Pin1 Promotes NLRP3 Inflammasome Activation by Phosphorylation of p38 MAPK Pathway in Septic Shock.

Ruijie Dong,Guangyue Fan,Guangliang Li,Zhenyi Xue,Na Zhang,Yurong Da,Chengzhi Wang

doi:10.3389/fimmu.2021.620238

Abstract

Pin1 is the only known peptidyl-prolyl cis-trans isomerase (PPIase) that can specifically recognize and isomerize the phosphorylated Serine/Threonine-Proline (pSer/Thr-Pro) motif, change the conformation of proteins through protein phosphorylation, thus regulate various cellular processes in the body. Pin1 plays an important role in cancer, Alzheimer’s disease, and autoimmune diseases. However, the specific mechanism of Pin1 regulation in LPS-induced septic shock is unclear. Here, we found that lack of Pin1 reduced shock mortality and organ damage in mice, and NLRP3 inflammasome activation also was reduced in this process. We further confirmed that Pin1 can affect the expression of NLRP3, ASC, Caspase1, and this process can be regulated through the p38 MAPK pathway. We analyzed that p38 MAPK signaling pathway was highly expressed in septic shock and showed a positive correlation with Pin1 in the Gene Expression Omnibus database. We found that Pin1 could affect the phosphorylation of p38 MAPK, have no obvious difference in extracellular signal-regulated kinases (ERK) and Jun-amino-terminal kinase (JNK) signaling. We further found that Pin1 and p-p38 MAPK interacted, but not directly. In addition, Pin1 deficiency inhibited the cleavage of gasdermin D (GSDMD) and promoted the death of macrophages with LPS treatment, and reduced secretion of inflammatory cytokines including IL-1β and IL-18. In general, our results suggest that Pin1 regulates the NLRP3 inflammasome activation by p38 MAPK signaling pathway in macrophages. Thus, Pin1 may be a potential target for the treatment of inflammatory diseases such as septic shock.

Highlights

Sepsis is the leading cause of death in clinically infected patients, especially in medical intensive care units [1]
We observed a lower mortality rate in mice with septic shock induced by intraperitoneal injection in the Pin1 knockout (Pin1-/-)group than in the wild-type group (Figure 1A)
We detected the damage to the internal organs of mice by HE staining, and found that the spleen, liver, and kidney were less damaged and inflammatory cells were less infiltrated in Pin1-/mice (Figures 1F, G)

Summary

Introduction

Sepsis is the leading cause of death in clinically infected patients, especially in medical intensive care units [1]. Inflammation is the body’s normal defense against the invasion of microorganisms. Excessive inflammation, such as sepsis, may cause tissue and organ damage and even death [2,3,4,5,6]. Pin Promotes NLRP3 Inflammasome Activation macrophages, play important role in inflammatory diseases. The biological activation of IL-1b and IL-18 are usually result of the inactive precursors (pro-IL-1b and pro-IL-18) cleaved by the intracellular cysteine-aspartic protease caspase-1. This process can be regulated by the inflammasome [1, 7, 8]

Methods

Results

Conclusion