Inflammation
Abstract
Authors
James G. Krueger, Mrinal K. Sarkar, Mark G. Lebwohl, Akimichi Morita, Kenneth Gordon, Rachael Bogle, Christopher Cole, Anthony Coon, Richard G. Langley, Richard B. Warren, Arash Mostaghimi, Bruce Strober, A. David Burden, Min Zheng, Aaron R. Mangold, Milan J. Anadkat, Jonathan N. Barker, Joseph F. Merola, Lam C. Tsoi, Ming Tang, Kolja Becker, Denis Delic, Christian Thoma, Johann E. Gudjonsson
Abstract
Pro-inflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the anti-inflammatory adenoviral RIDα/β protein complex in a cell type-specific manner. Suppression of adipocyte inflammation (“RIDad mice”) in a mammary tumor model driven by MMTV-PyMT (“PyMT-RIDad mice”) led to an elevated number of tumor-associated macrophages (TAMs) and upregulation of immunoregulatory molecules in the mammary fat pad (MFP). This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (“RIDMMTV mice”) decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.
Authors
Dae-Seok Kim, Toshiharu Onodera, Jan-Bernd Funcke, Kyounghee Min, Qingzhang Zhu, Qian Lin, Shiuhwei Chen, Chanmin Joung, Min Kim, R. Max Wynn, Joselin Velasco, Charlotte Lee, Megan Virostek, Chao Li, Philipp E. Scherer
Abstract
The mechanism of neutrophilic and mixed neutrophilic-eosinophilic asthma is poorly understood. We found that extracellular DNA and nucleosomes (Nuc) were elevated in the airways from neutrophilic-eosinophilic asthma patients and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma expressed increased DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when co- administered with the allergen Alternaria (Alt). Nuc alone induced anti-inflammatory/defensive genes whereas the Nuc-Alt combo increased TNF and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingf/f, IL7RCre:Rorαf/f and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc-induction of anti-inflammatory genes, facilitated Nuc uptake, induced ILC2s, which, in presence of Nuc, produced high levels of TNFα and promoted neutrophilic infiltration. We established a paradigm where allergens inhibit the anti-inflammatory effects of DNA/Nuc and facilitate STING-TNFα-driven neutrophilic-eosinophilic inflammation in asthma.
Authors
Anand Sripada, Divya Verma, Rangati Varma, Kapil Sirohi, Carolyn Kwiat, Mohini Pathria, Mukesh Verma, Anita Sahu, Vamsi P. Guntur, Laurie A. Manka, Brian Vestal, Camille M. Moore, Richard J. Martin, Magdalena M. Gorska, John Cambier, Andrew Getahun, Rafeul Alam
Abstract
Gestational hypertension (GH) is prevalent, with life-long health burdens for mothers and their children exposed in utero. We analyzed the nation-wide Epic Cosmos dataset and found significantly higher rates of seizures in children of mothers with GH than in children of normotensive mothers. Complementary studies of nested Iowa and Stanford cohorts and a large Taiwanese cohort also revealed significantly increased seizure risk after covariate adjustments. We modeled this association in an angiotensin (ANG) II mouse model of GH. Maternal ANG II significantly increased seizure grade and deaths elicited by pilocarpine among male but not female offspring. Electrical stimulation increased seizure grade and death across sexes in offspring from ANG II–treated dams. Proinflammatory and microglial gene expression in the brain were upregulated only in male offspring from ANG II–treated dams. Chronic phenylephrine, a GH model lacking the maternal proinflammatory aspects of ANG II, induced similar offspring seizure phenotypes. PLX5622-induced depletion of microglia or antiinflammatory pentoxifylline abolished this sensitized seizure response and lowered mortality in the ANG II model. These results suggest that GH programs offspring risk for seizures in a sex-dependent manner in humans and mice. Neuroinflammatory mechanisms may contribute to the elevated sensitivity and mortality from seizures elicited by GH exposure in utero.
Authors
Baojian Xue, Serena B. Gumusoglu, Grant Tiarks, Brittany P. Todd, Angela Wong, Donna A. Santillan, Chin-Chi Kuo, Hsiu-Yin Chiang, Rohith Ravindranath, Sophia Y. Wang, Vinit B. Mahajan, Alan Kim Johnson, Heath A. Davis, Polly Ferguson, Elizabeth A. Newell, Mark K. Santillan, Jason M. Misurac, Alexander G. Bassuk
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease characterized by impaired fibroblast clearance and excessive extracellular matrix (ECM) protein production. Wilms' Tumor 1 (WT1), a transcription factor, is selectively upregulated in IPF fibroblasts. However, the mechanisms by which WT1 contributes to fibroblast accumulation and ECM production remain unknown. Here, we investigated the heterogeneity of WT1-expressing mesenchymal cells using single-nucleus RNA sequencing of distal lung tissues from IPF patients and control donors. WT1 was selectively upregulated in a subset of IPF fibroblasts that co-expressed several pro-survival and ECM genes. The results of both loss-of-function and gain-of-function studies are consistent with a role for WT1 as a positive regulator of pro-survival genes to impair apoptotic clearance and promote ECM production. Fibroblast-specific overexpression of WT1 augmented fibroproliferation, myofibroblast accumulation, and ECM production during bleomycin-induced pulmonary fibrosis in young and aged mice. Together, these findings suggest that targeting WT1 is a promising strategy for attenuating fibroblast expansion and ECM production during fibrogenesis.
Authors
Harshavardhana H. Ediga, Chanukya P. Vemulapalli, Vishwaraj Sontake, Pradeep K. Patel, Hikaru Miyazaki, Dimitry Popov, Martin B. Jensen, Anil G. Jegga, Steven K. Huang, Christoph Englert, Andreas Schedl, Nishant Gupta, Francis X. McCormack, Satish K. Madala
Abstract
Despite effective antiretroviral therapy (ART), transcriptionally competent HIV-1 reservoirs persist and contribute to persistent immune activation in people living with HIV (PWH). HIV-1-infected macrophages are important mediators of chronic innate immune activation, though mechanisms remain unclear. We previously reported that nuclear export and cytoplasmic expression of HIV-1 intron-containing RNA (icRNA) activates mitochondrial antiviral signaling protein (MAVS)-mediated type I interferon (IFN) responses in macrophages. In this study, we demonstrate an essential role of melanoma differentiation-associated protein 5 (MDA5) in sensing HIV-1 icRNA and promoting MAVS-dependent IRF5 activation in macrophages. Suppression of MDA5, but not RIG-I expression nor disruption of endosomal TLR pathway, abrogated HIV-1 icRNA-induced type I IFN responses and IP-10 expression in macrophages. Furthermore, induction of IP-10 in macrophages upon HIV-1 icRNA sensing by MDA5 was dependent on IRF5. Additionally, monocytes and MDMs from older (>50 years) individuals exhibit constitutively higher levels of IRF5 expression compared to younger (<35 years) individuals, and HIV-1 icRNA induced IP-10 expression was significantly enhanced in older macrophages, which was attenuated upon ablation of IRF5 expression suggesting that IRF5 functions as a major mediator of pro-inflammatory response downstream of MDA5-dependent HIV-1 icRNA sensing, dysregulation of which might contribute to chronic inflammation in older PWH.
Authors
Sita Ramaswamy, Hisashi Akiyama, Jacob Berrigan, Andrés A. Quiñones-Molina, Alex J. Olson, Yunhan Chen, YanMei Liang, Andrew J. Henderson, Archana Asundi, Manish Sagar, Suryaram Gummuluru
Abstract
Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and von Willebrand factor (vWF). However, direct regulatory interaction with the complement cascade has not yet been described. We could show that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins, inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. Complement-regulatory function is validated in blood samples from patients with primary complement defects. Physiological relevance of TSP-1 is demonstrated in ANCA-associated vasculitis (AAV) patients by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis following TSP-1 deficiency in an in vitro and in vivo model of AAV. The newly described complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.
Authors
Swagata Konwar, Sophie Schroda, Manuel Rogg, Jessika Kleindienst, Eva L. Decker, Martin Pohl, Barbara Zieger, Jens Peter Panse, Hong Wang, Robert Grosse, Christoph Schell, Sabine Vidal, Xiaobo Liu, Christian Gorzelanny, Todor Tschongov, Karsten Häffner
Abstract
Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.
Authors
Mir J. Howlader, William G. Ambler, Madhavi Latha S. Chalasani, Aahna Rathod, Ethan S. Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D. Shipman III, Dragos C. Dasoveanu, Camila B. Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A. Rodeo, Doruk Erkan, Raghu P. Kataru, Babak J. Mehrara, Theresa T. Lu
Abstract
BACKGROUND. Microglia-mediated brain immune changes play a role in the pathogenesis of Parkinson’s disease (PD) but imaging microglia in living people with PD has relied on positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. We aimed to develop imaging of colony stimulating factor 1 receptor (CSF1R) as a microglial-sensitive marker of innate immunity. METHODS. Immunohistochemistry using a CSF1R antibody evaluated colocalization with Iba-1 in PD (n = 4) and control (n = 4) human brain samples. Autoradiography using a CSF1R tritiated ligand in PD (n = 5) and controls (n = 4) human brain samples was performed to obtain Bmax. PET imaging using a CSF1R radioligand was performed in 10 controls and 12 people with PD and VT was compared between groups and correlated with disease severity. RESULTS. Immunohistochemistry of CSF1R in human brain shows colocalization with Iba-1 and is significantly increased in PD compared to controls. Autoradiography revealed significantly increased CSF1R ligand binding in the inferior parietal cortex of PD patients. [11C]CPPC PET showed higher binding in people with moderate PD compared to controls and correlated with more severe motor disability and poorer verbal fluency. CONCLUSION. This study underscores the significance of CSF1R imaging as a promising biomarker for brain immune function in Parkinson's disease, which may be associated with cognitive and motor disease severity FUNDING. PET imaging: the Michael J. Fox Foundation and the RMS Family Foundation. Radiotracer development: NIH (R01AG066464 and P41 EB024495). Postmortem brain tissues: NIH P30 AG066507 and BIOCARD study NIH U19 AG033655.
Authors
Kelly A. Mills, Yong Du, Jennifer M. Coughlin, Catherine A. Foss, Andrew G. Horti, Katelyn R. Jenkins, Yana Skorobogatova, Ergi Spiro, Chelsie S. Motley, Robert F. Dannals, Wojciech G. Lesniak, Jae-Jin Song, Yu Ree Choi, Javier Redding-Ochoa, Juan C. Troncoso, Valina L. Dawson, Tae-In Kam, Martin G. Pomper, Ted M. Dawson
Abstract
Authors
Anna S. Pollack, Christian A. Kunder, Chandler C. Ho, Josephine Chou, Andrew J. Pollack, Rachel L. P. Geisick, Bing M. Zhang, Robert B. West, James D. Brooks, Jonathan R. Pollack
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