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Neutrophils are among the first cells implicated in acute inflammation. Leaving the blood circulation, they quickly migrate through the interstitial space of tissues and liberate oxidants and other antimicrobial proteins together with serine proteinases. Neutrophil elastase, cathepsin G, proteinase 3 (PR3), and neutrophil serine protease 4 are four hematopoietic serine proteases activated by dipeptidyl peptidase I during neutrophil maturation and are mainly stored in cytoplasmic azurophilic granules. They regulate inflammatory and immune responses after their release from activated neutrophils at inflammatory sites. Membrane-bound PR3 (mbPR3) at the neutrophil surface is the prime antigenic target of antineutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis (GPA), a vasculitis of small blood vessels and granulomatous inflammation of the upper and/or lower respiratory tracts. The interaction of ANCA with mbPR3 results in excessive activation of neutrophils to produce reactive oxygen species and liberation of granular proteinases to the pericellular environment. In this review, we focus on PR3 and dipeptidyl peptidase I as attractive pharmacological targets whose inhibition is expected to attenuate autoimmune activation of neutrophils in GPA. [ABSTRACT FROM AUTHOR]

The loss of smell (anosmia) related to SARS-CoV-2 infection is one of the most common symptoms of COVID-19. Olfaction starts in the olfactory epithelium mainly composed of olfactory sensory neurons surrounded by supporting cells called sustentacular cells. It is now clear that the loss of smell is related to the massive infection by SARS-CoV-2 of the sustentacular cells in the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamsters infected with an early circulating SARS-CoV-2 strain harboring the D614G mutation in the spike protein; we show here that rather than being related to a first wave of apoptosis as proposed in previous studies, the innate immune cells play a major role in the destruction of the olfactory epithelium. We observed that while apoptosis remains at a low level in the damaged area of the infected epithelium, the latter is invaded by Iba1+ cells, neutrophils and macrophages. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we could reduce the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease in SARS-CoV-2 infection levels in the olfactory epithelium. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus in the early phase of the SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Neutrophil serine proteases (NSPs), like proteinase 3 (PR3) and neutrophil elastase (NE) are implicated in ischemia-reperfusion responses after lung transplantation (LTx). Cathepsin C (CatC) acts as the key regulator of NSP maturation during biosynthesis. We hypothesized that CatC inhibitors would reduce vascular breakdown and inflammation during reperfusion in pretreated lung transplant recipients by blocking NSP maturation in the bone marrow. An orthotopic LTx model in mice was used to mimic the induction of an ischemia-reperfusion response after 18 h cold storage of the graft and LTx. Recipient mice were treated subcutaneously with a chemical CatC inhibitor (ICatC) for 10 days prior to LTx. We examined the effect of the ICatC treatment by measuring the gas exchange function of the left lung graft, protein content, neutrophil numbers and NSP activities in the bone marrow 4 h after reperfusion. Pre-operative ICatC treatment of the recipient mice improved early graft function and lead to the disappearance of active NSP protein in the transplanted lung. NSP activities were also substantially reduced in bone marrow neutrophils. Preemptive NSP reduction by CatC inhibition may prove to be a viable and effective approach to reduce immediate ischemia reperfusion responses after LTx. [ABSTRACT FROM AUTHOR]