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The intestine and its immune system have evolved to meet the extraordinary task of maintaining tolerance to the largest, most complex and diverse microbial commensal habitat, while meticulously attacking and containing even minute numbers of occasionally incoming pathogens. While our understanding is still far from complete, recent studies have provided exciting novel insights into the complex interplay of the many distinct intestinal immune cell types as well as the discovery of entirely new cell subsets. These studies have also revealed how proper development and function of the intestinal immune system is dependent on its specific microbiota, which appears to have evolutionarily co-evolved. Here we review key immune cells that maintain intestinal homeostasis and, conversely, describe how altered function and imbalances may lead to inflammatory bowel disease (IBD). We highlight the latest developments within this field, covering the major players in IBD including intestinal epithelial cells, macrophages, dendritic cells, adaptive immune cells, and the newly discovered innate lymphoid cells, which appear of characteristic importance for immune function at mucosal surfaces. We set these mucosal immune pathways in the functional context of IBD risk genes where such insight is available. Moreover, we frame our discussion of fundamental biological pathways that have been elucidated in model systems in the context of results from clinical trials in IBD that targeted key mediators secreted by these cells, as an attempt of ‘functional’ appraisal of these pathways in human disease.

A translational study reveals a role for interleukin-1–fibroblast–neutrophil signaling in drug-resistant inflammatory bowel disease, opening a potential path to targeted treatment.

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

Variants of the human gene C13orf31 ( LACC1 ) are associated with various disease risks. Kaser and colleagues identify a role for the protein encoded (called ‘FAMIN’) in regulating macrophage fatty-acid oxidation and lipogenesis. Single-nucleotide variations in C13orf31 ( LACC1 ) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.