A Dynamic Variation of Pulmonary ACE2 Is Required to Modulate Neutrophilic Inflammation in Response to Pseudomonas aeruginosa Lung Infection in Mice

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator capable of restraining overactivation of the renin–angiotensin system, which contributes to exuberant inflammation after bacterial infection. However, the mechanism through which ACE2 modulates this inflammatory response is not well understood. Accumulating evidence indicates that infectious insults perturb ACE2 activity, allowing for uncontrolled inflammation. In the current study, we demonstrate that pulmonary ACE2 levels are dynamically varied during bacterial lung infection, and the fluctuation is critical in determining the severity of bacterial pneumonia. Specifically, we found that a pre-existing and persistent deficiency of active ACE2 led to excessive neutrophil accumulation in mouse lungs subjected to bacterial infection, resulting in a hyperinflammatory response and lung damage. In contrast, pre-existing and persistent increased ACE2 activity reduces neutrophil infiltration and compromises host defense, leading to overwhelming bacterial infection. Further, we found that the interruption of pulmonary ACE2 restitution in the model of bacterial lung infection delays the recovery process from neutrophilic lung inflammation. We observed the beneficial effects of recombinant ACE2 when administered to bacterially infected mouse lungs following an initial inflammatory response. In seeking to elucidate the mechanisms involved, we discovered that ACE2 inhibits neutrophil infiltration and lung inflammation by limiting IL-17 signaling by reducing the activity of the STAT3 pathway. The results suggest that the alteration of active ACE2 is not only a consequence of bacterial lung infection but also a critical component of host defense through modulation of the innate immune response to bacterial lung infection by regulating neutrophil influx.

Emergence of Novel Coronavirus and COVID-19: whether to stay or die out?

“…ACE2 also protects an individual against severe acute lung damage that can be triggered by sepsis, acid aspiration, severe acute respiratory syndrome (SARS) and the lethal avian influenza A H5N1 and H7N9 virus infection (Kuba et al 2005;Yang et al 2014;Zou et al 2014). Moreover, recent studies have shown that ACE2 negatively regulates inflammatory responses during bacterial or viral infections (Yang et al 2014;Sodhi et al 2019). SARS-CoV-2 infection utilizes ACE2 for viral attachment and subsequent entry into cytosol, therefore rapid replication of SARS-CoV-2 may reduce the surface expression of ACE2 in the lung tissue which may cause further intensification of the inflammation and severity of the disease pathology (Glowacka et al 2010) (Figure 4).…”

COVID-19 in children and altered inflammatory responses

“…8 Patients with either very high ACE2 levels (such as in diabetes or cardiovascular disease) or very low levels (animal models of hypertension) can have an abnormal immune response and pulmonary inflammation. 9 Decreasing ACE2 is notable in animal models of ageing. 10 Sodhi et al demonstrated that neutrophil inflammation following bacterial pneumonia was altered by pulmonary ACE2 activity.…”

“…Alterations in ACE2 are critical for neutrophil influx and lung inflammation. 9 In respiratory syncytial virus (RSV), ACE2 protected against severe lung injury both in children and an experimental mouse model. RSV disease pathogenesis was worsened via activation of AT1R, and a recombinant ACE2 decreased the severity of RSVassociated lung injury (Guo et al, scientific reports).…”

Sepsis-associated Encephalopathy In ICU Admissions: Prevalence, Early Risk of Death, and its Early Prevent and Control

“…Moreover, the acute pneumonia/ALI play pivotal roles in the development of severe in ammatory storm in sepsis [10,21]. Like the current outbreak COVID-19 pneumonia, the mechanisms of bacterial pneumonia is also related to the angiotensin conversion enzyme 2 (ACE2) involved in ammatory response, leading to BBB leakage and in ammatory storm [20,22]. The third, a life-threatening brain failure is almost involved to MODS, and MODS (especially the brain) is the most vulnerable to hypoxia/ ischemia and oxidative stress caused by severe in ammatory storm [19,21].…”