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Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1β and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The immune response to mycobacteria is characterized by granuloma formation, which features multinucleated giant cells as a unique macrophage type. We previously found that multinucleated giant cells result from Toll-like receptor-induced DNA damage and cell autonomous cell cycle modifications. However, the giant cell progenitor identity remained unclear. Here, we show that the giant cell-forming potential is a particular trait of monocyte progenitors. Common monocyte progenitors potently produce cytokines in response to mycobacteria and their immune-active molecules. In addition, common monocyte progenitors accumulate cholesterol and lipids, which are prerequisites for giant cell transformation. Inducible monocyte progenitors are so far undescribed circulating common monocyte progenitor descendants with high giant cell-forming potential. Monocyte progenitors are induced in mycobacterial infections and localize to granulomas. Accordingly, they exhibit important immunological functions in mycobacterial infections. Moreover, their signature trait of high cholesterol metabolism may be piggy-backed by mycobacteria to create a permissive niche.

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10 + lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions., Competing Interests: Declaration of Interests E.E. is a consultant to DayTwo and BiomX. None of the topics related to this work involve these or other commercial entities. None of the other authors have any financial or non-financial competing interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disorder, in which the clinical manifestations may be influenced by genetic and unknown environmental factors. Here we show that ALS-prone Sod1 transgenic (Sod1-Tg) mice have a pre-symptomatic, vivarium-dependent dysbiosis and altered metabolite configuration, coupled with an exacerbated disease under germ-free conditions or after treatment with broad-spectrum antibiotics. We correlate eleven distinct commensal bacteria at our vivarium with the severity of ALS in mice, and by their individual supplementation into antibiotic-treated Sod1-Tg mice we demonstrate that Akkermansia muciniphila (AM) ameliorates whereas Ruminococcus torques and Parabacteroides distasonis exacerbate the symptoms of ALS. Furthermore, Sod1-Tg mice that are administered AM are found to accumulate AM-associated nicotinamide in the central nervous system, and systemic supplementation of nicotinamide improves motor symptoms and gene expression patterns in the spinal cord of Sod1-Tg mice. In humans, we identify distinct microbiome and metabolite configurations-including reduced levels of nicotinamide systemically and in the cerebrospinal fluid-in a small preliminary study that compares patients with ALS with household controls. We suggest that environmentally driven microbiome-brain interactions may modulate ALS in mice, and we call for similar investigations in the human form of the disease.

TGFβ1 has been implicated in regulating functional aspects of several distinct immune cell populations including central nervous system (CNS) resident microglia. Activation and priming of microglia have been demonstrated to contribute to the progression of neurodegenerative diseases and, thus, underlie stringent control by endogenous regulatory factors including TGFβ1. Here, we demonstrate that deletion of Tgfbr2 in adult postnatal microglia does neither result in impairment of the microglia-specific gene expression signatures, nor is microglial survival and maintenance affected. Tgfbr2-deficient microglia were characterised by distinct morphological changes and transcriptome analysis using RNAseq revealed that loss of TGFβ signalling results in upregulation of microglia activation and priming markers. Moreover, protein arrays demonstrated increased secretion of CXCL10 and CCL2 accompanied by activation of immune cell signalling as evidenced by increased phosphorylation of TAK1. Together, these data underline the importance of microglial TGFβ signalling to regulate microglia adaptive changes.

Objectives: To determine whether geriatric hip fractures can be managed effectively within a level 1 trauma center., Design: A prospective observational cohort study with a historical control group., Setting: Level 1 trauma center., Patients: A total of 199 patients admitted under our hip fracture service were prospectively identified from 2011-2012. These were compared with 191 hip fracture patients who were admitted before the service., Intervention: The hip fracture service includes coadmission under an orthopaedic and a geriatric team. A daily, consultant-led operating list was made available for hip fracture surgery. A "neck of femur" nurse was employed to coordinate patient care., Main Outcome Measurements: Time to surgery, length of stay, discharge destination, and mortality. A cost-benefit analysis and a comparison with a lower acuity hospital were also performed., Results: Since the hip fracture service, more patients underwent surgery within 48 hours (67% vs. 52%; P = 0.004), the length of stay significantly decreased from 26 to 22 days (P = 0.004), significantly more patients were admitted to the rehabilitation unit (58.7% vs. 3.5%; P < 0.001) and ultimately discharged to their own residence (51.6% vs. 40.5%; P = 0.034). Inpatient mortality rates did not change significantly (7.5% vs. 6.8%; P = 0.780). The estimated cost saving in 2011 was $981,040., Conclusions: Only minor changes are required to significantly improve the management of geriatric hip fracture patients. These patients can be managed effectively within a level 1 trauma center when an organized service prioritizing these patients is used., Level of Evidence: Therapeutic level III. See Instructions for authors for a complete description of levels of evidence.