Functional Characterisation of a Novel Tir-Domain containing Protein in Immune Signalling

Dysregulation of innate immune signalling pathways has been implicated in a host of chronic inflammatory disorders including Multiple Sclerosis, Crohn’s Disease and Rheumatoid Arthritis. As a result, it is critical that there are tight regulatory mechanisms in place to rigidly control such signalling pathways. The IL-17 family of cytokines, which comprises six members in mammals, are potent mediators of inflammation. Produced primarily by CD4+ T helper 17 (Th17) cells, they signal through IL-17 receptor family complexes and protect the host against bacterial infection. Each member of the IL-17R family is composed of an extracellular Fibronectin III-like (FnIII) domain, a single transmembrane domain and an intracellular similar expression to FGF genes (SEF)/IL-17R (SEFIR) domain, which is crucial for IL-17 signalling and is homologous to the TIR domains of Toll-Like Receptors (TLRs). Here, we describe a role for IL-17RD, also known as Sef, the remaining orphan receptor of the family, as a functional regulator of innate immune signalling. Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) were used to suppress endogenous expression of IL-17RD leading to enhanced activation of NF-κB and NF-κB responsive genes by TLR ligands such as Lipopolysaccharide (LPS) and poyinosinic:polycytidylic acid (Poly I:C). We demonstrate that IL-17RD can differentially regulate the various pathways employed by IL-17A. Neutrophil recruitment, in response to in vivo administration of IL-17A, is abolished in IL-17RD-deficient mice, correlating with reduced IL-17A-induced activation of p38 MAPK and expression of the neutrophil chemokine MIP-2. In contrast, IL-17RD deficiency results in enhanced IL-17A-induced activation of NF-κB and IL-6 and KC expression. IL-17RD disrupts the interaction of Act1 and TRAF6 causing differential regulation of NF-κB and p38 MAPK signalling pathways.

Level dc:type.qualificationlevel

masters

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2012

Author dc:creator

• Horgan, Alan

• Biology

Language dc:language

en