Lung environment determines unique phenotype of alveolar macrophages

Myeloid-derived suppressor cells (MDSCs) are emerging as potential promoters of metastatic tumor growth, and there is interest in targeting immature MDSCs by inducing their differentiation into more mature myeloid cells. We used all-trans retinoic acid (ATRA) to differentiate MDSCs in mice bearing metastatic 4T1 or 4TO7 murine mammary tumors, and assessed the immune-suppressive mechanisms and potencies of different myeloid cell subpopulations. Metastatic mammary tumors induced the accumulation of distinct populations of immature CD11b+Gr1+F4/80−Ly6CmidLy6G+ MDSCs (“Gr1+ cells”) and mature CD11b+Gr1−F4/80+ cells (“F4/80+ cells”) in metastatic target organs. ATRA triggered the differentiation of Gr1+ cells into F4/80+ cells in the lungs and, unexpectedly, enhanced pulmonary metastatic tumor growth. We found that F4/80+Ly6C−Ly6G− mature macrophages (Mϕs) were up to 30-fold more potent immune suppressors than Gr1+ cells on a per-cell basis, which we postulate may contribute to the increased metastatic growth observed with ATRA treatment. F4/80+ cells and Gr1+ cells used different reactive oxygen species (ROS)–mediated mechanisms of immunosuppression ex vivo, with F4/80+ cells producing higher levels of ROS, which is consistent with their superior immunosuppressive abilities. These data highlight the potent immunosuppressive functions of Mϕs, reveal that Mϕs can suppress T cell responses via ROS production, and suggest that ROS inhibitors may be useful in promoting antitumor immune responses. Our findings also caution against using ATRA to modulate myeloid cell differentiation and function to treat breast cancer metastases in the lung, and support the development of therapeutic strategies to enhance antitumor immunity by targeting myeloid cells as a collective group.

Section: Gr1mentioning

confidence: 99%

Macrophages Are More Potent Immune Suppressors Ex Vivo Than Immature Myeloid-Derived Suppressor Cells Induced by Metastatic Murine Mammary Carcinomas

Hamilton

Bosiljcic

LePard

et al. 2014

“…For the HA inhibition (HI) assay, the serum was treated as follows: serum, saline, and the KIO 4 solution (0.025 M) were mixed in a 1:1:1 volume. After a 2-h incubation at 37˚C to destroy any nonspecific inhibitors, a 5% glucose solution (2-fold volume for serum) was added to remove excess KIO 4 , making a final 1:5 dilution of the obtained serum. A fixed amount of influenza virus (2 HA) in 50 ml was added to every well of a 96-well plate, and a dilution series (1:5, 1:10, and 1:20) of K. pneumoniae antiserum in 50 ml was added.…”

Section: Ha Inhibition Assaymentioning

confidence: 99%

“…Therefore, the immune response generated against one pathogen will inevitably influence the immune response to another (1)(2)(3). For example, this often occurs in the immune responses against pathogens in the respiratory tract, which contains many inhaled Ags, including allergens, infectious agents, and particulate debris (4).…”

mentioning

confidence: 99%

Klebsiella pneumoniaeAlleviates Influenza-Induced Acute Lung Injury via Limiting NK Cell Expansion

Wang

Sun

et al. 2014

A protective effect induced by bacterial preinfection upon a subsequent lethal influenza virus infection has been observed, but the underlying immune mechanisms have not yet been fully elucidated. In this study, we used a mouse model of Klebsiella pneumoniae preinfection to gain insight into how bacterial preinfection influences the subsequent lethal influenza virus infection. We found that K. pneumoniae preinfection significantly attenuated lung immune injury and decreased mortality during influenza virus infection, but K. pneumoniae–specific immunity was not involved in this cross-protection against influenza virus. K. pneumoniae preinfection limited NK cell expansion, which was involved in influenza-induced immune injury and death. Furthermore, K. pneumoniae preinfection could not control NK cell expansion and death during influenza virus infection in Rag1−/− mice, but adoptive transfer of T cells from wild-type mice was able to restore this protective effect. Our data suggest that the adaptive immune response activated by bacterial infection limits the excessive innate immune response induced by a subsequent influenza infection, ultimately protecting mice from death.

“…This GM-CSF-derived p1 macrophage population most closely resembles alveolar macrophages, which are known to be CD11c + , bind HA, can self-renew (11,41,50), and depend on GM-CSF for their differentiation (45). Despite the p1 cells arising from GM-CSF cultured bone marrow cells, they are, like the alveolar macrophages, positive for CD200R and CD206, two markers associated with alternatively activated macrophages.…”

Section: Discussionmentioning

confidence: 91%

Hyaluronan Binding Identifies a Functionally Distinct Alveolar Macrophage–like Population in Bone Marrow–Derived Dendritic Cell Cultures

Poon

Dong

Marshall

et al. 2015

Although classical dendritic cells (DCs) arise from distinct progenitors in the bone marrow, the origin of inflammatory DCs and the distinction between monocyte-derived DCs and macrophages is less clear. In vitro culture of mouse bone marrow cells with GM-CSF is a well-established method to generate DCs, but GM-CSF has also been used to generate bone marrow–derived macrophages. In this article, we identify a distinct subpopulation of cells within the GM-CSF bone marrow–derived DC culture based on their ability to bind hyaluronan (HA), a major component of the extracellular matrix and ligand for CD44. HA identified a morphologically distinct subpopulation of cells within the immature DC population (CD11c+ MHC IImid/low) that were CCR5+/CCR7− and proliferated in response to GM-CSF, but, unlike immature DCs, did not develop into mature DCs expressing CCR7 and high levels of MHC II, even after stimulation with LPS. The majority of these cells produced TNF-α in response to LPS but were unable to activate naive T cells, whereas the majority of mature DCs produced IL-12 and activated naive T cells. This HA binding population shared many characteristics with alveolar macrophages and was retained in the alveolar space after lung instillation even after LPS stimulation, whereas the MHC IIhigh mature DCs were found in the draining lymph node. Thus, HA binding in combination with MHC II expression can be used to identify alveolar-like macrophages from GM-CSF–treated bone marrow cultures, which provides a useful in vitro model to study alveolar macrophages.