Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis.

Intestinal macrophages play a central role in regulation of immune responses against commensal bacteria. In general, intestinal macrophages lack the expression of innate-immune receptor CD14 and do not produce proinflammatory cytokines against commensal bacteria. In this study, we identified what we believe to be a unique macrophage subset in human intestine. This subset expressed both macrophage (CD14, CD33, CD68) and DC markers (CD205, CD209) and produced larger amounts of proinflammatory cytokines, such as IL-23, TNF-alpha, and IL-6, than typical intestinal resident macrophages (CD14-CD33+ macrophages). In patients with Crohn disease (CD), the number of these CD14+ macrophages were significantly increased compared with normal control subjects. In addition to increased numbers of cells, these cells also produced larger amounts of IL-23 and TNF-alpha compared with those in normal controls or patients with ulcerative colitis. In addition, the CD14+ macrophages contributed to IFN-gamma production rather than IL-17 production by lamina propria mononuclear cells (LPMCs) dependent on IL-23 and TNF-alpha. Furthermore, the IFN-gamma produced by LPMCs triggered further abnormal macrophage differentiation with an IL-23-hyperproducing phenotype. Collectively, these data suggest that this IL-23/IFN-gamma-positive feedback loop induced by abnormal intestinal macrophages contributes to the pathogenesis of chronic intestinal inflammation in patients with CD.

[1]  D. Hommes,et al.  Stimulation of the intracellular bacterial sensor NOD2 programs dendritic cells to promote interleukin-17 production in human memory T cells. , 2007, Immunity.

[2]  B. Pulendran,et al.  Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses , 2007, Nature Immunology.

[3]  F. Seibold,et al.  TREM-1--expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. , 2007, The Journal of clinical investigation.

[4]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

[5]  T. Hibi,et al.  Lamina propria c-kit+ immune precursors reside in human adult intestine and differentiate into natural killer cells. , 2007, Gastroenterology.

[6]  R. Xavier,et al.  Unravelling the pathogenesis of inflammatory bowel disease , 2007, Nature.

[7]  M. Schenk,et al.  Adaptations of intestinal macrophages to an antigen-rich environment. , 2007, Seminars in immunology.

[8]  R. Blumberg,et al.  Dependence of intestinal granuloma formation on unique myeloid DC-like cells. , 2007, The Journal of clinical investigation.

[9]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[10]  A. Sher,et al.  IL-23 plays a key role in Helicobacter hepaticus–induced T cell–dependent colitis , 2006, The Journal of experimental medicine.

[11]  F. Powrie,et al.  Interleukin-23 drives innate and T cell–mediated intestinal inflammation , 2006, The Journal of experimental medicine.

[12]  R. Sartor.  Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis , 2006, Nature Clinical Practice Gastroenterology &Hepatology.

[13]  H. Weiner,et al.  IL-23 Is Increased in Dendritic Cells in Multiple Sclerosis and Down-Regulation of IL-23 by Antisense Oligos Increases Dendritic Cell IL-10 Production , 2006, The Journal of Immunology.

[14]  G. Maggiore,et al.  SERONEGATIVE AUTOIMMUNE HEPATITIS IN CHILDHOOD , 2006, Journal of Pediatric Gastroenterology and Nutrition.

[15]  T. Mcclanahan,et al.  IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. , 2006, The Journal of clinical investigation.

[16]  M. Neurath,et al.  Both IL‐12p70 and IL‐23 are synthesized during active Crohn's disease and are down‐regulated by treatment with anti‐IL‐12 p40 monoclonal antibody , 2006, Inflammatory bowel diseases.

[17]  S. Gordon,et al.  Monocyte and macrophage heterogeneity , 2005, Nature Reviews Immunology.

[18]  T. Hibi,et al.  Abnormally Differentiated Subsets of Intestinal Macrophage Play a Key Role in Th1-Dominant Chronic Colitis through Excess Production of IL-12 and IL-23 in Response to Bacteria1 , 2005, The Journal of Immunology.

[19]  R. Sartor,et al.  Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. , 2005, Gastroenterology.

[20]  S. Akira,et al.  The Nuclear IκB Protein IκBNS Selectively Inhibits Lipopolysaccharide-Induced IL-6 Production in Macrophages of the Colonic Lamina Propria 1 , 2005, The Journal of Immunology.

[21]  T. Mcclanahan,et al.  IL-23 drives a pathogenic T cell population that induces autoimmune inflammation , 2005, The Journal of experimental medicine.

[22]  J. Orenstein,et al.  Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. , 2005, The Journal of clinical investigation.

[23]  Silvano Sozzani,et al.  The chemokine system in diverse forms of macrophage activation and polarization. , 2004, Trends in immunology.

[24]  Toshifumi Hibi,et al.  T-bet upregulation and subsequent interleukin 12 stimulation are essential for induction of Th1 mediated immunopathology in Crohn’s disease , 2004, Gut.

[25]  T. Mcclanahan,et al.  Divergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation , 2003, The Journal of experimental medicine.

[26]  Steffen Jung,et al.  Blood monocytes consist of two principal subsets with distinct migratory properties. , 2003, Immunity.

[27]  S. Akira,et al.  Toll-like receptor-dependent production of IL-12p40 causes chronic enterocolitis in myeloid cell-specific Stat3-deficient mice. , 2003, The Journal of clinical investigation.

[28]  R. Kastelein,et al.  Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain , 2003, Nature.

[29]  D. Mosser,et al.  The many faces of macrophage activation , 2003, Journal of leukocyte biology.

[30]  S. Akira,et al.  Macrophage-derived IL-18-mediated intestinal inflammation in the murine model of Crohn's disease. , 2001, Gastroenterology.

[31]  M. Russell,et al.  Intestinal Macrophages Lack CD14 and CD89 and Consequently Are Down-Regulated for LPS- and IgA-Mediated Activities1 , 2001, The Journal of Immunology.

[32]  T. Hibi,et al.  Interleukin 18 is a potent proliferative factor for intestinal mucosal lymphocytes in Crohn's disease. , 2000, Gastroenterology.

[33]  J. Massagué,et al.  Inhibition of transforming growth factor-β/SMAD signalling by the interferon-γ/STAT pathway , 1999, Nature.

[34]  J M Ward,et al.  Helicobacter hepaticus Triggers Colitis in Specific-Pathogen-Free Interleukin-10 (IL-10)-Deficient Mice through an IL-12- and Gamma Interferon-Dependent Mechanism , 1998, Infection and Immunity.

[35]  M. Hausmann,et al.  Isolation and phenotypic characterization of colonic macrophages , 1998, Clinical and experimental immunology.

[36]  P. Brandtzaeg,et al.  Cytokine profiles differ in newly recruited and resident subsets of mucosal macrophages from inflammatory bowel disease. , 1997, Gastroenterology.

[37]  M. Neurath,et al.  Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. , 1996, Journal of immunology.

[38]  P. Pavli,et al.  Evidence for a CD14+ population of monocytes in inflammatory bowel disease mucosa—implications for pathogenesis , 1995, Clinical and experimental immunology.

[39]  R. Coffman,et al.  Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. , 1994, Immunity.

[40]  M. Neurath.  IL-23: a master regulator in Crohn disease , 2007, Nature Medicine.

[41]  S. Akira,et al.  The nuclear IkappaB protein IkappaBNS selectively inhibits lipopolysaccharide-induced IL-6 production in macrophages of the colonic lamina propria. , 2005, Journal of immunology.

[42]  H. Ogata,et al.  Novel pathophysiological concepts of inflammatory bowel disease , 2005, Journal of Gastroenterology.

[43]  J. Massagué,et al.  Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. , 1999, Nature.