Congenital Asplenia Interrupts Immune Homeostasis and Leads to Excessive Systemic Inflammation in Zebrafish.

Lang Xie,Ronghua Wu,Xiaomin Miao,Hui Guo,Yun Li,Yixi Tao,Zheyu Chen

doi:10.3389/fcimb.2021.668859

Lang Xie, Ronghua Wu + Show 5 more

Open Access

https://doi.org/10.3389/fcimb.2021.668859

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Abstract

Splenectomy or congenital asplenia in humans increases susceptibility to infections. We have previously reported that congenital asplenia in zebrafish reduces resistance to Aeromonas hydrophila infection. However, the molecular mechanism of systemic immune response in congenitally asplenic individuals is largely unexplored. In this study, we found that pro-inflammatory cytokines were more highly induced in congenitally asplenic zebrafish than wild-type after pathogenic A. hydrophila infection and lipopolysaccharide exposure. In addition, a higher aggregation of apoptotic cells was observed in congenitally asplenic zebrafish than that in wild-type. Next, we examined the transcriptome profiles of whole kidneys from wild-type and congenitally asplenic zebrafish to investigate the effects of congenital asplenia on innate and adaptive immune responses induced by the inactivated A. hydrophila. Congenital asplenia inactivated the splenic anti-inflammatory reflex, disrupted immune homeostasis, and induced excessive inflammation as evidenced by the highly induced stress response–related biological processes, inflammatory and apoptosis-associated pathways, and pro-inflammatory cytokines/chemokines in congenitally asplenic zebrafish compared with wild-type after vaccination. In addition, complement component genes (c3a.1, c3a.6, c4, c6, and c9) and several important immune-related genes (tabp.1, tap1, hamp, prg4b, nfil3, defbl1, psmb9a, tfr1a, and sae1) were downregulated in congenitally asplenic zebrafish. Furthermore, congenital asplenia impaired adaptive immunity as demonstrated by downregulation of biological processes and signaling pathways involved in adaptive immune response after vaccination in congenitally asplenic zebrafish. The expression of MHCII/IgM was also significantly reduced in the congenitally asplenic zebrafish when compared with wild-type. Together, our study provides an in-depth understanding of spleen function in controlling immune homeostasis and may offer insight into the pathological response in splenectomized or congenitally asplenic patients after infections.

Highlights

The spleen is a secondary lymphatic and reticuloendothelial organ that performs several functions related to hemocatheresis, blood cell storage, and immune response against infections as well as extramedullary hematopoiesis (Mebius and Kraal, 2005; Bronte and Pittet, 2013)
Our study provides a better understanding of the effects of congenital asplenia on systemic immunity, and in the meantime, understanding the molecular mechanism of systemic immune response in congenitally asplenic zebrafish after vaccination may contribute to pathological understanding and complication control in splenectomized or congenitally asplenic patients after infections
It is reported that the spleen is the main source of TNF production, and rats with splenectomy reduced the levels of inflammatory cytokines and leukocyte infiltration and developed acute pancreatitis more slowly than rats without splenectomy

Summary

Introduction

The spleen is a secondary lymphatic and reticuloendothelial organ that performs several functions related to hemocatheresis, blood cell storage, and immune response against infections as well as extramedullary hematopoiesis (Mebius and Kraal, 2005; Bronte and Pittet, 2013). As an immune-related organ, the spleen is crucial in regulating immune homoeostasis through its ability to link innate and adaptive immunity and its function in protecting against infections. Studies show that the absence of the spleen, or hyposplenia and splenectomy in humans, often carries an increased risk of overwhelming infections caused by encapsulated bacteria (Thomsen et al, 2009; Ram et al, 2010; Kristinsson et al, 2014). There has been renewed interest in preserving the spleen in circumstances in which splenectomy is thought to be necessary (Tracy and Rice, 2008)

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