Model of colonic inflammation: immune modulatory mechanisms in inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is an immunoinflammatory illness of the gut initiated by an immune response to bacteria in the microflora. The resulting immunopathogenesis leads to lesions in epithelial lining of the colon through which bacteria may infiltrate the tissue causing recurring bouts of diarrhea, rectal bleeding, and malnutrition. In healthy individuals such immunopathogenesis is avoided by the presence of regulatory cells that inhibit the inflammatory pathway. Highly relevant to the search for treatment strategies is the identification of components of the inflammatory pathway that allow regulatory mechanisms to be overridden and immunopathogenesis to proceed. In vitro techniques have identified cellular interactions involved in inflammation-regulation crosstalk. However, tracing immunological mechanisms discovered at the cellular level confidently back to an in vivo context of multiple, simultaneous interactions has met limited success. To explore the impact of specific interactions, we have constructed a system of 29 ordinary differential equations representing different phenotypes of T-cells, macrophages, dendritic cells, and epithelial cells as they move and interact with bacteria in the lumen, lamina propria, and lymphoid tissue of the colon. Simulations revealed the positive inflammatory feedback loop formed by inflammatory M1 macrophage activation of T-cells as a driving force underlying the immunopathology of IBD. Furthermore, strategies that remove M1 from the site of infection, by either (i) increasing its potential to switch to a regulatory M2 phenotype or (ii) increasing the rate of reversion (for M1 and M2 alike) to a resting state, cease immunopathogenesis even as bacteria are eliminated by other inflammatory cells. Based on these results, we identify macrophages and their mechanisms of plasticity as key targets for mucosal inflammation intervention strategies. In addition, we propose that the primary mechanism behind the association of PPARgamma mutation with IBD is its ability to mediate the M1 to M2 switch.

Figure 1

Biological model of crosstalk between inflammatory and regulatory pathways in the gut. Solid lines represent either a reaction that induces cell differentiation from one type to another or the promotion by a cell type of a particular reaction. Dotted lines represent an inhibitory effect of a cell type on an interaction. The inflammatory pathway (right) is triggered by pathogenic (foreign) bacteria, Bf, and the regulatory pathway (left) is triggered by residential (commensal) bacteria, Bc. Each is described in the text along with other abbreviations.

Figure 2

Scheme of mathematical model of interacting populations represented explicitly in the model in the three location compartments: i) the lumen (top) ii) the lamina propria (middle), and iii) mesenteric lymph node (bottom). Solid arrows indicate cell transition from one population pool to another and are labelled with the rate or probability of this transition. Dashed arrows point from populations to the transition which they positively influence. The symbols for these parameters are described in Appendix A, table A.1. Red circles highlight the specific positive feedback loop that drives exponential growth of the activating cytokine population and epithelial cell depletion in the IBD model where Bc is able to stimulate Di and M0 to inflammatory phenotypes, De and M1.

Figure 3

Timecourse of fluctuations in select populations. A) Homeostasis: In the absence of an inflammatory response to bacteria in the lumen, the epithelial cell barrier remains intact and epithelial cells do not secrete inflammatory factors. Deactivating cytokines and induced T-regulatory cells are maintained at a basal level while activating cytokines and inflammatory T-helper cells are absent. Bacteria is compartmentalized to the lumen with no detectable invasion of the lamina propria (LP). B) Dysentery: The extended model that includes pathogenic bacteria that triggers an inflammatory response in macrophages and dendritic cells, epithelial cell erosion is seen as inflammatory markers rise in conjunction with translocation of bacteria into the LP. C) Chronic Inflammation: When a small fraction (0.0001) of bacteria in the lumen triggers an inflammatory response in macrophages and dendritic cells, the total epithelial cell population remains reduced in conjunction with elevated inflammatory markers and continued migration of bacteria into the lamina propria where it is readily eliminated by immune cells. This is typically seen in cases of inflammatory bowel disease.

Figure 4

Timecourse of fluctuations in select populations. The y-axis is in log scale to better compare population levels under chronic inflammation and rescue scenarios. A) Chronic inflammatory conditions of ν_Bc = 0.0001, ∊ = 1, and ν_M0 = 0. B) When the following parameter values are applied; ν_Bc = 0.0001, ∊ = 2, and ν_M0 = 0 requiring a lower de-activating cytokine concentration to induce transition from M1 to M2 in activated macrophages. This may also represent a higher activating cytokine threshold for inducing the opposite transition of M2 to M1. C) The following parameter values are applied; ν_Bc = 0.0001, ∊ = 1, and ν_M0 = 0.015 representing a system in which activated macrophages may become deactivated. As the value ν_M0 increases this recovery period is shortened (not shown).

Figure5

Timecourse of cell populations in the system that grow in proportion to the activating cytokine levels (far left) when ν_Bc ≥ 0.01. This indicates their critical roles in the positive feedback pathway described in section 3.3 of the main text.