Classical monocyte ontogeny dictates their functions and fates as tissue macrophages.

Classical monocytes (CMs) are ephemeral myeloid immune cells that circulate in the blood. Emerging evidence suggests that CMs can have distinct ontogeny and originate from either granulocyte-monocyte- or monocyte-dendritic-cell progenitors (GMPs or MDPs). Here, we report surface markers that allowed segregation of murine GMP- and MDP-derived CMs, i.e., GMP-Mo and MDP-Mo, as well as their functional characterization, including fate definition following adoptive cell transfer. GMP-Mo and MDP-Mo yielded an equal increase in homeostatic CM progeny, such as blood-resident non-classical monocytes and gut macrophages; however, these cells differentially seeded various other selected tissues, including the dura mater and lung. Specifically, GMP-Mo and MDP-Mo differentiated into distinct interstitial lung macrophages, linking CM dichotomy to previously reported pulmonary macrophage heterogeneity. Collectively, we provide evidence for the existence of two functionally distinct CM subsets in the mouse that differentially contribute to peripheral tissue macrophage populations in homeostasis and following challenge.

Artificial Intelligence in Long-Term Care: Technological Promise, Aging Anxieties, and Sociotechnical Ageism.

This article explores views about older people and aging underpinning practices and perceptions of development and implementation of Artificial Intelligence (AI) in long-term care homes (LTC). Drawing on semi-structured interviews with seven AI developers, seven LTC staff, and four LTC advocates, we analyzed how AI technologies for later life are imagined, designed, deployed, and resisted. Using the concepts of "promissory discourse" and "aging anxieties", we investigated manifestations of ageism in accounts of AI applications in LTC. Despite positive intentions, both AI developers and LTC staff/advocates engaged in simplistic scripts about aging, care, and the technological capacity of older people. We further uncovered what we termed sociotechnical ageism-a form that is not merely digital but rests on interacting pre-conceptions about the inability or lack of interest of older people to use emerging technologies coupled with social assumptions about aging, LTC, and technological innovation.

A global taxonomy of interpretable AI: unifying the terminology for the technical and social sciences.

Since its emergence in the 1960s, Artificial Intelligence (AI) has grown to conquer many technology products and their fields of application. Machine learning, as a major part of the current AI solutions, can learn from the data and through experience to reach high performance on various tasks. This growing success of AI algorithms has led to a need for interpretability to understand opaque models such as deep neural networks. Various requirements have been raised from different domains, together with numerous tools to debug, justify outcomes, and establish the safety, fairness and reliability of the models. This variety of tasks has led to inconsistencies in the terminology with, for instance, terms such as interpretable, explainable and transparent being often used interchangeably in methodology papers. These words, however, convey different meanings and are "weighted" differently across domains, for example in the technical and social sciences. In this paper, we propose an overarching terminology of interpretability of AI systems that can be referred to by the technical developers as much as by the social sciences community to pursue clarity and efficiency in the definition of regulations for ethical and reliable AI development. We show how our taxonomy and definition of interpretable AI differ from the ones in previous research and how they apply with high versatility to several domains and use cases, proposing a-highly needed-standard for the communication among interdisciplinary areas of AI.

Behaviour Recognition with Kinodynamic Planning Over Continuous Domains.

We investigate the application of state-of-the-art goal recognition techniques for behaviour recognition over complex continuous domains using model predictive control (MPC) for trajectory generation. We formally define the problem of kinodynamic behaviour recognition and establish a set of baseline behaviours and performance measures in the complex domain of unmanned aerial maneuvers. We evaluate how well our approach performs over a range of standard aerial maneuvers and representative initial configurations of varying complexity. The work also highlights future research directions in compound model-based behaviour recognition and team behaviour recognition where multiple agents may be acting simultaneously.

Defining murine monocyte differentiation into colonic and ileal macrophages.

Monocytes are circulating short-lived macrophage precursors that are recruited on demand from the blood to sites of inflammation and challenge. In steady state, classical monocytes give rise to vasculature-resident cells that patrol the luminal side of the endothelium. In addition, classical monocytes feed macrophage compartments of selected organs, including barrier tissues, such as the skin and intestine, as well as the heart. Monocyte differentiation under conditions of inflammation has been studied in considerable detail. In contrast, monocyte differentiation under non-inflammatory conditions remains less well understood. Here we took advantage of a combination of cell ablation and precursor engraftment to investigate the generation of gut macrophages from monocytes. Collectively, we identify factors associated with the gradual adaptation of monocytes to tissue residency. Moreover, comparison of monocyte differentiation into the colon and ileum-resident macrophages revealed the graduated acquisition of gut segment-specific gene expression signatures.

TLR2 Dimerization Blockade Allows Generation of Homeostatic Intestinal Macrophages under Acute Colitis Challenge.

Recruited blood monocytes contribute to the establishment, perpetuation, and resolution of tissue inflammation. Specifically, in the inflamed intestine, monocyte ablation was shown to ameliorate colitis scores in preclinical animal models. However, the majority of intestinal macrophages that seed the healthy gut are also monocyte derived. Monocyte ablation aimed to curb inflammation would therefore likely interfere with intestinal homeostasis. In this study, we used a TLR2 trans-membrane peptide that blocks TLR2 dimerization that is critical for TLR2/1 and TLR2/6 heterodimer signaling to blunt inflammation in a murine colitis model. We show that although the TLR2 peptide treatment ameliorated colitis, it allowed recruited monocytes to give rise to macrophages that lack the detrimental proinflammatory gene signature and reduced potentially damaging neutrophil infiltrates. Finally, we demonstrate TLR blocking activity of the peptide on in vitro cultured human monocyte-derived macrophages. Collectively, we provide a significantly improved anti-inflammatory TLR2 peptide and critical insights in its mechanism of action toward future potential use in the clinic.

IL-23-producing IL-10Rα-deficient gut macrophages elicit an IL-22-driven proinflammatory epithelial cell response.

Cytokines maintain intestinal health, but precise intercellular communication networks remain poorly understood. Macrophages are immune sentinels of the intestinal tissue and are critical for gut homeostasis. Here, we show that in a murine inflammatory bowel disease (IBD) model based on macrophage-restricted interleukin-10 (IL-10) receptor deficiency (Cx3cr1Cre:Il10rafl/fl mice), proinflammatory mutant gut macrophages cause severe spontaneous colitis resembling the condition observed in children carrying IL-10R mutations. We establish macrophage-derived IL-23 as the driving factor of this pathology. Specifically, we report that Cx3cr1Cre:Il10rafl/fl:Il23afl/fl mice harboring macrophages deficient for both IL-10R and IL-23 are protected from colitis. By analyzing the epithelial response to proinflammatory macrophages, we provide evidence that T cells of colitic animals produce IL-22, which induces epithelial chemokine expression and detrimental neutrophil recruitment. Collectively, we define macrophage-specific contributions to the induction and pathogenesis of colitis, as manifested in mice harboring IL-10R deficiencies and human IBDs.

Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge.

Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.