory cytokine expression, such as that of TNFα, IL-6, IL-1b, and IL-8. Therefore, Mφ activated by NE can contribute to tissue destruction on several levels, including release of proteolytic activity and by supporting chronic inflammation through expression of chemokines and cytokines. We also demonstrate that NE increases Mφ adhesion which can be attenuated by antibodies against integrin subunits. In support of our hypothesis of integrin involvement, we show an activation of the Srk kinase family in response to NE, which is a hallmark of integrin signaling pathway activation. Moreover, pretreatment of Mφ with specific Srk kinase inhibitor PP2 completely blocked cytokine production in response to NE. In summary, these data propose the mechanism of macrophage activation by NE and also suggest the inhibition of Srk can be potential therapeutic target to reduce NE-induced inflammation in lungs.