Publisher Correction: A tumor-myeloid cell axis, mediated via the cytokines IL-1α and TSLP, promotes the progression of breast cancer.

In the version of this article initially published, the far right label along the horizontal axis of the right plot of Fig. 1e (4T1-Tslp-/- 4-6), the middle and right labels along the horizontal axis of the far right plot of Fig. 3d (4T1-Tslpr-/- 4-6 and 4T1-Tslpr-/- 2-3, respectively), and the far right label along the horizontal axis of Fig. 6h (4T1-Tslpr-/- 2-3) were incorrect. The correct labels are as follows: Fig. 1e, 4T1-Tslpr-/- 4-6; Fig. 3d, 4T1-Tslp-/- 2-3 and 4T1-Tslpr-/- 4-6, respectively; and Fig. 6h, 4T1-Tslpr-/- 4-6. Also, Fig. 4e was incorrectly a duplicate of an adjacent panel. The errors have been corrected in the HTML and PDF version of the article.

A tumor-myeloid cell axis, mediated via the cytokines IL-1α and TSLP, promotes the progression of breast cancer.

Tumors actively manipulate the immune response through the production of factors that attract immune cells and subsequently alter their ability to recognize and effectively remove the tumor. While this mechanism for evading the immune system is an important aspect of tumor survival, the factors that serve as primary growth factors for the tumor are less understood. Here we demonstrate a previously unknown mechanism by which breast-cancer cells manipulate tumor-infiltrating myeloid cells to maintain their survival. Tumor-derived interleukin 1α (IL-1α), acting on infiltrating myeloid cells, induced the expression of a critical tumor survival factor, the cytokine TSLP. TSLP promoted the survival of the tumor cells through induction of the expression of the anti-apoptotic molecule Bcl-2. TSLP signaling was also required for metastasis to the lungs. These studies define a novel IL-1α-TSLP-mediated crosstalk between tumor-infiltrating myeloid cells and tumor cells in the control of metastatic breast cancer.

Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells.

Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN.

Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia.

To address the requirement for lymphatic capillaries in dendritic cell (DC) mobilization from skin to lymph nodes (LNs), we used mice bearing one inactivated allele of vascular endothelial growth factor receptor 3 (VEGFR3) where skin lymphatic capillaries are reported absent. Unexpectedly, DC mobilization from the back skin to draining LNs was similar in magnitude, and kinetics to control mice and humoral immunity appeared intact. By contrast, DC migration from body extremities, including ear and forepaws, was ablated. An evaluation in different regions of skin revealed rare patches of lymphatic capillaries only in body trunk areas where migration was intact. That is, whereas the ear skin was totally devoid of lymphatic capillaries, residual capillaries in the back skin were present though retained only at ∼10% normal density. This reduction in density markedly reduced the clearance of soluble tracers, indicating that normal cell migration was spared under conditions when lymphatic transport function was poor. Residual lymphatic capillaries expressed slightly higher levels of CCL21 and migration of skin DCs to LNs remained dependent on CCR7 in Chy mice. DC migration from the ear could be rescued by the introduction of a limited number of lymphatic capillaries through skin transplantation. Thus, the development of lymphatic capillaries in the skin of body extremities was more severely impacted by a mutant copy of VEGFR3 than trunk skin, but lymphatic transport function was markedly reduced throughout the skin, demonstrating that even under conditions when a marked loss in lymphatic capillary density reduces lymph transport, DC migration from skin to LNs remains normal.

Impaired humoral immunity and tolerance in K14-VEGFR-3-Ig mice that lack dermal lymphatic drainage.

Lymphatic vessels transport interstitial fluid, soluble Ag, and immune cells from peripheral tissues to lymph nodes (LNs), yet the contribution of peripheral lymphatic drainage to adaptive immunity remains poorly understood. We examined immune responses to dermal vaccination and contact hypersensitivity (CHS) challenge in K14-VEGFR-3-Ig mice, which lack dermal lymphatic capillaries and experience markedly depressed transport of solutes and dendritic cells from the skin to draining LNs. In response to dermal immunization, K14-VEGFR-3-Ig mice produced lower Ab titers. In contrast, although delayed, T cell responses were robust after 21 d, including high levels of Ag-specific CD8+ T cells and production of IFN-γ, IL-4, and IL-10 upon restimulation. T cell-mediated CHS responses were strong in K14-VEGFR-3-Ig mice, but importantly, their ability to induce CHS tolerance in the skin was impaired. In addition, 1-y-old mice displayed multiple signs of autoimmunity. These data suggest that lymphatic drainage plays more important roles in regulating humoral immunity and peripheral tolerance than in effector T cell immunity.

CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability.

Lymphatic collecting vessels direct lymph into and from lymph nodes (LNs) and can become hyperpermeable as the result of a previous infection. Enhanced permeability has been implicated in compromised immunity due to reduced flow of lymph and immune cells to LNs, which are the primary site of antigen presentation to T cells. Presently, very little is known about the molecular signals that affect lymphatic collecting vessel permeability. Here, we have shown that lymphatic collecting vessel permeability is controlled by CCR7 and that the chronic hyperpermeability of collecting vessels observed in Ccr7-/- mice is followed by vessel fibrosis. Reexpression of CCR7 in DCs, however, was sufficient to reverse the development of such fibrosis. IFN regulatory factor 4-positive (IRF4+) DCs constitutively interacted with collecting lymphatics, and selective ablation of this DC subset in Cd11c-Cre Irf4fl/fl mice also rendered lymphatic collecting vessels hyperpermeable and fibrotic. Together, our data reveal that CCR7 plays multifaceted roles in regulating collecting vessel permeability and fibrosis, with one of the key players being IRF4-dependent DCs.

A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation.

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

Lymph-migrating, tissue-derived dendritic cells are minor constituents within steady-state lymph nodes.

Observations that dendritic cells (DCs) constitutively enter afferent lymphatic vessels in many organs and that DCs in some tissues, such as the lung, turnover rapidly in the steady state have led to the concept that a major fraction of lymph node DCs are derived from migratory DCs that enter the lymph node through upstream afferent lymphatic vessels. We used the lysozyme M-Cre reporter mouse strain to assess the relationship of lymph node and nonlymphoid organ DCs. Our findings challenge the idea that a substantial proportion of lymph node DCs derive from the upstream tissue during homeostasis. Instead, our analysis suggests that nonlymphoid organ DCs comprise a major population of DCs within lymph nodes only after introduction of an inflammatory stimulus.