Fetal origin confers radioresistance on liver macrophages via p21

Soysa, Radika; Lampert, Sarah; Yuen, Sebastian; Douglass, Alyse N.; Li, Wanyu; Pfeffer, Klaus

doi:10.1016/j.jhep.2019.04.015

Cited by 32 publications

(29 citation statements)

References 42 publications

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“…A much less-severe, CD40 agonist-dependent, inflammation was, however, still observed in livers of WT mice reconstituted with CD40-deficient BM. This may be explained by anti-CD40 activity on liver stromal, or radioresistant immune populations that persist in WT mice following CD40 −/− BM reconstitution, 21 and that immunemediated damage is exacerbated by CD40 expressing BM-derived cells.…”

Section: Discussionmentioning

confidence: 99%

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

Bonnans

Thomas

et al. 2020

J Immunother Cancer

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BackgroundCD40 is a compelling target for cancer immunotherapy, however, attempts to successfully target this pathway have consistently been hampered by dose-limiting toxicity issues in the clinic that prevents the administration of efficacious doses.MethodsHere, using cytokine and cytokine receptor depletion strategies in conjunction with a potent CD40 agonist, we investigated mechanisms underlying the two primary sources of CD40 agonist-associated toxicity, hepatotoxicity and cytokine release syndrome (CRS).ResultsWe demonstrate that CD40 agonist -induced hepatotoxicity and CRS are mechanistically independent. Historical data have supported a role for interleukin-6 (IL-6) in CRS-associated wasting, however, our findings instead show that an inflammatory cytokine network involving TNF, IL-12p40, and IFNγ underlie this process. Deficiency of TNF or IFNγ did not influence CD40-induced hepatitis however loss of IL-12p40 significantly decreased circulating concentrations of liver enzymes and reduced the frequency of activated CD14+MHCII+myeloid cells in the liver, indicating a role for IL-12p40 in liver pathology.ConclusionsAs clinical research programs aim to circumnavigate toxicity concerns while maintaining antitumor efficacy it will be essential to understand which features of CD40 biology mediate antitumor function to develop both safe and efficacious agonists.

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Section: Discussionmentioning

confidence: 99%

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

Bonnans

Thomas

et al. 2020

J Immunother Cancer

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“…Interestingly, it has been very recently shown that a subset of the embryonically-derived KCs resists to lethal irradiation, through cdkn1a upregulation. This radio-resistance property is lost when native KCs are replaced by their monocyte-derived counterparts, showing clearly that ontogeny contribute to macrophage functional heterogeneity (44). Others have also successfully used the mass cytometry to analyze liver macrophages and notably described two subsets of KCs different from infiltrating monocytes (13).…”

Section: New Approaches To Improve Our Understanding Of Liver Macrophmentioning

confidence: 99%

Understanding the Heterogeneity of Resident Liver Macrophages

Blériot

Ginhoux

2019

Front. Immunol.

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Resident tissue macrophages (RTMs) are cells with a high functional plasticity assuming pleiotropic roles in their tissue of residence, from clearance of dead cells and metabolic sensing in steady state to cytokine production and tissue repair during inflammation. The liver has long been considered as only populated by Kupffer cells (KCs), a macrophage population assumed to be in charge of all of these functions. However, we know now that KCs are not the only macrophage population in the liver, that recently was shown to contain also capsular macrophages, monocyte-derived macrophages as well as recruited peritoneal macrophages inherited from previous inflammatory events. These macrophages exhibit different origins, time of establishing residence and locations in the liver, with both ontogenical and environmental factors shaping their identity and functions. Furthermore, liver macrophages reside in a complex environment with a pronounced metabolic zonation. Here, we briefly discuss how these intrinsic and extrinsic factors influence macrophage biology and liver physiology in general. We notably focus on how the recent advances of single cell transcriptomic approaches are changing our understanding of liver macrophages and diseases.

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“…For the subsequent intracellular staining analysis ( 6 ), cell pellets were resuspended with 250 μl of BD cytofix/Cytoperm (BD Bioscience, cat # 554722) at 4°C. Cells were pelleted with 500 × g for 7 min at 4°C and were washed twice with 1.0 ml of BD Perm/Wash buffer (BD Bioscience, cat # 554723).…”

Section: Methodsmentioning

confidence: 99%

“…Multiple, independent lines of evidence suggest that there are two populations of macrophages in the mouse and in the human liver, as well as other tissues. In mice, these populations are distinguished by their transcriptome (1)(2)(3), by anatomical location (4) and by origin (5)(6)(7)(8). There is a subset derived from the yolk sac and other early fetal progenitors (9), while other liver macrophages are the differentiation products of peripheral blood monocytes (2,7).…”

Section: Introductionmentioning

confidence: 99%

Human Liver Macrophage Subsets Defined by CD32

Hollingshead

Roberto

et al. 2020

Front. Immunol.

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Human liver myeloid cells are imperfectly defined, but it is broadly agreed that cells of stellate appearance in situ, expressing the markers CD11b and CD68, are the liver's resident macrophages, classically termed Kupffer cells. Recent investigations using single cell RNA sequencing and unsupervised clustering algorithms suggest there are two populations of cells with the characteristics of tissue macrophages in human liver. We therefore analyzed dissociated human liver tissue using the markers CD11b and CD68 to define macrophage-like cells and found within this population two subsets that differ in their expression of multiple surface markers. These subsets were FACS-sorted based on CD32 expression, and gene expression analysis identified them with human liver myeloid cell subsets that were previously defined by two independent single cell RNA sequencing studies. Using qRT-PCR we found that the two subsets differed in the expression of genes associated with T cell activation and immunosuppression, suggesting distinct roles in T cell tolerance. In addition, one subset expressed two markers, CD1C and CD11c, more often seen on classical dendritic cells. Criteria used to distinguish macrophages from dendritic cells in other tissues may need to be revised in the human liver.

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Fetal origin confers radioresistance on liver macrophages via p21

Cited by 32 publications

References 42 publications

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

CD40 agonist-induced IL-12p40 potentiates hepatotoxicity

Understanding the Heterogeneity of Resident Liver Macrophages

Human Liver Macrophage Subsets Defined by CD32

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