Evolution of LPS recognition and signaling: The bony fish perspective

Adopting orphan receptors: group IX/X transition metals as potential ligands of zebrafish Tlr4 homologs

“…In zebrafish, however, no convincing evidence demonstrates that LPS signals via TLR4; although LPS has impacts when applied to zebrafish (often only at extra-biologic high concentrations, and in screening efforts to discover phytobiologicals) as demonstrated in scores of papers (Athapaththu et al, 2022; Bates et al, 2007; Fernando et al, 2017; Hwang et al, 2016; Lee et al, 2013; Li et al, 2022; Urzi et al, 2023; Yang et al, 2014; Yu et al, 2022; Zhang et al, 2018), these impacts of LPS have not been shown to require TLR4. The reason for the disparity between TLR4 signalling in mammals and fish may be attributed to TLR4 itself and/or to the evolution of the associated intracellular signalling pathways (Candel et al, 2015; Candel et al, 2016; Liu et al, 2010; Martinez-Lopez et al, 2023; Novoa et al, 2009; Palti, 2011), or perhaps the appropriate source of LPS has yet to be tested. In mammals, signalling through TLR4 using LPS requires multiple different co-receptors acting in concert with one another including: LPS binding protein (LBP), cluster differentiation 14 (CD14), and myeloid differentiation factor 2 (MD-2) (Ryu et al, 2017).…”

“…Unlike mammalian TLR4, zebrafish Tlr4 has not been demonstrated to respond to LPS, and zebrafish lack the co-receptor CD14. LPS is a modular structure that can be capped by an O-antigen, referred to as “smooth” LPS, where CD14 is required for TLR4 activation by smooth LPS in mammals (Martinez-Lopez et al, 2023; Sepulcre et al, 2009; Sullivan et al, 2009). Nevertheless, zebrafish TLR4 proteins are structurally congruent with their mammalian counterparts, with all three homologs coding for an extracellular leucine-rich repeat (LRR) ectodomain, a transmembrane domain and a toll/interleukin-1 receptor (TIR) containing domain (Vaure & Liu, 2014) (Supplementary Figure 1).…”

“…MD-2 contributes to signalling through LPS, but it also plays a role in signalling through other TLR4 ligands such as metals. Overall, the detection of LPS via TLR4 appears to have evolved in mammals after that lineage split from other vertebrates, and thus the function of TLR4 in fishes, including those related to important models of disease, has remained elusive (Martinez-Lopez et al, 2023).…”

Immune Transcriptional Response in Head Kidney Primary Cell Cultures Isolated from the Three Most Important Species in Chilean Salmonids Aquaculture

“…These TLRs are expressed in the membrane of B cells, macrophages, and dendritic cells [13] and can interact with Polyinosinic: polycytidylic acid (POLY I:C), which is used to simulate viral infections. POLY I:C is structurally similar to double-stranded RNA and can be recognized by TLR-3 and TLR-8 [14]. In addition, Lipopolysaccharide (LPS) is the main component of the outer membrane of gram-negative bacteria and is recognized by TLR1, TLR4 and TLR5 [14,15].…”

“…POLY I:C is structurally similar to double-stranded RNA and can be recognized by TLR-3 and TLR-8 [14]. In addition, Lipopolysaccharide (LPS) is the main component of the outer membrane of gram-negative bacteria and is recognized by TLR1, TLR4 and TLR5 [14,15]. Therefore, LPS and POLY I:C are commonly used for scientific research on the fish immune system as bacterial and viral stimuli, respectively [16].…”