Pretreatment with interleukin 35-engineered mesenchymal stem cells protected against lipopolysaccharide-induced acute lung injury via pulmonary inflammation suppression

Abstract

Acute lung injury (ALI)-triggered pulmonary injury has been associated with high mortality, despite advances in drug treatment and supportive therapy. Remarkable progress has been made in attenuating the inflammatory injury associated with ALI using mesenchymal stem cells (MSCs)-based cell and gene therapy. However, to date, the benefits of interleukin-35 (IL-35)-modified MSCs in ALI intervention have not been investigated. In the present study, adult male C57BL/6 mice randomly received intravenous infusion of adipose-derived mesenchymal stem cells (ADSCs) constitutively expressing IL-35 (IL-35-GFP-ADSCs) or GFP (GFP-ADSCs) via retrovirus-mediated transduction (8 × 10 5 cells per mice) or isotonic saline 7 days before ALI modeling to investigate the effect and related mechanism. ALI was performed by lipopolysaccharide (LPS) inhalation for 24 h. Normal mice served as the sham group. The results indicated that compared with GFP-ADSCs, IL-35-modified ADSCs significantly increased cellular and pulmonary IL-10 and IL-35 production. Pretreatment with IL-35-ADSCs markedly reduced body weight loss, pulmonary wet/dry weight ratio and pathological injury. The PO 2 was rescued to normal levels in mice that received IL-35-ADSCs. IL-35-ADSCs infusion apparently inhibited IL-6 release, protein leakage and MPO activity but greatly elevated IL-35 level in the bronchoalveolar lavage fluid (BALF). Splenic regulatory T cells in IL-35-ADSCs-pretreated mice got effective increase. Moreover, IL-35-ADSCs pretreatment remarkably inhibited neutrophil and macrophage infiltration and greatly decreased IL-6, tumor necrosis factor α (TNF-α) and Toll-like receptor 4 (TLR4) expression. In conclusion, pretreatment with IL-35-engineered ADSCs provided effective protection against LPSinduced ALI through suppression of pulmonary inflammation and, thus, might be a promising strategy to improve outcomes after ALI. The enhanced paracrine and immunosuppressive capacity of IL-35-ADSCs might contribute to their beneficial effects. However, further studies are needed to illuminate the detailed mechanism.

IL35 attenuated LPS-induced acute lung injury by regulating macrophage polarization

“…LPS is an important component of gram-negative bacteria and a ligand of TLR4[ 25 ]. TLR4, an important transmembrane pattern-recognition receptor of the innate immune system, is recruited and activated after LPS stimulation, leading to the activation of the NFκB-P65 signaling pathway and the release of proinflammatory cytokines, such as IL1β and IL 6 [ 26 , 35 ]. In our study, upregulation of IL35 expression obviously suppressed the expression of TLR4 and MD2, as well as p-P65/P65.…”

“…An increasing number of studies have confirmed that inflammation plays a crucial role in the initiation and development of ALI[ 4 , 5 ]. With the increase in the proinflammatory response and the decrease in the anti-inflammatory response in ALI, a large number of inflammatory cytokines, such as interleukin (IL)6 and TNF-α, are secreted, and resulting in the development of the cytokine storm, in which causes respiratory failure and ARDS[ 6 ]. Macrophage activation is considered the critical initial stage of the inflammatory response[ 7 , 8 ].…”

Computational insight of dexamethasone against potential targets of SARS-CoV-2

“…Suppression of inflammation can be achieved by inhibiting the activities of IL-6. Molecules that inhibit the IL-6RA would inactivate IL-6R and further decrease the inflammation of the lung tissue in individuals with COVID-19 (Conti et al., 2020 ; Mahmud-Al-Rafat et al., 2019 ; Zhang et al., 2020 ).…”

Overexpression of FoxM1 Enhanced the Protective Effect of Bone Marrow-Derived Mesenchymal Stem Cells on Lipopolysaccharide-Induced Acute Lung Injury through the Activation of Wnt/β-Catenin Signaling

“…However, the potential mechanisms involved remain unclear. Recent preclinical studies have demonstrated that MSCs influence essential pathobiological mechanisms in ARDS and sepsis by releasing paracrine factors [ 12 ], which exert anti-inflammatory [ 38 , 39 ] and antiapoptotic [ 21 ] effects and reduce the permeability of alveolar epithelium [ 40 ] and vascular endothelium [ 41 ]. Modifying certain genes can further induce the impact of MSCs in treating ALI [ 42 – 44 ].…”