RESUMO
Macrophages are involved in tissue homeostasis and are critical for innate immune responses, yet distinct macrophage populations in different tissues exhibit diverse gene expression patterns and biological processes. While tissue-specific macrophage epigenomic and transcriptomic profiles have been reported, proteomes of different macrophage populations remain poorly characterized. Here we use mass spectrometry and bulk RNA sequencing to assess the proteomic and transcriptomic patterns, respectively, of 10 primary macrophage populations from seven mouse tissues, bone marrow-derived macrophages and the cell line RAW264.7. The results show distinct proteomic landscape and protein copy numbers between tissue-resident and recruited macrophages. Construction of a hierarchical regulatory network finds cell-type-specific transcription factors of macrophages serving as hubs for denoting tissue and functional identity of individual macrophage subsets. Finally, Il18 is validated to be essential in distinguishing molecular signatures and cellular function features between tissue-resident and recruited macrophages in the lung and liver. In summary, these deposited datasets and our open proteome server ( http://macrophage.mouseprotein.cn ) integrating all information will provide a valuable resource for future functional and mechanistic studies of mouse macrophages.
Assuntos
Proteômica , Transcriptoma , Camundongos , Animais , Macrófagos , Proteoma , Contagem de LeucócitosRESUMO
Inflammasomes and their product interleukin 18 (IL-18) play important roles in gut microbiota monitoring and homeostasis, and their loss of function could lead to microbiota dysbiosis and accelerate disease progression. However, the impacts of the resulting microbiota dysbiosis on the mucosal immune system are largely unknown. Here, we show that dysbiotic microbiota from Il18-/- mice induced immune cell loss in the small intestine (SI) in an inflammasome-independent manner. Cohousing experiments revealed that the immunotoxic phenotype of these microbiota was transferable to wild type (WT) mice and induced immune cell death through the receptor-interacting protein kinase 3 (RIP3)-mixed lineage kinase domain like pseudokinase (MLKL) pathway. Analysis of microbiota composition identified two types of bacteria at the genus level, Ureaplasma and Parasutterella, that accumulated in Il18-/- mice and negatively mediated changes in immune cells in the SI. Furthermore, dysbiosis in Il18-/- mice also contributed to increased susceptibility to Listeria infection. Collectively, our results demonstrate that IL-18 is essential to microbiota homeostasis and that dysbiotic microbiota could significantly shape the landscape of the immune system.
Assuntos
Interleucina-18 , Microbiota , Camundongos , Animais , Interleucina-18/metabolismo , Inflamassomos/metabolismo , Disbiose , Mucosa Intestinal , HomeostaseRESUMO
Much attention has focused on commensal bacteria in health and disease, but the role of commensal viruses is understudied. Although metagenomic analysis shows that the intestine of healthy humans and animals harbors various commensal viruses and the dysbiosis of these viruses can be associated with inflammatory diseases, there is still a lack of causal data and underlying mechanisms to understand the physiological role of commensal viruses in intestinal homeostasis. In the present study, we show that commensal viruses are essential for the homeostasis of intestinal intraepithelial lymphocytes (IELs). Mechanistically, the cytosolic viral RNA-sensing receptor RIG-I in antigen-presenting cells can recognize commensal viruses and maintain IELs via a type I interferon-independent, but MAVS-IRF1-IL-15 axis-dependent, manner. The recovery of IELs by interleukin-15 administration reverses the susceptibility of commensal virus-depleted mice to dextran sulfate sodium-induced colitis. Collectively, our results indicate that commensal viruses maintain the IELs and consequently sustain intestinal homeostasis via noncanonical RIG-I signaling.