Origin and Expansion of the Serine Protease Repertoire in the Myelomonocyte Lineage

Abstract

The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly controlled by substrate-induced activation and TNFα-induced locally upregulated protein secretion. However, the present-day descendants are produced and converted to mature enzymes in precursor cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The potential site and duration of action of these cell-associated serine proteases are tightly controlled by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have been achieved by exploiting the high structural plasticity of the trypsin fold.

The mechanism by which enoxaparin sodium–high-viscosity bone cement reduces thrombosis by regulating CD40 expression in endothelial cells

“…The effect of enoxaparin sodium is mainly dependent on by anticoagulant factor Xa [ 25 ], which is a serine protease [ 26 ]. Serine protease exists in the digestive enzyme and complement system [ 27 , 28 ]. The complement system is composed of inherent complement components, complement regulatory proteins and complement receptors [ 29 ].…”

Mechanism of novel enoxaparin sodium high viscosity bone cement reducing thrombosis by regulating the expression of CD40 in endothelial cells

“…Immuno uorescence method detected that the uorescence value of CD40 in M group was lower than that in Con group. CD40 is one of the molecules in the tumor necrosis factor receptor superfamily (TNFRSF), also known as Bp50 and TNFRSF5, and is a type I membrane glycoprotein, which is composed of 62 amino acid (AA) cytoplasmic tail, 22 AA transmembrane domains and 173 AA extracellular domains in human body [48].The anticoagulant effect of enoxaparin sodium is mainly played by anticoagulant factor a [49], which belongs to a serine protease [50,51], and serine protease exists in digestive enzyme and complement system [52][53][54]. The complement system is composed of complement inherent components, complement regulatory proteins and complement receptors [55].…”

Monitoring Human Neutrophil Activation by a Proteinase 3 Near-Infrared Fluorescence Substrate-Based Probe

“…PR3 is primarily regulated by a1-protease inhibitor, serpin B1, and elafin, but not by secretory leukocyte protease inhibitor. 10 Under pathological conditions, downregulation and/or inactivation of PR3 inhibitors result in an uncontrolled PR3 activity, which may further contribute to tissue damage and inflammatory cascades. More specifically, PR3 participates in the activation of IL-8, TNF-a and IL-1b as well the degradation of fibronectin or laminin, and is involved in the maturation of cathelicidin hCAP-18 to generate LL-37, a potent antimicrobial peptide.…”

“…Mature PR3 is dormant in the acidic environment of the azurophilic granules and is activated upon translocation to a neutral pH environment by a slow conformational change. PR3 is primarily regulated by α1-protease inhibitor, serpin B1, and elafin but not by secretory leukocyte protease inhibitor . Under pathological conditions, downregulation and/or inactivation of PR3 inhibitors result in an uncontrolled PR3 activity, which may further contribute to tissue damage and inflammatory cascades.…”