Research Topic

Pharmacological Regulation of Innate Immune Cell Plasticity: a Novel Strategy for the Treatment of IBD?

About this Research Topic

The mechanisms involved in inflammatory bowel disease (IBD) pathogenesis are still under investigation. It is now accepted that an abnormal immune response against the intestinal microbiota in genetically susceptible individuals is responsible for the initiation and progression of the disease. Traditionally, most research efforts have been directed to unravel the function of adaptive lymphocytes, as they have been considered to play a major role in the development of IBD. However, recent advances in mucosal immunology have drawn much attention to the role of the innate immune response in the pathogenesis of intestinal inflammation, and increasing evidence has shown that defects in the innate immunity are in fact at the centre of both Crohn’s disease and ulcerative colitis. The gastrointestinal mucosa is continuously exposed to microorganisms and other antigens, and it is the innate immune system responsibility to provide a rapid, effective immune response against pathogenic bacteria, while maintaining tolerance towards food and “good” bacterial antigens. In addition, the innate immune system shapes and direct adaptive immune responses, thus perturbation in this fine balance may result in the aberrant immune response that characterizes autoimmune diseases, such as IBD.

Macrophages are central mediators of intestinal immune homeostasis and inflammation. A hallmark of macrophages is their plasticity as well as the ability to change phenotype and function according to the immediate environment. Following the M1–M2 paradigm, macrophages are classified as pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Similarly innate lymphoid cells (ILCs) have an essential role in the initiation, regulation and resolution of inflammation. They rapidly respond to cytokine and microbial signals and are potent innate cellular sources of multiple pro-inflammatory and immuno-regulatory cytokines. Although originally considered cells with a rather fixed phenotype, ILCs exhibit a certain degree of functional plasticity, and they seem to modify their cytokine secretion pattern according to different environmental signals.

Chronic inflammation in IBD massively alters the number, diversity and function of the intestinal innate immune cells. For example, in IBD, macrophages massively infiltrate the intestinal mucosa and present phenotypes and distribution distinct from tissue-resident macrophages in homeostasis. Whereas tissue-resident macrophages are mostly tolerogenic, tissue-infiltrating intestinal macrophages secrete pro-inflammatory cytokines such as TNF, IL-6, IL-8, IL-23, IL-1β, and IFNγ. This pro-inflammatory macrophage phenotype might result from polarization of any monocytic cell entering the pro-inflammatory environment of the inflamed intestinal mucosa. M1 macrophages seem to be increased while M2 macrophages are decreased in colitis, suggesting that disequilibrium of macrophage subsets promotes colitis development. Sustained crosstalk between ILCs and the microbiota suggest that ILCs may have a role in IBD development. ILCs may contribute to intestinal inflammation through the secretion of cytokines, such as IL17A and IFN-γ, and recruitment of other inflammatory cells. Several investigators have demonstrated that ILC compartments are altered in IBD, with a decrease of IL-22 producing ILC3 and increase of inflammatory IFN-producing ILC1. In addition, a marked and selective accumulation of IL-17A-producing ILCs has also been observed in the inflamed intestine of patients with IBD. On the other hand, different subsets of ILCs have the potential of limiting chronic inflammation through indirect and direct regulation of the adaptive immune cell response.

Taken together, many open questions remain with regard to specifics of the involvement of different subpopulations innate cells in the pathogenesis and the chronicity of IBD. Given the role of innate immune cells in the initiation, regulation and resolution of inflammation and characterized alterations of these cells in defined patient populations, there is an urgent need to investigate whether therapeutic strategies can be employed to modulate innate immune responses and provide clinical benefit. Further dissecting the diversity and local distribution of these cells in the gut will help to define their clinical relevance and studying the mechanisms that regulate their polarization and functional plasticity will certainly open new horizons in the knowledge about the immunologic mechanisms implicated in gut inflammation. In this sense, the development of treatments that promote a shift from the pathologic to the protective phenotype in innate immune cells could for instance constitute a novel approach to IBD therapy.


Keywords: innate lymphoid cells, macrophages, dendritic cells, inflammatory bowel disease, plasticity


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

The mechanisms involved in inflammatory bowel disease (IBD) pathogenesis are still under investigation. It is now accepted that an abnormal immune response against the intestinal microbiota in genetically susceptible individuals is responsible for the initiation and progression of the disease. Traditionally, most research efforts have been directed to unravel the function of adaptive lymphocytes, as they have been considered to play a major role in the development of IBD. However, recent advances in mucosal immunology have drawn much attention to the role of the innate immune response in the pathogenesis of intestinal inflammation, and increasing evidence has shown that defects in the innate immunity are in fact at the centre of both Crohn’s disease and ulcerative colitis. The gastrointestinal mucosa is continuously exposed to microorganisms and other antigens, and it is the innate immune system responsibility to provide a rapid, effective immune response against pathogenic bacteria, while maintaining tolerance towards food and “good” bacterial antigens. In addition, the innate immune system shapes and direct adaptive immune responses, thus perturbation in this fine balance may result in the aberrant immune response that characterizes autoimmune diseases, such as IBD.

Macrophages are central mediators of intestinal immune homeostasis and inflammation. A hallmark of macrophages is their plasticity as well as the ability to change phenotype and function according to the immediate environment. Following the M1–M2 paradigm, macrophages are classified as pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Similarly innate lymphoid cells (ILCs) have an essential role in the initiation, regulation and resolution of inflammation. They rapidly respond to cytokine and microbial signals and are potent innate cellular sources of multiple pro-inflammatory and immuno-regulatory cytokines. Although originally considered cells with a rather fixed phenotype, ILCs exhibit a certain degree of functional plasticity, and they seem to modify their cytokine secretion pattern according to different environmental signals.

Chronic inflammation in IBD massively alters the number, diversity and function of the intestinal innate immune cells. For example, in IBD, macrophages massively infiltrate the intestinal mucosa and present phenotypes and distribution distinct from tissue-resident macrophages in homeostasis. Whereas tissue-resident macrophages are mostly tolerogenic, tissue-infiltrating intestinal macrophages secrete pro-inflammatory cytokines such as TNF, IL-6, IL-8, IL-23, IL-1β, and IFNγ. This pro-inflammatory macrophage phenotype might result from polarization of any monocytic cell entering the pro-inflammatory environment of the inflamed intestinal mucosa. M1 macrophages seem to be increased while M2 macrophages are decreased in colitis, suggesting that disequilibrium of macrophage subsets promotes colitis development. Sustained crosstalk between ILCs and the microbiota suggest that ILCs may have a role in IBD development. ILCs may contribute to intestinal inflammation through the secretion of cytokines, such as IL17A and IFN-γ, and recruitment of other inflammatory cells. Several investigators have demonstrated that ILC compartments are altered in IBD, with a decrease of IL-22 producing ILC3 and increase of inflammatory IFN-producing ILC1. In addition, a marked and selective accumulation of IL-17A-producing ILCs has also been observed in the inflamed intestine of patients with IBD. On the other hand, different subsets of ILCs have the potential of limiting chronic inflammation through indirect and direct regulation of the adaptive immune cell response.

Taken together, many open questions remain with regard to specifics of the involvement of different subpopulations innate cells in the pathogenesis and the chronicity of IBD. Given the role of innate immune cells in the initiation, regulation and resolution of inflammation and characterized alterations of these cells in defined patient populations, there is an urgent need to investigate whether therapeutic strategies can be employed to modulate innate immune responses and provide clinical benefit. Further dissecting the diversity and local distribution of these cells in the gut will help to define their clinical relevance and studying the mechanisms that regulate their polarization and functional plasticity will certainly open new horizons in the knowledge about the immunologic mechanisms implicated in gut inflammation. In this sense, the development of treatments that promote a shift from the pathologic to the protective phenotype in innate immune cells could for instance constitute a novel approach to IBD therapy.


Keywords: innate lymphoid cells, macrophages, dendritic cells, inflammatory bowel disease, plasticity


Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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14 December 2017 Manuscript

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14 December 2017 Manuscript

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