Blocking triggering receptor expressed on myeloid cells-1 attenuates lipopolysaccharide-induced acute lung injury via inhibiting NLRP3 inflammasome activation

Abstract

Acute lung injury (ALI) is associated with high mortality and uncontrolled inflammation plays a critical role in ALI. TREM-1 is an amplifier of inflammatory response, and is involved in the pathogenesis of many infectious diseases. NLRP3 inflammasome is a member of NLRs family that contributes to ALI. However, the effect of TREM-1 on NLRP3 inflammasome and ALI is still unknown. This study aimed to determine the effect of TREM-1 modulation on LPS-induced ALI and activation of the NLRP3 inflammasome. We showed that LR12, a TREM-1 antagonist peptide, significantly improved survival of mice after lethal doses of LPS. LR12 also attenuated inflammation and lung tissue damage by reducing histopathologic changes, infiltration of the macrophage and neutrophil into the lung, and production of the pro-inflammatory cytokine, and oxidative stress. LR12 decreased expression of the NLRP3, pro-caspase-1 and pro-IL-1β, and inhibited priming of the NLRP3 inflammasome by inhibiting NF-κB. LR12 also reduced the expression of NLRP3 and caspase-1 p10 protein, and secretion of the IL-1β, inhibited activation of the NLRP3 inflammasome by decreasing ROS. For the first time, these data show that TREM-1 aggravates inflammation in ALI by activating NLRP3 inflammasome, and blocking TREM-1 may be a potential therapeutic approach for ALI.

TREM‐1 deficiency attenuates the inflammatory responses in LPS‐induced murine endometritis

“…In the present study, the higher expressions of IL‐1β, IL‐6 and TNF‐α in serum or inflammatory endometrium after LPS treatment suggested an acute inflammatory reaction and potential fibrinogen and cell apoptosis in the uterus. Previous studies reported that inhibition of TREM‐1 suppressed IL‐1β‐induced chondrocyte injury, reduced colitis in mice, alleviated Streptococcus ‐induced syndrome and attenuated LPS‐induced acute lung injury (Liu, et al , ; Kökten, et al , ; Tang and Dong, ; Han, et al , ). Consistent with these results, the lower levels of IL‐1β, IL‐6 and TNF‐α in serum or uteri in the Trem1 −/− mice than in the wild‐type mice after LPS stimulation suggested that the TREM‐1 gene knockout could attenuate LPS‐induced endometritis, probably by inhibiting inflammatory cytokines.…”

“…TNF‐α, IL‐1β, IL‐8 and IL‐6) or to induce the release of myeloperoxidase (MPO) (Bouchon, et al , ). Furthermore, inhibition of TREM‐1 either by antibodies or by gene targeting could protect mice against LPS or live E. coli ‐induced shock or sepsis (Bouchon, et al , ; Liu, et al , ). Additionally, it has been demonstrated that TREM‐1‐Ig Fc fusion protein treatment could lower the serum levels of TNF‐α and IL‐1β after LPS administration (Wang, et al , ).…”

Expression pattern of soluble triggering receptor expressed on myeloid cells-1 in mice with Acinetobacter baumannii colonization and infection in the lung

“…Mild pulmonary edema and infiltration of inflammatory cells was seen in mice from the control and colonization groups directly after aerosol inhalation and disappeared the next day, which we thought was caused by the non-infectious irritation during inhalation. TREM-1 is a receptor that triggers an inflammatory cascade and is highly expressed in neutrophils and monocytes (21). It has been reported that activation of TREM-1 immediately induces rapid degranulation of neutrophilic granules and drives the release of proinflammatory factors, including MIP-1, MCP-1 and IL-8, thus playing an important regulatory role in inflammation (22).…”

Mitochondria Targeted Peptide Attenuates Mitochondrial Dysfunction, Controls Inflammation and Protects Against Spinal Cord Injury-Induced Lung Injury

“…NLRP3 inflammasome is assembled by NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1 released after an endogenous ‘‘danger signal” and exogenous infection, comprise an important cytosolic protein complex [34]; this provides a caspase-1-activation platform to promote the maturation and release of proinflammatory cytokines, including IL-1β and IL-18 [35]. NLRP3 inflammasome plays a critical role in lung injury in diverse models [34, 36]. Inhibition of NLRP3 inflammasome activation attenuated lung tissue damage and the pulmonary inflammatory response in a mouse model of LPS-induced lung injury [36].…”

“…NLRP3 inflammasome plays a critical role in lung injury in diverse models [34, 36]. Inhibition of NLRP3 inflammasome activation attenuated lung tissue damage and the pulmonary inflammatory response in a mouse model of LPS-induced lung injury [36]. Inhibition of NLRP3 inflammasome also attenuated ventilation-induced lung injury [34].…”