Lacteals are lymphatic vessels located at the center of each intestinal villus and provide essential transport routes for lipids and other lipophilic molecules. However, it is unclear how absorbed molecules are transported through the lacteal. Here, we used reporter mice that express GFP under the control of the lymphatic-specific promoter
Kibaek Choe, Jeon Yeob Jang, Intae Park, Yeseul Kim, Soyeon Ahn, Dae-Young Park, Young-Kwon Hong, Kari Alitalo, Gou Young Koh, Pilhan Kim
Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis that is associated with granulomatous inflammation and the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). We previously determined that PR3 on the surface of apoptotic neutrophils interferes with induction of antiinflammatory mechanisms following phagocytosis of these cells by macrophages. Here, we demonstrate that enzymatically active membrane-associated PR3 on apoptotic cells triggered secretion of inflammatory cytokines, including granulocyte CSF (G-CSF) and chemokines. This response required the IL-1R1/MyD88 signaling pathway and was dependent on the synthesis of NO, as macrophages from animals lacking these pathways did not exhibit a PR3-associated proinflammatory response. The PR3-induced microenvironment facilitated recruitment of inflammatory cells, such as macrophages, plasmacytoid DCs (pDCs), and neutrophils, which were observed in close proximity within granulomatous lesions in the lungs of GPA patients. In different murine models of apoptotic cell injection, the PR3-induced microenvironment instructed pDC-driven Th9/Th2 cell generation. Concomitant injection of anti-PR3 ANCAs with PR3-expressing apoptotic cells induced a Th17 response, revealing a GPA-specific mechanism of immune polarization. Accordingly, circulating CD4+ T cells from GPA patients had a skewed distribution of Th9/Th2/Th17. These results reveal that PR3 disrupts immune silencing associated with clearance of apoptotic neutrophils and provide insight into how PR3 and PR3-targeting ANCAs promote GPA pathophysiology.
Arnaud Millet, Katherine R. Martin, Francis Bonnefoy, Philippe Saas, Julie Mocek, Manal Alkan, Benjamin Terrier, Anja Kerstein, Nicola Tamassia, Senthil Kumaran Satyanarayanan, Amiram Ariel, Jean-Antoine Ribeil, Loïc Guillevin, Marco A. Cassatella, Antje Mueller, Nathalie Thieblemont, Peter Lamprecht, Luc Mouthon, Sylvain Perruche, Véronique Witko-Sarsat
Calcium/calcineurin signaling is critical for normal cellular physiology. Abnormalities in this pathway cause many diseases, including podocytopathy; therefore, understanding the mechanisms that underlie the regulation of calcium/calcineurin signaling is essential. Here, we showed that critical components of calcium/calcineurin signaling, including
Junnan Wu, Chunxia Zheng, Xiao Wang, Shifeng Yun, Yue Zhao, Lin Liu, Yuqiu Lu, Yuting Ye, Xiaodong Zhu, Changming Zhang, Shaolin Shi, Zhihong Liu
Polarized activation of adipose tissue macrophages (ATMs) is crucial for maintaining adipose tissue function and mediating obesity-associated cardiovascular risk and metabolic abnormalities; however, the regulatory network of this key process is not well defined. Here, we identified a PPARγ/microRNA-223 (miR-223) regulatory axis that controls macrophage polarization by targeting distinct downstream genes to shift the cellular response to various stimuli. In BM-derived macrophages, PPARγ directly enhanced miR-223 expression upon exposure to Th2 stimuli. ChIP analysis, followed by enhancer reporter assays, revealed that this effect was mediated by PPARγ binding 3 PPARγ regulatory elements (PPREs) upstream of the pre–miR-223 coding region. Moreover, deletion of miR-223 impaired PPARγ-dependent macrophage alternative activation in cells cultured ex vivo and in mice fed a high-fat diet. We identified
Wei Ying, Alexander Tseng, Richard Cheng-An Chang, Andrew Morin, Tyler Brehm, Karen Triff, Vijayalekshmi Nair, Guoqing Zhuang, Hui Song, Srikanth Kanameni, Haiqing Wang, Michael C. Golding, Fuller W. Bazer, Robert S. Chapkin, Stephen Safe, Beiyan Zhou
Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.
Zhan-Peng Huang, Masaharu Kataoka, Jinghai Chen, Gengze Wu, Jian Ding, Mao Nie, Zhiqiang Lin, Jianming Liu, Xiaoyun Hu, Lixin Ma, Bin Zhou, Hiroko Wakimoto, Chunyu Zeng, Jan Kyselovic, Zhong-Liang Deng, Christine E. Seidman, J.G. Seidman, William T. Pu, Da-Zhi Wang
IgG molecules exert both pro- and antiinflammatory effector functions based on the composition of the fragment crystallizable (Fc) domain glycan. Sialylated IgG Fc domains have antiinflammatory properties that are attributed to their ability to increase the activation threshold of innate effector cells to immune complexes by stimulating the upregulation of the inhibitory Fcγ receptor IIB (FcγRIIB). Here, we report that IgG Fc sialylation of human monoclonal IgG1 molecules impairs their efficacy to induce complement-mediated cytotoxicity (CDC). Fc sialylation of a CD20-targeting antibody had no impact on antibody-dependent cellular cytotoxicity and did not change the affinity of the antibody for activating Fcγ receptors. In contrast, the presence of sialic acid abrogated the increased binding of C1q to Fc-galactosylated IgG1 and resulted in decreased levels of C3b deposition on the cell surface. Similar to monoclonal antibodies, sialic acid inhibited the increased C1q binding to galactosylated Fc fragments in human polyclonal IgG. In sera derived from patients with chronic inflammatory demyelinating polyneuropathy, an autoimmune disease of the peripheral nervous system in which humoral immune responses mediate tissue damage, induction of IgG Fc sialylation was associated with clinical disease remission. Thus, impairment of CDC represents an FcγR-independent mechanism by which Fc-sialylated glycovariants might limit proinflammatory IgG effector functions.
Isaak Quast, Christian W. Keller, Michael A. Maurer, John P. Giddens, Björn Tackenberg, Lai-Xi Wang, Christian Münz, Falk Nimmerjahn, Marinos C. Dalakas, Jan D. Lünemann
This month’s cover image shows insulin staining (brown) of pancreatic islets in a mouse model of type 1 diabetes (T1D) after treatment with a hyaluronan synthase inhibitor. On page 3928, Nagy et al. report that hyaluronan deposits promote islet-destructive insulitis by impairing the differentiation of Tregs and suggest that targeting this pathway could potentially be used to prevent T1D progression.
JCI This Month is a digest of the research, reviews, and other features published each month.
In the mid-1800s, Rudolf Virchow noted the presence of surfeit inflammatory cells in many tumors. Roughly 50 years later, Paul Ehrlich postulated that the immune system both recognizes and protects against cancer. Since then, researchers have been trying to elucidate the relationship between cancer, inflammation, and the innate and adaptive immune systems, starting with the theory of immunosurveillance introduced by Lewis Thomas and further developed by Sir MacFarlane Burnet. We now know that tumor cells display antigens that are recognized by immune cells, but that anti-tumor immunity can be circumvented directly by tumor cells themselves via a variety of escape mechanisms. The goal of cancer immunotherapy is to mount an effective anti-tumor immune response by repairing, stimulating or, enhancing the immune system’s response to cancer cells. Reviews in this series detail progress in cancer immunoediting, immunosuppressive cells in the tumor microenvironment, cancer-associated inflammation, therapeutic cancer vaccines, genomic approaches in immunotherapy, adoptive transfer of genetically engineered T cells, and checkpoint blockade therapy.