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Cancer-associated fibroblasts (CAFs) are key actors in modulating the progression of many solid tumors, such as breast cancer (BC). Herein, we identify an integrin [alpha]11/PDGFR[beta]-positive CAF subset displaying tumor-promoting features in BC. In the preclinical MMTV-PyMT mouse model, integrin [alpha]11 deficiency led to a drastic reduction of tumor progression and metastasis. A clear association between integrin [alpha]11 and PDGFR[beta] was found at both transcriptional and histological levels in BC specimens. High stromal integrin [alpha]11/PDGFR[beta] expression was associated with high grades and poorer clinical outcome in human BC patients. Functional assays using 5 CAF subpopulations (1 murine, 4 human) revealed that integrin [alpha]11 promotes CAF invasion and CAF-induced tumor cell invasion upon PDGF-BB stimulation. Mechanistically, the proinvasive activity of integrin [alpha]11 relies on its ability to interact with PDGFR[beta] in a ligand-dependent manner and to promote its downstream JNK activation, leading to the production of tenascin C, a proinvasive matricellular protein. Pharmacological inhibition of PDGFR[beta] and JNK impaired tumor cell invasion induced by integrin [alpha][11.sup.+] CAFs. Collectively, our study uncovers an integrin [alpha][11.sup.+] subset of protumoral CAFs that exploits the PDGFR[beta]/JNK signaling axis to promote tumor invasiveness in BC., Introduction Breast cancer (BC) is the most common type of cancer and the second leading cause of cancer-related death in women worldwide. Despite increasing knowledge of BC biology and huge [...]

The respiratory tract is continuously exposed to both innocuous airborne antigens and immunostimulatory molecules of microbial origin, such as LPS. At low concentrations, airborne LPS can induce a lung DC-driven Th2 cell response to harmless inhaled antigens, thereby promoting allergic asthma. However, only a small fraction of people exposed to environmental LPS develop allergic asthma. What prevents most people from mounting a lung DC-driven Th2 response upon exposure to LPS is not understood. Here we have shown that lung interstitial macrophages (IMs), a cell population with no previously described in vivo function, prevent induction of a Th2 response in mice challenged with LPS and an experimental harmless airborne antigen. IMs, but not alveolar macrophages, were found to produce high levels of IL-10 and to inhibit LPS-induced maturation and migration of DCs loaded with the experimental harmless airborne antigen in an IL-10-dependent manner. We further demonstrated that specific in vivo elimination of IMs led to overt asthmatic reactions to innocuous airborne antigens inhaled with low doses of LPS. This study has revealed a crucial role for IMs in maintaining immune homeostasis in the respiratory tract and provides an explanation for the paradox that although airborne LPS has the ability to promote the induction of Th2 responses by lung DCs, it does not provoke airway allergy under normal conditions., Introduction Respiratory mucosal surfaces are constantly exposed to a broad range of nonpathogenic environmental antigens. In the absence of proinflammatory signals, inhalation of harmless antigens results in immunological tolerance. Indeed, [...]

Many patients suffering from asthma are not fully controlled by currently available treatments, and some of them display an airway remodeling leading to exaggerated lung function decline. The aim of the present study was to unveil new mediators in asthma to better understand pathophysiology and propose or validate new potential therapeutic targets. A mouse model of asthma mimicking acute or chronic asthma disease was used to select genes undergoing a modulation in both acute and chronic conditions. Mice were exposed to ovalbumin or PBS for 1, 5, and 10 wk [short-, intermediate-, and long-term model (ST, IT, and LT)], and gene expression in the lung was studied using an Affymetrix 430 2.0 genome-wide microarray and further confirmed by RT-PCR and immunohistochemistry for selected targets. We report that 598, 1,406, and 117 genes were upregulated and 490, 153, 321 downregulated at ST, IT, and LT, respectively. Genes related to mucous secretion displayed a progressively amplified expression during the allergen exposure protocol, whereas genes corresponding to growth and differentiation factors, matrix metalloproteinases, and collagens were mainly upregulated at IT. By contrast, genes related to cell division were upregulated at ST and IT and were downregulated at LT. In this study, besides confirming that Arg1, Slc26a4, Ear11, and Mmpl2 genes are highly modulated throughout the asthma pathology, we show for the first time that Agr2, Scin, and Cd209e genes are overexpressed throughout the allergen exposure and might therefore be considered as suitable new potential targets for the treatment of asthma. microarray; ovalbumin-induced asthma; airway inflammation; remodeling

Gammaherpesviruses (γHVs) have coevolved with their host, leading to a remarkably high infection prevalence and establishment of latency. The lifelong persistence of γHVs in hosts appears to broadly shape host immunity, and we show here that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse γHV, drives the recruitment of Ly6Chi monocytes (MOs) into the airway, thereby modulating the host immune response. The absence of Ly6Chi MOs is associated with severe virus-induced immunopathology and the systemic release of inflammatory mediators. Mechanistically, MuHV-4–imprinted MOs recruit CD4 T cells to the airways and trigger immunosuppressive signaling pathways through the PD-L1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi MOs in modulating CD4 T cell functions and reveal pathways that could be targeted therapeutically to reduce detrimental immunopathological responses associated with respiratory viral infections. Monocyte mediator: Gammaherpesviruses (γHVs) coevolved with their hosts in a manner that allows for the lifelong persistence of these viruses in immunocompetent individuals. The presence of latent γHVs in host organisms has been shown to shape adaptive immunity, and here, Maquet et al. observed that pulmonary infection of mice with a murine γHV (MuHV-4) leads to recruitment of Ly6Chi monocytes (MOs) to airways. These γHV-imprinted Ly6Chi MOs recruit CD4 T cells to airways followed by engagement of the immunosuppressive PD-1/PD-L1 signaling pathway, which limits pathological cytotoxic CD4 T cell responses. These findings highlight a role for γHV-imprinted Ly6Chi MOs in shaping CD4 T cell functions and suggest a potential pathway for the development of therapeutics that target respiratory viral infections. [ABSTRACT FROM AUTHOR]