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Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis.

ABSTRACT: The fundamental mechanism how heterogeneous hepatic macrophage (M?) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9(+) inflammatory M?s play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9(+)M?s, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident M?s. First, irradiated mice developed less liver injury with less M?s accumulation by Concanavalin A (Con A) regardless of liver shielding. In mice receiving further BM transplantation, CD11b(low)F4/80(high) hepatic-resident M?s were not replaced by transplanted donors under steady state, while under inflammatory state by Con A, CCR9(+)M?s were firmly replaced by donors, indicating that CCR9(+)M?s originate from BM, but not from hepatic-resident cells. Regarding the mechanism of differentiation and proliferation, EdU(+)CCR9(+)M?s with a proliferative potential were detected specifically in the inflamed liver, and in vitro study revealed that BM-derived CD11b(+) cells co-cultured with hepatic stellate cells (HSCs) or stimulated with retinoic acids could acquire CCR9 with antigen-presenting ability. Collectively, our study demonstrates that inflammatory M?s originate from BM and became locally differentiated and proliferated by interaction with HSCs via CCR9 axis during acute liver injury.

SUBMITTER: Amiya T

PROVIDER: S-EPMC5057133 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis.

Amiya Takeru T Nakamoto Nobuhiro N Chu Po-Sung PS Teratani Toshiaki T Nakajima Hideaki H Fukuchi Yumi Y Taniki Nobuhito N Yamaguchi Akihiro A Shiba Shunsuke S Miyake Rei R Katayama Tadashi T Ebinuma Hirotoshi H Kanai Takanori T

Scientific reports 20161011

The fundamental mechanism how heterogeneous hepatic macrophage (Mφ) subsets fulfill diverse functions in health and disease has not been elucidated. We recently reported that CCR9<sup>+</sup> inflammatory Mφs play a critical role in the course of acute liver injury. To clarify the origin and differentiation of CCR9<sup>+</sup>Mφs, we used a unique partial bone marrow (BM) chimera model with liver shielding for maintaining hepatic resident Mφs. First, irradiated mice developed less liver injury w ...[more]

PMID: 27725760

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Project description:BackgroundChronic obstructive pulmonary disease (COPD) is an inflammatory airway disease characterized by emphysema and chronic bronchitis and a leading cause of mortality worldwide. COPD is commonly associated with several comorbid diseases which contribute to exacerbated patient outcomes. Cigarette smoke (CS) is the most prominent risk factor for COPD development and progression and is known to be detrimental to numerous effector functions of lung resident immune cells, including phagocytosis and cytokine production. However, how CS mediates the various pathologies distant from the lung in COPD, and whether CS has a similar biological effect on systemic immune cells remains unknown.MethodsC57BL/6 mice were exposed to 8 weeks of CS as an experimental model of COPD. Bone marrow cells were isolated from both CS-exposed and room air (RA) control mice and differentiated to bone marrow-derived macrophages (BMDMs). Airspace macrophages (AMs) were isolated from the same CS-exposed and RA mice and bulk RNA-Seq performed. The functional role of differentially expressed genes was assessed through gene ontology analyses. Ingenuity Pathway Analysis was used to determine the activation states of canonical pathways and upstream regulators enriched in differentially expressed genes in both cell types, and to compare the differences between the two cell types.ResultsCS induced transcriptomic changes in BMDMs, including an upregulation of genes in sirtuin signalling and oxidative phosphorylation pathways and a downregulation of genes involved in histone and lysine methylation. In contrast, CS induced decreased expression of genes involved in pathogen response, phagosome formation, and immune cell trafficking in AMs. Little overlap was observed in differentially expressed protein-coding genes in BMDMs compared to AMs and their associated pathways, highlighting the distinct effects of CS on immune cells in different compartments.ConclusionsCS exposure can induce transcriptomic remodelling in BMDMs which is distinct to that of AMs. Our study highlights the ability of CS exposure to affect immune cell populations distal to the lung and warrants further investigation into the functional effects of these changes and the ensuing role in driving multimorbid disease.

Dataset Information

Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis.

Publications

Bone marrow-derived macrophages distinct from tissue-resident macrophages play a pivotal role in Concanavalin A-induced murine liver injury via CCR9 axis.

Similar Datasets

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