Distinct Colitis-Associated Macrophages Drive NOD2-Dependent Bacterial Sensing and Gut Homeostasis.

Single-cell studies have revealed that intestinal macrophages maintain gut homeostasis through the balanced actions of reactive (inflammatory) and tolerant (non-inflammatory) subpopulations. How such balance is impaired in inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), remains unresolved. Here, we define colon-specific macrophage states and reveal the critical role of on- nflammatory olon- ssociated acrophages (niColAMs) in IBD recovery.

A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics.

Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects.

Macrophage states: there's a method in the madness.

Single-cell approaches have shone a spotlight on discrete context-specific tissue macrophage states, deconstructed to their most minute details. Machine-learning (ML) approaches have recently challenged that dogma by revealing a context-agnostic continuum of states shared across tissues. Both approaches agree that 'brake' and 'accelerator' macrophage subpopulations must be balanced to achieve homeostasis.

Diverse gut pathogens exploit the host engulfment pathway via a conserved mechanism.

Macrophages clear infections by engulfing and digesting pathogens within phagolysosomes. Pathogens escape this fate by engaging in a molecular arms race; they use WxxxE motif-containing "effector" proteins to subvert the host cells they invade and seek refuge within protective vacuoles. Here, we define the host component of the molecular arms race as an evolutionarily conserved polar "hot spot" on the PH domain of ELMO1 (Engulfment and Cell Motility protein 1), which is targeted by diverse WxxxE effectors.

Machine learning identifies signatures of macrophage reactivity and tolerance that predict disease outcomes.

Background: Single-cell transcriptomic studies have greatly improved organ-specific insights into macrophage polarization states are essential for the initiation and resolution of inflammation in all tissues; however, such insights are yet to translate into therapies that can predictably alter macrophage fate.

Method: Using machine learning algorithms on human macrophages, here we reveal the continuum of polarization states that is shared across diverse contexts. A path, comprised of 338 genes accurately identified both physiologic and pathologic spectra of "reactivity" and "tolerance", and remained relevant across tissues, organs, species, and immune cells (>12,500 diverse datasets).