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

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

JOURNAL=Frontiers in Cellular and Infection Microbiology

VOLUME=Volume 11 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2021.668859

DOI=10.3389/fcimb.2021.668859

ISSN=2235-2988

ABSTRACT=<p>Splenectomy or congenital asplenia in humans increases susceptibility to infections. We have previously reported that congenital asplenia in zebrafish reduces resistance to <italic>Aeromonas hydrophila</italic> 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 <italic>A. hydrophila</italic> 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  <italic>A. hydrophila</italic>. 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 (<italic>c3a.1</italic>, <italic>c3a.6</italic>, <italic>c4</italic>, <italic>c6</italic>, and <italic>c9</italic>) and several important immune-related genes (<italic>tabp.1</italic>, <italic>tap1</italic>, <italic>hamp</italic>, <italic>prg4b</italic>, <italic>nfil3</italic>, <italic>defbl1</italic>, <italic>psmb9a</italic>, <italic>tfr1a</italic>, and <italic>sae1</italic>) 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 <italic>MHCII/IgM</italic> 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.</p>