Hepatic cecum: a key integrator of immunity in amphioxus

Abstract

The vertebrate liver is regarded as an organ essential to the regulation of immunity and inflammation as well as being central to the metabolism of nutrients. Here, we discuss the functions that the hepatic cecum of amphioxus plays in the regulation of immunity and inflammation, and the molecular basis of this. It is apparent that the hepatic cecum performs important roles in the immunity of amphioxus including immune surveillance, clearance of pathogens and acute phase response. Therefore, the hepatic cecum, like the vertebrate liver, is an organ functioning as a key integrator of immunity in amphioxus.

Keywords: Acute phase response; Amphioxus; Hepatic cecum; Immunity; Inflammation.

Fig. 1

Anatomical organization of the hepatic cecum as an immune organ of amphioxus. a The digestive system, including the pharyngeal gill slits, hepatic cecum and intestine, is regarded as the major line of defense against microbial infection. When food particles enter the pharynx, they are trapped by mucus and formed into a mucus cord, which is then transported posteriorly to the mid-gut. In the mid-gut, food particles within the mucus cord are mixed with digestive enzymes, and some small particles containing algal and microbial cells (around 2 μm in diameter or less) pass into the lumen of hepatic cecum, a structure arising from the mid-gut and expands anteriorly along the right side of the pharynx. b These algal and microbial cells are phagocytized by the epithelial cells of hepatic cecum and degraded by lysosomes. Then, the degrading products enter the hepatic blood vessel plexus, in which the blood is mainly delivered from intestine via the subintestinal vein which is ultimately joined to the hepatic vein. Gathering intestine-derived blood components and hepatic epithelial cells derived products, the blood in the hepatic plexus is rich in nutrients, pathogen-derived molecules, and even surviving pathogenic microbes. The cells of the hepatic cecum are responsible for the production of complement proteins and acute phase proteins

Fig. 2

Putative immune signaling network in amphioxus hepatic cells. The TLR signals can induce activation of the IKK complex and NF-κB through either the MyD88-TRAF6 or TICAM-RIP1b pathway. A group of TIR domain-containing adaptors are involved in the activation and regulation of the TLR pathway. The ligands of amphioxus TLRs remain to be determined. Putative antiviral mechanisms include viral RNA recognition by DExD/H-box helicase domain-containing receptors (e.g., LGP2 and DDX23) and activation of the TBK1-IKKɛ complex and IRFs. The transcription factor IRF family contains nine members which constitute a dynamic feedback regulatory framework among IRFs and NF-κB. In the scheme of the oxidative burst machinery, NOX2 and p22phox are transmembrane components, while p47phox, p67phox, p40phox and Rac are cytosolic subunits that are recruited to the NOX2-p22phox on activation. This phagocytic respiratory burst machinery, through releasing a large amount of ROS into the phagosome, participates in the bactericidal process of the hepatic epithelial cells. In the putative TNF system, TNF can either activate the IKK complex and NF-κB through the TNFR-TRAF pathway, or trigger caspase-dependent apoptosis through the Death receptor (TNFR with death domain)-FADD/CRADD pathway. Amphioxus has a large number of NLRs that share similar domain architectures containing a central NOD domain, a C-terminal LRR region and various N-terminal region. However, the NLR signaling pathway is unclear and needs further study. Solid lines indicate a pathway with experimental evidence; dashed lines represent no experimental support

Fig. 3

Amphioxus complement systems are activated and amplified by the formation of C3 convertases through the C1q-mediated, lectin and alternative pathways. C3 can be cleaved by C3 convertases to form C3a and C3b. The C3a fragment has bactericidal activity and is capable of enhancing phagocyte phagocytosis against bacteria. The C3b fragment can bind covalently to cell surface carbohydrates via its reactive thioester. Amphioxus has five C6-like proteins, but it is unclear whether they participate in the formation of the membrane attack complex (MAC). A solid arrow indicates that the pathway was supported by experimental data; a dashed arrow indicates that no experimental support is present