Protective effect of suppressing STAT3 activity in LPS-induced acute lung injury

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are diseases with high mortality. Macrophages and neutrophils are responsible for inflammatory responses in ALI and ARDS, which are characterized by excessive production of proinflammatory mediators in bronchoalveolar lavage fluid (BALF) and plasma. Aberrant activation of the JAK/STAT pathway is critical for persistent inflammation in many conditions such as infection and autoimmunity. Given the importance of the STAT3 transcription factor in activating macrophages and neutrophils and augmenting inflammation, we investigated the therapeutic potential of inhibiting STAT3 activity using the small-molecule STAT3 inhibitor, LLL12. Our results demonstrate that LPS induces STAT3 activation in macrophages in vitro and in CD45CD11b cells from BALF in the LPS-induced ALI model in vivo. LLL12 treatment inhibits LPS-induced lung inflammation in the ALI model, which is accompanied by suppression of LPS-induced STAT3 activation and an inhibition of macrophage and inflammatory cell infiltration in lung and BALF. LLL12 treatment also suppresses expression of proinflammatory genes including IL-1β, IL-6, TNF-α, iNOS, CCL2, and MHC class II in macrophages and inflammatory cells from BALF and serum as determined by ELISA. Furthermore, hyperactivation of STAT3 in LysMCre-SOCS3 mice accelerates the severity of inflammation in the ALI model. Both pre- and post-LPS treatment with LLL12 decrease LPS-induced inflammatory responses in mice with ALI. Importantly, LLL12 treatment attenuates STAT3 phosphorylation in human peripheral blood mononuclear cells induced by plasma from patients with ARDS, which suggests the feasibility of targeting the STAT3 pathway therapeutically for patients with ALI and ARDS.

Cardiotrophin‐1 is an anti‐inflammatory cytokine and promotes IL‐4–induced M2 macrophage polarization

“…In support of the critical role of CT-1 in mediating protection from endotoxic shock, even with high doses of LPS in vivo, we have found that repeated doses of CT-1 injected prior to high doses of LPS were able to suppress LPS-induced sepsis, as has been reported with LIF (18). In concordance with other studies, we demonstrate that CT-1 signaling regulates phosphorylation of downstream STAT-3, which is involved in signal transduction for TLR signals and proinflammatory cytokine signals (31).…”

Neutrophils and IL17A mediate flagellar hook protein FlgE-induced mouse acute lung inflammation

“…However, the decrease of pro‐NET activity in Il17a −/− organoid could be partially restored by exogenous IL17A (Figure b,c, right panel). Because STAT3 had been reported to be involved in both acute lung injury (Gao et al, ; Zhao et al, ) and neutrophil function (Khan & Palaniyar, ; Wang et al, ; Zhang, Hwaiz, Luo, Herwald, & Thorlacius, ), we herein tested whether STAT3 was involved in the context of FlgE stimulation. As shown in Figure a–c, adding STAT3 inhibitor III, (SIn III) with FlgE in WT lung organoid culture decreased the pro‐NET activity.…”

Resveratrol decreases CD45+CD206− subtype macrophages in LPS‐induced murine acute lung injury by SOCS3 signalling pathway

“…More activation of STAT3 induces more expression of cytokine expression. Blocking STAT3 activation by small‐molecule STAT3 inhibitor (LLL12) can suppress the expression of IL‐1beta, IL‐6, TNF‐alpha, iNOS, CCL2 and MHC class II in macrophages and inflammatory cells from LPS‐induced ALI mouse model, indicating the pro‐inflammatory function of STAT3 . It is known that SOCS3 is a negative regulator of STAT3.…”

“…Blocking STAT3 activation by small-molecule STAT3 inhibitor (LLL12) can suppress the expression of IL-1beta, IL-6, TNF-alpha, iNOS, CCL2 and MHC class II in macrophages and inflammatory cells from LPS-induced ALI mouse model, indicating the pro-inflammatory function of STAT3. 19 It is known that SOCS3 is a negative regulator of STAT3. Activation of STAT3 induces transcriptional up-regulation of SOCS3 and subsequently suppresses STAT3 activation in the inflammatory condition.…”