Jeffrey J. Yu¹, Sarah L. Gaffen ^1,2

1 Department of Microbiology and Immunology, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY, ² Department of Oral Biology, University at Buffalo School of Dental Medicine, Buffalo, NY

FIGURES

Figure 1. Regulation of neutrophil recruitment and homeostasis by IL-17. IL-17 promotes the production of CXC chemokines, G-CSF and increased ICAM-1 from tissues, which in turn increase neutrophil tethering, recruitment and expansion. In order to maintain steady-state levels of neutrophils, excess neutrophils migrate into tissues and are phagocytosed by macrophages. This event inhibits production of IL-23, whose absence then limits IL-17 production by a failure to expand the Th17 population. In turn, the reduced levels of IL-17 lead to decreased production of G-CSF and thus a loss of new neutrophils from the bone marrow. Conversely, in the absence of apoptotic neutrophils, tissue macrophages produce IL-23, which stimulates IL-17 production from T cells by inducing expansion of the Th17 population, which specifically expresses IL-23R. Secretion of IL-17 by Th17 cells leads to increased production of G-CSF and subsequent granulopoiesis in the bone marrow (17).

Figure 2. Similarities of IL-17RA to TLR and IL-1R signaling. TLR/IL-1 receptors recruit the adaptor proteins such as MyD88 via a conserved structural motif in the cytoplasmic tail, termed a "Toll-IL-R (TIR) domain". MyD88 is upstream of the ubiquitin ligase TRAF6, which then initiate a cascade of events resulting in the liberation of NF-kappaB and transcription of TLR/IL-1-responsive genes (74). Similarly, the SEFIR and TILL domains of IL-17RA recruit the SEFIR-containing adaptor protein Act1, which activates TRAF6 and leads to transcription of IL-17-responsive genes (36-39). The SEFIR/TILL domain is also upstream of several other signaling pathways, including ERK1/2 and C/EBPbeta and C/EBPdelta (6, 37). Additionally, a poorly-defined distal domain within IL-17RA also contributes to C/EBPbeta activation, a transcription factor also required for the induction of many IL-17-responsive genes (31, 37).