Inflammatory Bowel Disease . Mucosal Immunology . MacrophageDendritic Cell . T Cell

Gastroenterology

Mononuclear phagocytes in mucosal immune responses

Inflammatory bowel diseases (IBD), such as Crohn`s disease and ulcerative colitis,are chronic relapsing diseases with increasing incidence and prevalence in the developed world. Innate and adaptive immune responses to constituents of the intestinal microbiota are essential for the development of IBD. Intestinal mononuclear phagocytes are in direct contact with the intestinal microbiota, initiate innate immune responses and shape adaptive immune responses. Phagocytes are located in the lamina propria of the gastrointestinal tract, in cryptopatches and isolated lymph follicles in close proximity to innate lymphoid cells (ILCs). Infection of animals with the mouse pathogen C. rodentium leads to IL-22 production by ILCs,which regulates the expression of REG family proteins required for the defense to infections with enteric pathogens. The depletion of phagocytes decreased IL-22production by ILCs. This means that phagocytes support IL-22 production by ILCs required for host defense in the gut (Manta et al, Mucosal Immunol, 2013).
Mononuclear phagocytes may also initiate adaptive immune responses in the gutas indicated by the close proximity of phagocytes to T cells in the lamina propria of the gastrointestinal tract. Colonic phagocytes sample continuously fluorescent labelled E. coli. To reduce the complex interactions between phagocytes and T cells in presence of the intestinal microflora with vast array pf potential antigens,an antigen-specific colitis model was developed. In this model the challenge of E.coli expressing the antigen ovalbumin induces colitis in immunodeficient animals(RAG animals) reconstituted with antigen-specific T cells. Ex vivo confocal imaging allows the visualization of phagocytes that have sampled E.coli in proximity toT cells. In vitro studies indicated that the phagocytes deliver the antigen to dendritic cells, which migrate to mesenteric lymph nodes. In mesenteric lymph nodes the dendritic cells prime T cells, which home back to the lamina propria. In the lamina propria phagocytes are able to activate the effector T cells (Rossini et al, Mucosal Immunol, 2014).
These findings support the hypothesis that mononuclear phagocytes in the gastro-intestinal tract are of importance for the sampling of constituents of the microbiota, the initiation of innate and adaptive immune responses. Likely, mononuclearphagocytes play a key role in the pathogenesis of IBD.

Fig. 1: Mononuclear phagocytes sample constituents of the intestinal microflora, initiate effector T cell responses (adaptive immunity) and facilitate IL-22 production by innate lymphoid cells (innate immunity).

monocytes - macrophages – cirrhosis - liver failure – TAM receptors
Monocyte and macrophage biology in cirrhosis of the liver
(Project leader: PD Dr. Christine Bernsmeier)

Cirrhosis of the liver is a systemic condition depicted by its high morbidity and mortality and raising prevalence worldwide. There is no treatment option other than transplantation, applicable to only a minority of patients. Infectious complications are highly frequent and independent predictors of adverse prognosis - being the leading cause of acute decompensation, ‘acute-on-chronic’ liver failure (ACLF) and death. Infection susceptibility in cirrhosis has been attributed to a state termed “immuneparesis” and monocyte and macrophage dysfunction, defined by defective immune responses to microbial challenge. A detailed understanding of the mechanisms underlying immuneparesis in patients with cirrhosis is desired in order to identify prognostic markers and define potential future immunotherapeutic targets that may enhance innate immune responses and reduce the need for liver transplantation and death.

Our research team seeks to decipher the pathophysiology of immuneparesis and monocyte and macrophage dysfunction in patients with cirrhosis. Specifically we focus on receptor tyrosine kinases of the TAM receptor family (Tyro-3, AXL and MERTK), expressed on monocytes and macrophages, which play a pivotal role in regulating innate immune responses. We have recently discovered the expansion of circulating immune-regulatory AXL- and MERTK-expressing monocyte subsets in patients with cirrhosis at different stages that suppressed cytokine responses (TNF-α and IL-6) to lipopolysaccharide. Also other monocyte functions of the distinct subsets were modified. In advanced stages of cirrhosis these dysfunctional subsets may prevail and lead to reduced capacity to repel microbial challenge and infection susceptibility. We aim to understand as to how differential TAM receptor signalling is regulated in the progression from compensated to decompensated cirrhosis and controls innate immune responses. We further investigate whether specific inhibition of TAM receptor signalling can restore innate immune responses of monocytes from patients with cirrhosis.