Abstract
Invariant natural killer T (iNKT) cells and neutrophils play an increasingly important part in the pathogenesis of inflammatory diseases, but their precise roles in modulating colitis remain unclear. Previous studies have shown important interplays between host immune system and the gut microbiota, and the resulting modulation of inflammation. However, the interactions between iNKT cells, neutrophil and gut microbiota in regulating colitis pathology are poorly understood. Here, we show iNKT cell-deficient Jα18−/− mice display reduced dextran sodium sulfate (DSS)-induced colonic inflammation compared to their wild-type (WT) counterparts. We reveal that there is a distinct gut microbiota shaped by the absence of iNKT cells, which comprises of microorganisms that are associated with protection from colonic inflammation. Additionally, the reduced inflammation in Jα18−/− mice was correlated with increased expressions of neutrophil chemoattractant (Cxcl1 and Cxcl2) and increased neutrophil recruitment. However, these neutrophils were recruited to the colon at day 3 of our model, prior to observable clinical signs at day 5. Further analysis shows that these neutrophils, primed by the microbiota shaped by the lack of iNKT cells, exhibit anti-inflammatory and immune-modulatory properties. Indeed, depletion of neutrophils in DSS-treated Jα18−/− mice demonstrates that neutrophils confer an anti-colitogenic effect in the absence of iNKT cells. Thus, our data supports a changing dogma that neutrophils possess important regulatory roles in inflammation and highlights the complexity of the iNKT cell–microbiota–neutrophil axis in regulating colonic inflammation.
Highlights
Inflammatory bowel disease describes a group of chronic and idiopathic inflammatory diseases of the gastrointestinal tract and includes Crohn’s disease (CD) and ulcerative colitis (UC)
Consistent with the DAI data, colons from Jα18−/− mice exhibited significantly lower histology scores compared to WT mice (Figure 1E). These dextran sodium sulfate (DSS)-induced differences in pathology between WT and Jα18−/− mice were independent of increased intestinal permeability, which was similar in WT and Jα18−/− mice following DSS treatment (Figure S1B in Supplementary Material). These results demonstrate that Jα18−/− mice have less severe colon inflammation following DSS-induced colitis, and suggest that invariant natural killer T (iNKT) cells play a key role in contributing to the colonic inflammation and pathology in this model
INKT cells activated by the treatment of α-GalCer or OCH9 (Th2-polarizing agonist) attenuate the development of DSS-induced colitis [45,46,47] while in a Th2-predominant model of oxazolone-induced colitis, NKT cells play a crucial role in disease development [48]
Summary
Inflammatory bowel disease describes a group of chronic and idiopathic inflammatory diseases of the gastrointestinal tract and includes Crohn’s disease (CD) and ulcerative colitis (UC). Despite earlier findings showing a pathogenic role for neutrophils [2], there is a growing body of evidence to demonstrate that neutrophils participate iNKT-microbiota-neutrophil axis in colitis in protective functions in colitis [3]. It is noteworthy that therapies aimed at inhibiting leukocyte recruitment, such as blockade of P-selectin glycoprotein ligand-1 or very late antigen-4 present on leukocytes have shown promise in attenuating dextran sodium sulfate (DSS)-induced colitis [4]. Strategies to inhibit other adhesion molecules, such as L-selectin, or depletion of neutrophils, have resulted in aggravated pathology in multiple rodent models of colitis [5]. The findings from these studies indicate that treatment regimens targeting neutrophils and their recruitment to the colon have heterogeneous effects. A better understanding of the mechanisms underlying neutrophil recruitment and their function is required for the development of more effective therapy
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