RESUMEN
Macrophages are a heterogeneous cell population involved in tissue homeostasis, inflammation, and various pathologies. Although the major tissue-resident macrophage populations have been extensively studied, interstitial macrophages (IMs) residing within the tissue parenchyma remain poorly defined. Here we studied IMs from murine lung, fat, heart, and dermis. We identified two independent IM subpopulations that are conserved across tissues: Lyve1loMHCIIhiCX3CR1hi (Lyve1loMHCIIhi) and Lyve1hiMHCIIloCX3CR1lo (Lyve1hiMHCIIlo) monocyte-derived IMs, with distinct gene expression profiles, phenotypes, functions, and localizations. Using a new mouse model of inducible macrophage depletion (Slco2b1 flox/DTR), we found that the absence of Lyve1hiMHCIIlo IMs exacerbated experimental lung fibrosis. Thus, we demonstrate that two independent populations of IMs coexist across tissues and exhibit conserved niche-dependent functional programming.
Asunto(s)
Pulmón/inmunología , Pulmón/patología , Macrófagos/inmunología , Animales , Antígenos Ly , Receptor 1 de Quimiocinas CX3C/genética , Linaje de la Célula , Dermis/inmunología , Modelos Animales de Enfermedad , Fibrosis , Glicoproteínas/análisis , Antígenos de Histocompatibilidad Clase II/genética , Proteínas de Transporte de Membrana , Ratones , Ratones Endogámicos C57BL , Monocitos/inmunología , Miocardio/inmunología , Transportadores de Anión Orgánico/genética , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , TranscriptomaRESUMEN
Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half-life. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using mass cytometry (CyTOF) and cell-cycle-based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non-proliferating immature neutrophils and mature neutrophils. Transcriptomic profiling and functional analysis revealed that preNeu require the C/EBPε transcription factor for their generation from the GMP, and their proliferative program is substituted by a gain of migratory and effector function as they mature. preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited to the periphery of tumor-bearing mice. In summary, our study identifies specialized BM granulocytic populations that ensure supply under homeostasis and stress responses.
Asunto(s)
Células de la Médula Ósea/fisiología , Neutrófilos/fisiología , Animales , Células de la Médula Ósea/inmunología , Proteínas Potenciadoras de Unión a CCAAT/fisiología , Linaje de la Célula , Movimiento Celular , Proliferación Celular , Células Cultivadas , Perfilación de la Expresión Génica , Humanos , Ratones , Neoplasias Experimentales/inmunología , Neutrófilos/inmunologíaRESUMEN
Circulating CCR2+ monocytes are crucial for maintaining the adult tissue-resident F4/80hiMHCIIhi macrophage pool in the intestinal lamina propria. Here we show that a subpopulation of CCR2-independent F4/80hiMHCIIlow macrophages, which are the most abundant F4/80hi cells in neonates, gradually decline in number in adulthood; these macrophages likely represent the fetal contribution to F4/80hi cells. In colon adenomas of ApcMin/+ mice, F4/80hiMHCIIlow macrophages are not only preserved, but become the dominant subpopulation among tumour-resident macrophages during tumour progression. Furthermore, these pro-tumoural F4/80hiMHCIIlow and F4/80hiMHCIIhi macrophages can self-renew in the tumour and maintain their numbers mostly independent from bone marrow contribution. Analyses of colon adenomas indicate that CSF1 may be a key facilitator of macrophage self-renewal. In summary, the tumour microenvironment creates an isolated niche for tissue-resident macrophages that favours macrophage survival and self-renewal.
Asunto(s)
Adenoma/inmunología , Autorrenovación de las Células , Neoplasias del Colon/inmunología , Pólipos del Colon/inmunología , Macrófagos/citología , Nicho de Células Madre , Microambiente Tumoral , Adenoma/genética , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Antígenos de Diferenciación , Supervivencia Celular , Neoplasias del Colon/genética , Pólipos del Colon/genética , Antígenos de Histocompatibilidad Clase II , Factor Estimulante de Colonias de Macrófagos , Ratones , Ratones Noqueados , Ratones Transgénicos , Neoplasias Experimentales , Receptores CCR2/genéticaRESUMEN
DCs are crucial for sensing pathogens and triggering immune response. Upon activation by pathogen-associated molecular pattern (PAMP) ligands, GM-CSF myeloid DCs (GM-DCs) secrete several cytokines, including IL-2. DC IL-2 has been shown to be important for innate and adaptive immune responses; however, IL-2 importance in DC physiology has never been demonstrated. Here, we show that autocrine IL-2 signaling is functional in murine GM-DCs in an early time window after PAMPs stimulation. IL-2 signaling selectively activates the JAK/STAT5 pathway by assembling holo-receptor complexes at the cell surface. Using the sensitivity of targeted mass spectrometry, we show conclusively that GM-DCs express CD122, the IL-2 receptor ß-chain, at steady state. In myeloid DCs, this cytokine pathway inhibits survival of PAMP-matured GM-DCs which is crucial for maintaining immune tolerance and preventing autoimmunity. Our findings suggest that immune regulation by this novel autocrine signaling pathway can potentially be used in DC immunotherapy.