Anti-Semaphorin-7A single chain antibody demonstrates beneficial effects on pulmonary inflammation during acute lung injury

Abstract

Pulmonary inflammation is a primary characteristic of lung injury initiated by the accession of immune cells into the alveolar space. Neutrophil migration serves an important role in pulmonary inflammation mediated by the migration of neutrophils into hypoxic tissue sites. The elimination of pulmonary inflammation is directly associated with rehabilitation in patients with lung injury. Anti-inflammatory treatment is essential following lung injury and ultimately determines patient outcomes. Semaphorin-7A (SEMA-7A) is a member of the Semaphorin family that influences the migration of neutrophils into hypoxic tissue sites, thus promoting inflammation. However, understanding of the role of SEMA-7A serves during lung injury is limited and the immunological function of SEMA-7A during the migration of neutrophils into acute injury sites remains unknown. The present study investigated SEMA-7A expression and constructed a single chain antibody for SEMA-7A (Anti-SEMA-7A) to study its therapeutic efficacy against pulmonary inflammation in a mouse model of acute injury sites. The data indicated that the expression of SEMA-7A was upregulated due to induction by pro-inflammatory cytokines and demonstrated that Anti-SEMA-7A inhibited SEMA-7A expression in vitro and in vivo. The current study also indicated that the production of pro-inflammatory cytokines induced by SEMA-7A in endothelial and epithelial cells enhanced pulmonary inflammation. Anti-SEMA-7A suppressed the transendothelial migration of neutrophils mediated by SEMA-7A. Anti-SEMA-7A treatment neutralized SEMA-7A expression and reduced signs of pulmonary inflammation, leading to the elimination of pulmonary inflammation in rat with acute lung injury. The current study identified Anti-SEMA-7A as a potential agent to interfere with the inflammatory pathway during acute lung injury, which may be the basis for anti-inflammatory strategies to treat lung injuries in the future.

Platelet-Released Growth Factors Influence Wound Healing-Associated Genes in Human Keratinocytes and Ex Vivo Skin Explants

“…SEMA7A, also known as CD108, is a membrane-bound semaphorin that associates with cell surfaces via glycosylphosphatidylinositol binding and generally has proinflammatory effects [ 28 , 29 , 30 ]. In addition, SEMA7A appears to have a positive influence on wound healing [ 31 ].…”

The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical Diseases of Acute Inflammation

“…Evaluation of live lung slices from mice stimulated with SEMA3F demonstrates reduced neutrophil speed, lower F-actin content, and increased rounding of neutrophils, all of which likely contribute to retention of neutrophils at sites of inflammation ( 57 ). Additionally, SEMA7A induces transendothelial migration of neutrophils into lung tissue in conditions of hypoxia and after LPS inhalation ( 54 , 60 ), and blockade of SEMA7A in both in vivo and in vitro models reveals attenuated injury-induced influx of neutrophils correlating with dampened lung injury ( 54 , 60 , 101 ). This action is dependent on binding of SEMA7A to the PLXNC1 receptor ( 53 , 54 ), and animal models of ventilator-induced lung injury (VILI) demonstrate robust induction of PLXNC1 on neutrophils.…”

“…This action is dependent on binding of SEMA7A to the PLXNC1 receptor ( 53 , 54 ), and animal models of ventilator-induced lung injury (VILI) demonstrate robust induction of PLXNC1 on neutrophils. Furthermore, in vivo inhibition of SEMA7A and PLXNC1 by use of neutralizing antibodies in models of VILI and inhaled LPS models results in improved survival, reduced neutrophil migration and overall reduced cytokine response and lung injury ( 53 , 101 ), suggesting their use a novel therapeutic agent for the management of ALI.…”

The involvement of semaphorin 7A in tumorigenic and immunoinflammatory regulation

“…Furthermore, increasing evidence has verified that SEMA7A is a strong regulator of the induction and progression of autoimmune and inflammatory diseases, including contact hypersensitivity, experimental autoimmune encephalomyelitis (EAE), colitis, pulmonary fibrosis, and cancers (Elder et al, 2018; H. Kang et al, 2007; S. Kang et al, 2012; Ma et al, 2015; Suzuki et al, 2007). Furthermore, anti‐SEMA7A treatment has been proven effective in some of these diseases (Chen et al, 2018; Mizutani et al, 2015).…”

“…Kang et al, 2007; S. Kang et al, 2012;Ma et al, 2015;Suzuki et al, 2007). Furthermore, anti-SEMA7A treatment has been proven effective in some of these diseases (Chen et al, 2018;Mizutani et al, 2015).…”