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Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade [Ipt]

ABSTRACT: Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Recently, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2 has been described in several models of organ injury and cancer, and linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Unexpectedly, using a bleomycin and COVID19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not by themselves drivers of fibrosis in the lung.

ORGANISM(S): Mus musculus

PROVIDER: GSE277297 | GEO | 2024/09/16

REPOSITORIES: GEO

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Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade

Project description:Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Recently, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2 has been described in several models of organ injury and cancer, and linked to fibrosis in mice and humans. Here, we show that Notch2 blockade given systemically or locally led to an increase in this putative pro-fibrotic macrophage in the lung. Single cell RNA sequencing suggested that the newly arising population derived from monocytes when Notch2 blockade was systemic or derived from alveolar macrophages when Notch2 blockade was local. Unexpectedly, using a bleomycin and COVID19 model of lung injury and fibrosis, we found that the expansion of these macrophages before lung injury ameliorated rather than promoted fibrosis. This suggests that these damage-associated macrophages are not drivers of fibrosis in the lung.

2024-09-14 | GSE243289 | GEO

Ontogeny of alveolar macrophages is a critical determinant of function during lung fibrosis [RNA-seq]

Project description:Little is known about the relative importance of monocyte and tissue-resident macrophages in the development of lung fibrosis. We show that specific genetic deletion of monocyte-derived alveolar macrophages after their recruitment to the lung ameliorated lung fibrosis, whereas tissue-resident alveolar macrophages did not contribute to fibrosis. Using transcriptomic profiling of flow-sorted cells, we found that monocyte to alveolar macrophage differentiation unfolds continuously over the course of fibrosis and its resolution. During the fibrotic phase, monocyte-derived alveolar macrophages differ significantly from tissue-resident alveolar macrophages in their expression of profibrotic genes. A population of monocyte-derived alveolar macrophages persisted in the lung for one year after the resolution of fibrosis, where they became increasingly similar to tissue-resident alveolar macrophages. Human homologues of profibrotic genes expressed by mouse monocyte-derived alveolar macrophages during fibrosis were up-regulated in human alveolar macrophages from fibrotic compared with normal lungs. Our findings suggest that selectively targeting alveolar macrophage differentiation within the lung may ameliorate fibrosis without the adverse consequences associated with global monocyte or tissue-resident alveolar macrophage depletion.

2017-06-25 | GSE82158 | GEO

Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction

Project description:Mononuclear phagocytes promote injury and repair following myocardial infarction but discriminating functions within mixed populations remains challenging. We utilized fate mapping and single cell RNA-sequencing to delineate fate specification trajectories of heterogeneous cardiac macrophage subpopulations. In steady state, TIMD4 expression tracked with a dominant resident cardiac macrophage subset that persisted via in situ self-renewal with minimal monocyte input. Following ischemic injury, monocytes displayed significant plasticity, ultimately adopting transcriptional states similar to resident macrophages, but also multiple unique states. Ischemic injury reduced resident macrophage abundance within infarct tissue, and despite transcriptional similarity, TIMD4 expression distinguished resident from recruited macrophages. Specific lineage-based depletion of resident cardiac macrophages resulted in depressed cardiac function and adverse remodeling primarily within the peri-infarct zone, the only region of the myocardium where resident macrophages expanded numerically following injury. Together, these data highlight a non-redundant, cardioprotective role of resident cardiac macrophages, and the diverse transcriptional fates recruited monocytes can adopt.

2018-12-15 | GSE119355 | GEO

CD11b restricts alveolar macrophage activation during pneumococcal pneumonia and prevents excessive lung inflammation

Project description:Bacterial lung infections are associated with strong infiltration of CD11b+ myeloid cells, which limit life-threatening disease, but also severely damage lung tissue. In a murine lung infection model with Streptococcus pneumoniae, we found intrinsic upregulation of CD11b on resident alveolar macrophages. Such CD11b expression was associated with transcriptomic and proteomic adaptations by alveolar macrophages, leading to the identification of specific molecules and pathways that depended on CD11b. In the absence of CD11b, the antimicrobial defense of alveolar macrophages was strongly reduced, and the production of neutrophil-recruiting chemokines was more pronounced. Moreover, CD11b expression limited the infection and prevented excessive alveolar damage. In conclusion, our study provides detailed molecular insights into the alveolar macrophage-specific immune response to Streptococcus pneumoniae lung infection and reveals profound CD11b-dependent alterations that are critical for effective antimicrobial immunity, neutrophil recruitment, and prevention of alveolar damage.

2023-10-08 | PXD035269 | Pride

Generation of Alveolar Assembloids (AlvAssemb) with Functional Alveolar-like Macrophages

Project description:Within the human lung, interplay between alveolar epithelial cells and resident macrophages shape lung development and function in both health and disease. To study these processes, we devised a strategy for co-culturing hPSC-derived alveolar epithelial organoids and induced macrophages to form functional environment, which we name alveolar assembloids (AlvAssemb). By scRNAseq and functional analysis of AlvAssemb, we identified alveolar type 2-like cells that produced GM-CSF, a response associated with tissue adaptation of macrophages, and that resident alveolar macrophage-like cells secreted interleukin-1β and interleukin-6, a core immune response function, and expressed genes required for surfactant metabolism. Remarkably, in response to alveolar epithelial injury, we found that macrophage-like cells within AlvAssemb efficiently eliminated damaged cells and absorbed oxidized lipids. Moreover, in response to lipopolysaccharide exposure and Mycobacterium tuberculosis infection, we found that core features of the human respiratory defense response were replicated in AlvAssemb. These findings support that AlvAssemb could serve as a valuable platform to investigate human lung development and pathology.

2024-09-30 | GSE269733 | GEO

Cell origin dictates programming of resident versus recruited macrophages during acute lung injury

Project description:The primary objective of this study was to compare global differences in transcriptional programming of resident and recruited alveolar macrophages in a time-limited murine model of lung inflammation. We first performed RNA sequencing of the resident and recruited alveolar macrophages from initiation through resolution of LPS-induced lung inflammation in the mouse. Our results indicate that despite existing in a shared environment, cell origin is the major determinant of programming of resident and recruited AMs during an acute inflammatory response. Major areas of difference include cell proliferation, inflammatory cytokine production and metabolism.

2017-09-19 | GSE94749 | GEO

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia [scRNA-seq]

Project description:Cardiac macrophages are heterogenous in phenotype and functions, which has been associated with differences in their ontogeny. Despite extensive research, our understanding of the precise role of different subsets of macrophages in ischemia/reperfusion injury remains incomplete. We here investigated macrophage lineages and ablated tissue macrophages in homeostasis and after I/R injury in a CSF1R-dependent manner. Genomic deletion of a fms-intronic regulatory element (FIRE) in the Csf1r locus resulted in specific absence of resident homeostatic and antigen-presenting macrophages, without affecting the recruitment of monocyte-derived macrophages to the infarcted heart. Specific absence of homeostatic, monocyte-independent macrophages altered the immune cell crosstalk in response to injury and induced proinflammatory neutrophil polarization, resulting in impaired cardiac remodelling without influencing infarct size. In contrast, continuous CSF1R inhibition led to depletion of both resident and recruited macrophage populations. This augmented adverse remodelling after I/R and led to an increased infarct size and deterioration of cardiac function. In summary, resident macrophages orchestrate inflammatory responses improving cardiac remodelling, while recruited macrophages determine infarct size after I/R injury. These findings attribute distinct beneficial effects to different macrophage populations in the context of myocardial infarction.

2024-04-14 | GSE263545 | GEO

Resident and recruited macrophages differentially contribute to cardiac healing after myocardial ischemia [bulk RNA-seq]

2024-04-14 | GSE263544 | GEO

Smith2011 - Three Stage Innate Immune Response to a Pneumococcal Lung Infection

Project description:Pneumococcal pneumonia is a leading cause of death and a major source of human morbidity. The initial immune response plays a central role in determining the course and outcome of pneumococcal disease. We combine bacterial titer measurements from mice infected with Streptococcus pneumoniae with mathematical modeling to investigate the coordination of immune responses and the effects of initial inoculum on outcome. To evaluate the contributions of individual components, we systematically build a mathematical model from three subsystems that describe the succession of defensive cells in the lung: resident alveolar macrophages, neutrophils and monocyte-derived macrophages. The alveolar macrophage response, which can be modeled by a single differential equation, can by itself rapidly clear small initial numbers of pneumococci. Extending the model to include the neutrophil response required additional equations for recruitment cytokines and host cell status and damage. With these dynamics, two outcomes can be predicted: bacterial clearance or sustained bacterial growth. Finally, a model including monocyte-derived macrophage recruitment by neutrophils suggests that sustained bacterial growth is possible even in their presence. Our model quantifies the contributions of cytotoxicity and immune-mediated damage in pneumococcal pathogenesis.

2024-09-02 | BIOMD0000000924 | BioModels

Role of CCR2+ Myeloid Cells in Inflammatory Responses Driven by Mutation in Surfactant Protein-C Expression

Project description:Acute inflammatory exacerbations (AIE) represent precipitous deteriorations of a number of chronic lung conditions, including pulmonary fibrosis (PF), chronic obstructive pulmonary disease and asthma. AIEs are marked by diffuse and persistent polycellular alveolitis that profoundly accelerate lung function decline and mortality. In particular, excess monocyte mobilization during AIE and their persistence in the lung have been suggested to be linked to poor disease outcome. We have developed a mutant model of pulmonary fibrosis leveraging the PF-linked missense isoleucine to threonine substitution at position 73 [I73T] in the alveolar type-2 cell-restricted Surfactant Protein-C [SP-C] gene [SFTPC]. With this toolbox at hand, the present work investigates the dynamics of resident alveolar macrophages and peripheral monocytes during the initiation and progression of AIE-PF. FACS analysis of SigF+CD11b- alveolar macrophages and Ly6Chi monocytes isolated 3 d and 14 d after SP-CI73T injury and performed RNA sequencing. Pathway and gene expression analysis revelaed dynamic transcriptional changes associated with “Innate Immunity’ and ‘Extracellular Matrix Organization’ signaling. Supported by previous pharmacological evidence, genetic ablation of CCR2+ monocytes (SP-CI73TCCR2KO) resulted in improved lung histology, mouse survival, and reduced inflammation compared to SP-CI73TCCR2WT cohorts. Immunohistochemical and in situ hybridization analysis revealed comparable levels of tgfb1 mRNA expression localized primarily parenchymal cells found nearby foci of injury. Our results also confirmed reduced inflammatory activation (iNOS, Arg1) in SP-CI73TCCR2KO lungs as well as partial colocalization of tgfb1 mRNA expression in Arg1+ cells. These results provide a detailed picture on the role of resident macrophages and recruited monocytes in the context of AIE-PF driven by alveolar epithelial dysfunction.

2021-02-07 | GSE166300 | GEO

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