Autoimmune Renal Disease Is Exacerbated by S1P-Receptor-1-Dependent Intestinal Th17 Cell Migration to the Kidney

摘要

class="head no_bottom_margin" id="sec1title">IntroductionCD4⁺ T cells are critical for defense against a wide array of invading microbes and pathogens but are also major drivers of autoimmune diseases. Based on their cytokine secretion profile and expression of specific transcription factors, CD4⁺ T cells can be classified into functionally different subsets, e.g., Th1, Th2, Th17, and regulatory T cells (Tregs) (). It was generally accepted that IFN-γ-expressing Th1 cells primarily initiate and perpetuate tissue damage in autoimmunity (). This paradigm was challenged in 2005 by the discovery of a highly pathogenic IL-17-producing CD4⁺ effector T cell subset, termed Th17 cells (, ). Th17 cells are characterized by their key transcription factors RORγt and STAT3 (, ), the production of the cytokines IL-17A, IL-17F, IL-22 and GM-CSF (, ), and high expression of CCR6 (). Today, their central role in the pathogenesis of several autoimmune diseases is clearly established ().Crescentic glomerulonephritis (cGN) is the most aggressive form of autoimmune kidney diseases that destroys kidneys over a period of days to weeks, leading to end-stage renal failure with associated high morbidity, mortality, and public health costs (, ). The infiltration of leukocytes, including T cells, and the proliferation of resident glomerular cells lead to the formation of glomerular crescents and a disrupted anatomical structure of the glomerulus, ultimately leading to loss of kidney function. Current treatment protocols are unspecific and hampered by toxic side effects that deteriorate patient outcome.Recent studies have highlighted the substantial impact of the Th17 immune response in cGN (, ). This includes the identification and characterization of CCR6⁺ IL-17-producing T cells in murine kidneys in experimental models of cGN (, href="#bib55" rid="bib55" class=" bibr popnode">Turner et al., 2010), as well as evidence for the contribution of IL-17A, IL-17F, IL-17RA, IL-23p19, and RORγt to renal tissue injury in cGN (href="#bib40" rid="bib40" class=" bibr popnode">Paust et al., 2009, href="#bib45" rid="bib45" class=" bibr popnode">Ramani et al., 2014, href="#bib46" rid="bib46" class=" bibr popnode">Riedel et al., 2016, href="#bib50" rid="bib50" class=" bibr popnode">Steinmetz et al., 2011, href="#bib51" rid="bib51" class=" bibr popnode">Summers et al., 2009). Th17-cell-derived IL-17A and IL-17F promote the expression of chemokines such as CXCL1 and CXCL5 in the kidney and thereby drive recruitment of neutrophils and other leukocyte subtypes, which mediate renal tissue destruction in cGN (href="#bib12" rid="bib12" class=" bibr popnode">Disteldorf et al., 2015, href="#bib55" rid="bib55" class=" bibr popnode">Turner et al., 2010). Although we are beginning to understand the effector functions of Th17 cells in the target tissue, the developmental origin of Th17 cells that infiltrate inflamed tissues, e.g., the kidney in glomerulonephritis, is still a matter of debate.Under homeostatic conditions, Th17 cells are most abundant in the small intestinal lamina propria, and their presence in the gut of mice requires the colonization with specific adhesive microorganisms (href="#bib23" rid="bib23" class=" bibr popnode">Ivanov et al., 2009). Colonization of mice with segmented filamentous bacteria (SFB) results in the generation of SFB-specific Th17 cells (href="#bib57" rid="bib57" class=" bibr popnode">Yang et al., 2014). In addition to SFB, infection of mice with enterohemorrhagic Escherichia coli (EHEC) or Citrobacter rodentium results in the expansion of intestinal Th17 cells (href="#bib5" rid="bib5" class=" bibr popnode">Atarashi et al., 2015, href="#bib23" rid="bib23" class=" bibr popnode">Ivanov et al., 2009, href="#bib47" rid="bib47" class=" bibr popnode">Sano et al., 2015). In line with this, germ-free mice lack intestinal Th17 cells, and antibiotic treatment of mice can reduce intestinal Th17 cell frequencies (href="#bib4" rid="bib4" class=" bibr popnode">Atarashi et al., 2008, href="#bib22" rid="bib22" class=" bibr popnode">Ivanov et al., 2008, href="#bib44" rid="bib44" class=" bibr popnode">Rakoff-Nahoum et al., 2004). In addition, Th17 cells from lymphoid tissues preferentially home to the gut after transfer and are phenotypically almost indistinguishable from intestinal Th17 cells (href="#bib18" rid="bib18" class=" bibr popnode">Hirota et al., 2013). Th17 cells highly express CCR6, which orchestrates their trafficking to the small intestine (href="#bib13" rid="bib13" class=" bibr popnode">Esplugues et al., 2011) but also to sites of peripheral inflammation, such as the kidney in glomerulonephritis (href="#bib55" rid="bib55" class=" bibr popnode">Turner et al., 2010). Furthermore, organ-specific Th17 immune responses in experimental autoimmune encephalomyelitis (EAE) and arthritis are diminished in mice with reduced intestinal Th17 cells, i.e., in germ-free mice (href="#bib29" rid="bib29" class=" bibr popnode">Lee et al., 2011, href="#bib56" rid="bib56" class=" bibr popnode">Wu et al., 2010). Taken together, these observations indicate a close relationship of Th17 cells with the intestinal microbiota. However, the mechanisms by which microbiota-induced Th17 cells promote extra-intestinal Th17 immune responses remain to be fully elucidated.Here, using transgenic mice that ubiquitously express the photoconvertible Kaede-protein, we directly demonstrated the migration of intestinal Th17 cells to the kidney in experimental cGN. Experiments in microbiota-manipulated mice underscore the concept of pathogenic Th17 cells migrating from the gut to the inflamed kidney. Our findings provide evidence supporting a role for intestinal Th17 cells in the exacerbation of GN and suggest that migration of intestinal Th17 cells may contribute to pathology in other autoimmune diseases.