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

Lu Hu,Liyang Li,Zhihong Chen,Lei Zhu,Zhilong Jiang

doi:10.1111/jcmm.14680

Abstract

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are life‐threatening condition in critically ill patients. Resveratrol (Res), a natural polyphenol, has therapeutic effect in animal model with ALI; however, whether Res attenuates ALI through modulation of macrophage phenotypes in the animal model remains unknown. We in this study treated LPS‐induced murine ALI with 30 mg/kg Res and observed significantly reduced severity of ALI in the Res‐treated mice 48 hours after Res treatment. Neutrophil infiltrates were significantly reduced, accompanied with lower infiltration of CD45+Siglec F− phenotype macrophages, but higher population of CD45+Siglec F+ and CD45+CD206+ alternatively activated macrophages (M2 cells) in the Res‐treated mice with ALI. In addition, the expression of IL‐1beta and CXCL15 cytokines was suppressed in the treated mice. However, Res treatment in mice with myeloid cell‐restricted SOCS3 deficiency did not significantly attenuate ALI severity and failed to increase population of both CD45+Siglec F+ and CD45+CD206+ M2 subtype macrophages in the murine ALI. Further studies in wild‐type macrophages revealed that Res treatment effectively reduced the expression of IL‐6 and CXCL15, and increased the expression of arginase‐1, SIRT1 and SOCS3. However, macrophages’ lack of SOCS3 expression were resistant to the Res‐induced suppression of IL‐6 and CXCL15 in vitro. Thus, we conclude that Res suppressed CD45+Siglec F− and CD45+CD206− M1 subtype macrophages through SOCS3 signalling in the LPS‐induced murine ALI.

Highlights

Acute respiratory distress syndrome (ARDS) is an acute diffuse pulmonary exudative disorder in critically ill patients
The results revealed the important role of macrophage signal transducer and activator of transcription‐3 (STAT3)/SOCS3 signalling in the Res‐mediated therapy of ALI
Two days after clodronate liposome (CL) administration alone, we observed over 90% F4/80(high)CD11b(low) alveolar macrophages (AMs) were depleted in bronchoalveolar lavage (BAL) and 85% F4/80(high)CD11b(low) MNs were depleted in peripheral blood monocytes (Figure 3A)

Summary

| INTRODUCTION

Acute respiratory distress syndrome (ARDS) is an acute diffuse pulmonary exudative disorder in critically ill patients. The different macrophage subtypes exclusively release high amount of pro‐inflammatory, anti‐inflammatory cytokines and chemokines, participating in the pathogenesis of ALI/ARDS, asthma and other inflammatory lung diseases.[2,3]. 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. Our previous study and report from other group[21] indicated that STAT3/SOCS3 signalling suppressed macrophage polarization and activation in the murine ALI mouse model, whereas disruption of STAT3/SOCS3 signalling in SOCS3 myeloid cell‐restricted conditional knock‐out mice (cKO) significantly enhanced the severity of LPS‐induced ALI and sepsis, accompanied with high expression of M1 cell genes (IL‐1beta, IL‐6, IL‐12, IL‐23, inducible NO synthase).[2,20]. The results revealed the important role of macrophage STAT3/SOCS3 signalling in the Res‐mediated therapy of ALI

| MATERIAL AND METHODS

| DISCUSSION

Findings

CONFLICT OF INTEREST