Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jan;2(1):10-9.
doi: 10.1177/1947601911402682.

A Role for PML in Innate Immunity

Andrea Lunardi  1 , Mirella Gaboli, Marco Giorgio, Roberta Rivi, Anne Bygrave, Michael Antoniou, Dubravka Drabek, Elaine Dzierzak, Marta Fagioli, Leonardo Salmena, Marina Botto, Carlos Cordon-Cardo, Lucio Luzzatto, Pier Giuseppe Pelicci, Frank Grosveld, Pier Paolo Pandolfi
Affiliations

A Role for PML in Innate Immunity

Andrea Lunardi et al. Genes Cancer. 2011 Jan.

Abstract

The promyelocytic leukemia gene (PML) of acute promyelocytic leukemia is an established tumor suppressor gene with critical functions in growth suppression, induction of apoptosis, and cellular senescence. Interestingly, although less studied, PML seems to play a key role also in immune response to viral infection. Herein, we report that Pml(-/-) mice spontaneously develop an atypical invasive and lethal granulomatous lesion known as botryomycosis (BTM). In Pml(-/-) mice, BTM is the result of impaired function of macrophages, whereby they fail to become activated and are thus unable to clear pathogenic microorganisms. Accordingly, Pml(-/-) mice are resistant to lipopolysaccharide (LPS)-induced septic shock as a result of an ineffective production of cytokines and chemokines, suggesting a role for PML in the innate immune Toll-like receptor (TLR)/NF-κB prosurvival pathway. These results not only shed light on a new fundamental function of PML in innate immunity, but they also point to a proto-oncogenic role for PML in certain cellular and pathological contexts.

Keywords: PML; botryomycosis; innate immunity.

PubMed Disclaimer

Conflict of interest statement

The author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article.

Figures

Figure 1.
Figure 1.
Spontaneous botryomycosis in Pml −/− mice. Pathological features of spontaneous botryomicosis affecting Pml −/− mutants. (A) Botryomycosis in the salivary gland. The left glandular lobe is almost completely replaced by the lesion; overt hyperplasia of the salivary gland is visible (B, D) and also involves the right lobe as indicated by the arrowheads (B). Magnification of the granulomatous area is shown (C): pink cauliflower-like structure consisting of bacterial and proteinaceous material is surrounded by granulocytes and macrophages but mainly by plasma cells. Plasma cell infiltration also affected organs not directly involved in the infection such as the lung and kidney (not shown). (E) Plasma cell proliferation, as indicated by the arrowheads, massively involves the surrounding lymph nodes. (F) Lipochrome granulation of macrophages surrounding the lesion (arrowheads). These cells were also infiltrating the lymph nodes and the lungs (not shown). (G) Extramedullary hemopoiesis in the liver. The arrowheads indicate islands of hemopoiesis. (H) Extramedullary hemopoiesis in the spleen of infected Pml −/− mice (many megakaryocytes are visible), accompanied by massive splenomegaly (I). (J) Interstitial infiltrates of mononuclear cells in the lung. The arrowheads indicate a thickened alveolar wall. Atelectasis of the lung parenchyma is also visible. This picture is frequently observed in apparently uninfected mice.
Figure 2.
Figure 2.
Aberrant response to infections and impaired macrophage function in Pml −/− mice. (A) Massive abscess and atelectasis due to hyperproliferative infiltration of the lung parenchyma in Pml −/− mice infected intraperitoneally with Staphylococcus aureus. Overt peritonitis in 4 of 8 Pml −/− mice was also observed. In control mice, abscesses were confined to the kidney and heart (not shown). In all infected Pml −/− mice, plasma cells and lipochrome macrophages (arrowheads) infiltrated the spleen and lymph nodes. In 3 cases, these cells completely replaced the red pulp of the spleen as shown (B). (C) Hyperplasia of the salivary gland in Pml −/− mice injected locally with Staphylococcus aureus. At postmortem analysis, the injected lobe of the salivary gland of all the Pml −/− was overtly swollen. The injected salivary gland of a representative Pml −/− mutant is shown on the right (k/o). Note the hyperplasia of the left lobe of the salivary gland itself and the hyperplasia of the surrounding lymph nodes that are fused to the lobe. On the left is an injected salivary gland from a control mouse. In this case, the only noticeable alteration is the fibrosis of the injected lobe. (D) Pml −/− mice show impaired response to Listeria monocytogenes infections. The number of Listeria colonies from the spleen of the first of 3 consecutive experiments performed with 4 Pml −/− and 4 wild-type animals is shown. The value obtained from one Pml −/− mutant, which in this experiment spontaneously died at day 5, is indicated by the crossed circle. The 2 mean values from the 2 groups are presented by the dashed open circles. The values obtained from the liver in 2 groups were comparable to the value obtained for the spleen (not shown). Two additional experiments on 8 Pml −/− and 8 wild-type mice, repeated using the same experimental conditions, showed virtually identical results (not shown). The mean values in the 3 experiments showed at least a 100-fold difference between the 2 groups. (E) Nitric oxide production by the Pml −/− macrophages. Resident untreated macrophages were collected from both wild-type and Pml −/− mice and cultured with or without 1,000 U/mL IFNγ, 100 ng/mL LPS, or both IFNγ and LPS for 48 hours. NO2 concentration in the medium was measured with Griess reagent. The experiment shown represents triplicate measurements from the macrophage of 2 Pml −/− and 2 wild-type mice. Three independent experiments showed similar results. (F-I) Defective activation in Pml −/− macrophages is shown (F). Wild-type macrophage upon exposure to Listeria. The plasma membrane is convoluted with pronounced ruffling. The cytoplasm is large and contains numerous lysosomes as indicated by the arrowheads. (G) Pml −/− macrophages upon exposure to Listeria. The plasma membrane is smoother, and the cytoplasm is smaller with few or no lysosomes. (H) Phagocytosing wild-type macrophage. Phagolysosomes with phagocytosed Listeria and fusing lysosomes are clearly visible. The arrowheads indicate lysosomes ready to fuse to the endosome. The asterisk indicates a phagocytosed bacterium, and the open circle indicates a bacterium already partially digested. (I) Phagocytosing Pml −/− macrophage. Phagocytosed bacteria are in vacuoles (see asterisks), but no lysosomes are ready to fuse to them, nor does the macrophage seem to be activated. Magnifications are as follows: 4.400x (F, G) and 10.400x (H, I).
Figure 3.
Figure 3.
Impaired IL6 production in Pml −/− MEFs. Secreted IL6 was measured in the medium by ELISA and is expressed relative to total protein content of incubated MEFs. Five independent experiments showed a statistically significant 2-fold decrease of IL6 protein secretion from Pml −/− versus wild-type MEFs after LPS treatment. The mean values are presented by the solid lines ± standard deviation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bernardi R, Papa A, Pandolfi PP. Regulation of apoptosis by PML and the PML-NBs. Oncogene. 2008;27:6299-312 - PubMed
    1. Salomoni P, Pandolfi PP. The role of PML in tumor suppression. Cell. 2002;108:165-70 - PubMed
    1. Lin HK, Bergmann S, Pandolfi PP. Cytoplasmic PML function in TGF-beta signalling. Nature. 2004;431:205-11 - PubMed
    1. Bernardi R, Pandolfi PP. Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol. 2007;8:1006-16 - PubMed
    1. Shen TH, Lin HK, Scaglioni PP, Yung TM, Pandolfi PP. The mechanisms of PML-nuclear body formation. Mol Cell. 2006;24:331-9 - PMC - PubMed