Abstract
Pattern-recognition receptors (PRRs) initiate innate immunity via pathogen recognition. Recent studies suggest that signalling pathways downstream of different PRRs and their crosstalk effectively control immune responses. However, the cross-regulation among PRRs and its effects have yet to be fully described in fish. Here, we examined the crosstalk between OmPGRP-L1, a long form of PGRP in rainbow trout, and other PRRs during pathogenic infections. OmPGRP-L1 expression was increased in RTH-149 cells by iE-DAP and MDP, which are agonists of NOD1 and NOD2, respectively. The silencing of NOD1 and NOD2 specifically inhibited the upregulation of OmPGRP-L1 expression induced by their cognate ligands. Suppression of RIP2 and NF-κB activation prevented the induction of OmPGRP-L1 expression. An in silico analysis and electrophoretic mobility shift assay revealed that the promoter of OmPGRP-L1 has NF-κB binding sites, suggesting that OmPGRP-L1 is produced through the NOD-RIP2-NF-κB signalling pathway. Loss-of-function and gain-of-function experiments indicated that OmPGRP-L1 downregulates the induction of NOD-mediated pro-inflammatory cytokine expression. Mechanistically, secreted OmPGRP-L1 inhibited the activation of the NOD-induced NF-κB pathway via downregulation of TAK1 and IκBα phosphorylation through A20 expression. Our data demonstrate that OmPGRP-L1 and NODs might play interdependent roles in the inflammatory response to bacterial infections in rainbow trout.
Highlights
The innate immune system is the host’s first line of defence against infection[1]
P1(-1605)Luc and P1(-920)Luc were highly induced by both iE-DAP and muramyl dipeptide (MDP), whereas induction was abrogated using the 473-bp promoter (Fig. 3b). These results indicate that the regulatory elements necessary for the induction of OmPGRP-L1 transcription in RTH-149 cells stimulated with iE-DAP and MDP are located within the 473–920-bp region upstream of the start codon
Our present study is the first to demonstrate that peptidoglycan recognition proteins (PGRPs) and nucleotide-binding oligomerisation domain-containing proteins (NODs), two different Pattern-recognition receptors (PRRs), might play interdependent roles in the inflammatory response to bacterial infections in rainbow trout
Summary
The innate immune system is the host’s first line of defence against infection[1]. The main role of this system is to recognise invading pathogens at an early stage and trigger an appropriate inflammatory response. After the recognition of PAMPs, PRRs induce several extracellular activation cascades, such as the complement pathway, and various intracellular signalling pathways, which lead to inflammatory responses These inflammatory responses are essential for the effective clearance of pathogens; excessive responses can be dangerous to the host as exemplified by sepsis[4]. PRRs, such as Toll-like receptors (TLRs), nucleotide-binding oligomerisation domain-containing proteins (NODs) and peptidoglycan recognition proteins (PGRPs), recognise a given pathogen simultaneously or sequentially and activate distinct and shared signalling pathways. This raises the possibility of crosstalk between the pathways as well as with other immunomodulatory signalling pathways generated by particular inflammatory environments. We examined the role of OmPGRP-L1 as a negative regulator of inflammatory responses in RTH-149 cells by assessing the crosstalk between OmPGRP-L1 and other PRRs with respect to pathogen recognition
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