CXCL10+ T cells and NK cells assist in the recruitment and activation of CXCR3+ and CXCL11+ leukocytes during Mycobacteria-enhanced colitis

Abstract

BackgroundThe role of Mycobacteria in the etiology of Crohn's disease (CD) has been a contentious subject for many years. Recently, our laboratory showed that spontaneous colitis in IL-10-/- mice is driven in part by antigens (Ags) conserved in Mycobacteria. The present study dissects some of the common cellular and molecular mechanism that drive Mycobacteria-mediated and spontaneous colitis in IL-10-/- mice.ResultsWe show that serum from inflammatory bowel disease (IBD) patients contain significantly higher levels of Mycobacterium avium paratuberculosis-specific IgG1 and IgG2 antibodies (Abs), serum amyloid A (SAA) as well as CXCR3 ligands than serum from healthy donors. To study the cellular mechanisms of Mycobacteria-associated colitis, pathogen-free IL-10-/- mice were given heat-killed or live M. avium paratuberculosis. The numbers of mucosal T cells, neutrophils, NK/NKT cells that expressed TNFα, IFN-γ, and/or CXCL10 were significantly higher in mice that received live Mycobacteria than other groups. The numbers of mucosal CXCR3+, CXCL9+, CXCL11+ and/or IFN-γ+ dendritic cells (DCs) were also significantly higher in M. avium paratuberculosis-challenged mice, than compared to control mice.ConclusionThe present study shows that CD and UC patients mount significant Mycobacteria-specific IgG1 > IgG2 and CXCR3 ligand responses. Several cellular mechanisms that drive spontaneous colitis also mediate Mycobacteria-enhanced colitis in IL-10-/- mice. Similar to IL-10-/- mice under conventional housing, we show that Mycobacteria-challenge IL-10-/- mice housed under otherwise pathogen-free conditions develop colitis that is driven by CXCR3- and CXCR3 ligand-expressing leukocytes, which underscores another important hallmark and molecular mechanism of colitis. Together, the data show that Mycobacteria-dependent host responses, namely CXCL10+ T cells and NK cells, assist in the recruitment and activation of CXCR3+ and CXCL11+ leukocytes to enhance colitis of susceptible hosts.

Resveratrol (Trans-3,5,4′-trihydroxystilbene) Induces Silent Mating Type Information Regulation-1 and Down-Regulates Nuclear Transcription Factor-κB Activation to Abrogate Dextran Sulfate Sodium-Induced Colitis

“…4) and that the number of these cells significantly declined in MLN and LP after resveratrol treatment. These results confirmed our earlier findings that the numbers of CD4 ϩ T cells in spleens, MLN, and LP represent the majority of lymphocytes expressing inflammatory cytokines during colitis (Singh et al, 2008a). This finding is also in agreement with the findings of other studies using DSS-induced colitis models that showed the potentiation of CD4 ϩ T cells in colitis (Dieleman et al, 1998;Shintani et al, 1998;Grose et al, 2001;Ogawa et al, 2004).…”

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

“…Deleterious effects of NK cell activation were reported after infection with both gram-negative (for example, E. coli [185] and Ehrlichia chaffensis [186]) and grampositive bacteria (for example, Streptococcus pneumoniae [187] and Streptococcus pyogenes [188]) independent of the site of infection (systemic, peritoneal or pulmonary). Most interestingly, NK cells may also contribute to adverse evolution of the infectious diseases as shown by their association with a Helicobacter pylori-dependent state of early-stage highgrade gastric mucosa-associated lymphoid tissue lymphoma (189) and Mycobacteria-mediated colitis in susceptible hosts (190). Of course and as expected, NK cells contribute to the deleterious effects seen after LPS injections (85,191).…”

Oxymatrine Prevents NF-κB Nuclear Translocation And Ameliorates Acute Intestinal Inflammation

“…Though oxymatrine blocks LPS-induced TNFα production in both IECs and BMDCs in vitro , the in vivo source of TNFα is not clear. Intestinal myofibroblasts34 and NKT35 cells are an important source of TNFα and could be unaffected by oxymatrine exposure. In addition, it is possible that the effect of oxymatrine on NF-κB in vivo could be coupled with effects on other signaling pathways such as p38MAPK1112 and acts to balance target gene transactivation lowering pro-inflammatory effects while preserving cyto-protective ones.…”