Programmed ‘disarming’ of the neutrophil proteome reduces the magnitude of inflammation

Abstract

The antimicrobial functions of neutrophils are facilitated by a defensive armamentarium of proteins stored in granules, and by the formation of neutrophil extracellular traps (NETs). However, the toxic nature of these structures poses a threat to highly vascularized tissues, such as the lungs. Here, we identified a cell-intrinsic program that modified the neutrophil proteome in the circulation and caused the progressive loss of granule content and reduction of the NET-forming capacity. This program was driven by the receptor CXCR2 and by regulators of circadian cycles. As a consequence, lungs were protected from inflammatory injury at times of day or in mouse mutants in which granule content was low. Changes in the proteome, granule content and NET formation also occurred in human neutrophils, and correlated with the incidence and severity of respiratory distress in pneumonia patients. Our findings unveil a 'disarming' strategy of neutrophils that depletes protein stores to reduce the magnitude of inflammation.

Circadian Features of Neutrophil Biology

“…This was explained by the progressive loss of microvilli needed for efficient rolling as neutrophils aged over time (17). Further, expression of CXCR2 is reduced in aged neutrophils and we have recently shown that these cells feature reduced granule content and NET-forming capacity relative to fresh neutrophils (59), altogether suggesting blunted inflammatory properties for aged neutrophils. However, these blunted inflammatory properties are in apparent contradiction with reports showing elevated inflammogenic properties of aged neutrophils in mice (57), as well as increased adhesion, ROS production and phagocytic capacity in human aged neutrophils (18).…”

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

“…Indeed, NET levels in plasma are higher in patients with transfusion-associated ARDS than in subjects without ARDS (Caudrillier et al, 2012). Furthermore, neutrophils from patients with pneumonia-associated ARDS appear “primed” to form NETs, and both the extent of priming and the level of NETs in blood correlate with disease severity and mortality (Adrover et al, 2020; Bendib et al, 2019; Ebrahimi et al, 2018; Lefrançais et al, 2018; Mikacenic et al, 2018). Extracellular histones, likely partly originating from NETs, are elevated in the bronchoalveolar lavage fluid and plasma of ARDS patients (Lv et al, 2017).…”

Oxidative Stress and Inflammation in COVID-19-Associated Sepsis: The Potential Role of Anti-Oxidant Therapy in Avoiding Disease Progression

“…Rises in circulating NETs levels have been previously found in patients with ARDS [ 71 ]. Likewise, neutrophils appear “primed” to activate the NETosis process in patients with pneumonia-associated ARDS, which may explain the correlation between this priming and the blood NET levels with severity and mortality [ 72 , 73 , 74 , 75 , 76 ]. Furthermore, oxidative stress may increase the formation of NETs and alter the adaptive immune system by contributing to T-cell suppression [ 77 ].…”

“…For example, IL-6 overexpression and oxidative stress lead to increased fibrinogen processing and fibrin levels which, in turn, interacts with NET’s facilitating coagulation phenotypes, contributing to the COVID-19-associated coagulopathy [ 88 , 91 , 92 ] and shock [ 4 ]. Some patients also suffer neutrophilia, which results in increasing NET production and correlates with severe COVID-19 phenotypes and poor outcomes [ 72 , 73 , 74 , 75 , 76 , 93 ].…”