Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players, and defining their interactions. We describe a striking layering of the chronic HS infiltrate and identify the contribution of two fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrate the central role of the Hippo pathway in promoting extensive fibrosis in HS and provide pre-clinical evidence that the pro-fibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide novel insights into key aspects of HS pathogenesis with broad therapeutic implications.
Kelsey R. van Straalen, Feiyang Ma, Pei-Suen Tsou, Olesya Plazyo, Mehrnaz Gharaee-Kermani, Marta Calbet, Xianying Xing, Mrinal K. Sarkar, Ranjitha Uppala, Paul W. Harms, Rachael Wasikowski, Lina Nahlawi, Mio Nakamura, Milad Eshaq, Cong Wang, Craig J. Dobry, Jeffrey H. Kozlow, Jill R. Cherry-Bukowiec, William D. Brodie, Kerstin Wolk, Özge Uluckan, Megan N. Mattichak, Matteo Pellegrini, Robert L. Modlin, Emanual Maverakis, Robert Sabat, J. Michelle Kahlenberg, Allison C. Billi, Lam C. Tsoi, Johann E. Gudjonsson
The study investigates a mechanistic link if bacterial biofilm mediated host-pathogen interaction leads to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. The study included 178 subjects divided in three cohorts. Eighty-six patients reported symptoms consistent with BII. Control group I (non-BII, N=55) included patients with breast implants without BII symptoms but went through explantation of the breast implant. Control group II (normal tissue, N=37) was comprised of women without an implant, whose breast tissue was removed as an unrelated clinically indicated surgical procedures. We report that periprosthetic breast tissue of BII had increased abundance of biofilm and biofilm-derived oxylipin, 10-HOME. S. epidermidis biofilm was observed to be higher in the BII group (73.33%) compared to non-BII group (16.67%, p=0.018) and the normal group (10%, p=0.036). The oxylipin was found to be immunogenic capable of polarizing naïve CD4+ T cells with a resulting Th1 subtype in vitro and in vivo. Consistently, an abundance of CD4+Th1 subtype was observed in the periprosthetic breast tissue and blood of BII subjects. Mice injected with 10-HOME also had increased Th1 subtype in blood akin to BII patients and demonstrated fatigue-like symptoms. The identification of an oxylipin-mediated mechanism of immune activation induced by local bacterial biofilm associated with BII provides insight into the possible pathogenesis of implant-associated immune symptoms of BII.
Imran Khan, Robert E. Minto, Christine Kelley-Patteson, Kanhaiya Singh, Lava Timsina, Lily J. Suh, Ethan Rinne, Bruce W. Van Natta, Colby R. Neumann, Ganesh Mohan, Mary Lester, R. Jason VonDerHaar, Rana German, Natascia Marino, Aladdin H. Hassanein, Gayle M. Gordillo, Mark H. Kaplan, Chandan K. Sen, Marshall E. Kadin, Mithun Sinha
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the AGER pattern recognition receptor and the NLRP3 inflammasome, which leads to increased placental inflammation. In adult offspring, we find that this memory is associated with DNMT1 upregulation and epigenetic changes in hematopoietic progenitors. Altogether, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes, and that this memory constitutes a new pathway connecting gestational health to adult pathologies.
Vinothini Govindarajah, Masahide Sakabe, Samantha Good, Michael Solomon, Ashok Arasu, Nong Chen, Xuan Zhang, H. Leighton Grimes, Ady Kendler, Mei Xin, Damien Reynaud
Dual-specificity phosphatase 8 (DUSP8) is a MAPK phosphatase that dephosphorylates and inactivates the kinase JNK. DUSP8 is highly expressed in T cells; however, the in vivo role of DUSP8 in T cells remains unclear. Using T cell–specific Dusp8 conditional KO (T-Dusp8 cKO) mice, mass spectrometry analysis, ChIP-Seq, and immune analysis, we found that DUSP8 interacted with Pur-α, stimulated interleukin-9 (IL-9) gene expression, and promoted Th9 differentiation. Mechanistically, DUSP8 dephosphorylated the transcriptional repressor Pur-α upon TGF-β signaling, leading to the nuclear export of Pur-α and subsequent IL-9 transcriptional activation. Furthermore, Il-9 mRNA levels were induced in Pur-α–deficient T cells. In addition, T-Dusp8–cKO mice displayed reduction of IL-9 and Th9-mediated immune responses in the allergic asthma model. Reduction of Il-9 mRNA levels in T cells and allergic responses of T-Dusp8–cKO mice was reversed by Pur-α knockout. Remarkably, DUSP8 protein levels and the DUSP8–Pur-α interaction were indeed increased in the cytoplasm of T cells from people with asthma and patients with atopic dermatitis. Collectively, DUSP8 induces TGF-β–stimulated IL-9 transcription and Th9-induced allergic responses by inhibiting the nuclear translocation of the transcriptional repressor Pur-α. DUSP8 may be a T-cell biomarker and therapeutic target for asthma and atopic dermatitis.
Huai-Chia Chuang, Chia-Hsin Hsueh, Pu-Ming Hsu, Ching-Yi Tsai, Ying-Chun Shih, Hsien-Yi Chiu, Yi-Ming Chen, Wen-Kuang Yu, Ming-Han Chen, Tse-Hua Tan
Heart Failure with Preserved Ejection Fraction (HFpEF) is a widespread syndrome with limited therapeutic options and poorly understood immune-pathophysiology. Using a two-hit preclinical model of cardiometabolic HFpEF that induces obesity and hypertension, we found that cardiac T cell infiltration and lymphoid expansion occur concomitantly with cardiac pathology, and that diastolic dysfunction, cardiomyocyte hypertrophy and cardiac phospholamban phosphorylation are T cell-dependent. Heart-infiltrating T cells were not restricted to cardiac antigens and were uniquely characterized by impaired activation of the Inositol-requiring enzyme-1α (IRE1α)-X-box binding protein 1 (XBP1) arm of the unfolded protein response. Notably, selective ablation of XBP1 in T cells enhanced their persistence in the heart and lymphoid organs of mice with preclinical HFpEF. Furthermore, T cell IRE1α-XBP1 activation was restored after withdrawal of the two comorbidities inducing HFpEF, resulting in partial improvement of cardiac pathology. Our results demonstrate that diastolic dysfunction and cardiomyocyte hypertrophy in preclinical HFpEF are T cell-dependent, and that reversible dysregulation of the T cell IRE1α-XBP1 axis is a T cell signature of HFpEF.
Sasha Smolgovsky, Abraham L. Bayer, Kuljeet Kaur, Erin Sanders, Mark Aronovitz, Mallory E. Filipp, Edward B. Thorp, Gabriele G. Schiattarella, Joseph A. Hill, Robert M. Blanton, Juan R. Cubillos-Ruiz, Pilar Alcaide
Alisa A. Mueller, Takanori Sasaki, Joshua W. Keegan, Jennifer P. Nguyen, Alec Griffith, Alice M. Horisberger, Thomas Licata, Elizabeth Fieg, Ye Cao, Mehreen Elahee, Kathryne E. Marks, Daimon P. Simmons, Lauren C. Briere, Laurel A. Cobban, J. Carl Pallais, Frances A. High, Melissa A. Walker, Jenny J. Linnoila, Jeffrey A. Sparks, V. Michael Holers, Karen H. Costenbader, Undiagnosed Diseases Network (UDN), David A. Sweetser, Joel B. Krier, Joseph Loscalzo, James A. Lederer, Deepak A. Rao
The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet–induced (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR’s effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte-derived SPARC confers CR-like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.
Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit
Endothelial dysfunction is a critical and initiating factor of the vascular complications of diabetes. Inflammation plays an important role in endothelial dysfunction regulated by epigenetic modifications. N6-methyladenosine (m6A) is one of the most prevalent epigenetic modifications in eukaryotic cells. In this research, we identified an m6A demethylase, fat mass and obesity-associated protein (FTO), as an essential epitranscriptomic regulator in diabetes-induced vascular endothelial dysfunction. We showed that enhanced FTO reduced the global level of m6A in hyperglycemia. FTO knockdown in endothelial cells (ECs) resulted in less inflammation and compromised ability of migration and tube formation. Compared with EC Ftofl/fl diabetic mice, EC-specific Fto-deficient (EC FtoΔ/Δ) diabetic mice displayed less retinal vascular leakage and acellular capillary formation. Furthermore, methylated RNA immunoprecipitation sequencing (MeRIP-Seq) combined with RNA-Seq indicated that Tnip1 served as a downstream target of FTO. Luciferase activity assays and RNA pull-down demonstrated that FTO repressed TNIP1 mRNA expression by erasing its m6A methylation. In addition, TNIP1 depletion activated NF-κB and other inflammatory factors, which aggravated retinal vascular leakage and acellular capillary formation, while sustained expression of Tnip1 by intravitreal injection of adeno-associated virus alleviated endothelial impairments. These findings suggest that the FTO-TNIP1-NF-κB network provides potential targets to treat diabetic vascular complications.
Chuandi Zhou, Xinping She, Chufeng Gu, Yanan Hu, Mingming Ma, Qinghua Qiu, Tao Sun, Xun Xu, Haibing Chen, Zhi Zheng
Type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and dyslipidemia, leads to nonproliferative diabetic retinopathy (NPDR). NPDR is associated with blood-retina barrier disruption, plasma exudates, microvascular degeneration, elevated inflammatory cytokine levels, and monocyte (Mo) infiltration. Whether and how the diabetes-associated changes in plasma lipid and carbohydrate levels modify Mo differentiation remains unknown. Here, we show that mononuclear phagocytes (MPs) in areas of vascular leakage in DR donor retinas expressed perilipin 2 (PLIN2), a marker of intracellular lipid load. Strong upregulation of PLIN2 was also observed when healthy donor Mos were treated with plasma from patients with T2DM or with palmitate concentrations typical of those found in T2DM plasma, but not under high-glucose conditions. PLIN2 expression correlated with the expression of other key genes involved in lipid metabolism (ACADVL, PDK4) and the DR biomarkers ANGPTL4 and CXCL8. Mechanistically, we show that lipid-exposed MPs induced capillary degeneration in ex vivo explants that was inhibited by pharmaceutical inhibition of PPARγ signaling. Our study reveals a mechanism linking dyslipidemia-induced MP polarization to the increased inflammatory cytokine levels and microvascular degeneration that characterize NPDR. This study provides comprehensive insights into the glycemia-independent activation of Mos in T2DM and identifies MP PPARγ as a target for inhibition of lipid-activated MPs in DR.
Guillaume Blot, Rémi Karadayi, Lauriane Przegralek, Thérèse-Marie Sartoris, Hugo Charles-Messance, Sébastien Augustin, Pierre Negrier, Frédéric Blond, Frida Paulina Muñiz-Ruvalcaba, David Rivera-de la Parra, Lucile Vignaud, Aude Couturier, José-Alain Sahel, Niyazi Acar, Aida Jimenez-Corona, Cécile Delarasse, Yonathan Garfias, Florian Sennlaub, Xavier Guillonneau
BACKGROUND. Macrophage activation syndrome (MAS) is a life-threatening complication of Still’s disease (SD) characterized by overt immune cell activation and cytokine storm. We aimed to further understand the immunologic landscape of SD and MAS. METHOD. We profiled peripheral blood mononuclear cells (PBMC) from healthy controls and patients with SD with or without MAS using bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq). We validated and expanded the findings by mass cytometry, flow cytometry and in vitro studies. RESULTS. Bulk RNA-seq of PBMC from patients with SD-associated MAS revealed strong expression of genes associated with type I interferon (IFN-I) signaling and cell proliferation, in addition to the expected IFN-γ signal, compared to healthy controls and SD patients without MAS. scRNA-seq analysis of > 65,000 total PBMC confirmed IFN-I and IFN-γ signatures and localized the cell proliferation signature to cycling CD38+HLA-DR+ cells within CD4+ T cell, CD8+ T cell and NK cell populations. CD38+HLA-DR+ lymphocytes exhibited prominent IFN-g production, glycolysis, and mTOR signaling. Cell-cell interaction modeling suggested a network linking CD38+HLA-DR+ lymphocytes with monocytes through IFN-γ signaling. Notably, the expansion of CD38+HLA-DR+ lymphocytes in MAS was greater than in other systemic inflammatory conditions in children. In vitro stimulation of PBMC demonstrated that IFN-I and IL-15 – both elevated in MAS patients – synergistically augmented the generation of CD38+HLA-DR+ lymphocytes, while Janus kinase inhibition mitigated this response. CONCLUSION. MAS associated with SD is characterized by overproduction of IFN-I, which may act in synergy with IL-15 to generate CD38+HLA-DR+ cycling lymphocytes that produce IFN-γ.
Zhengping Huang, Kailey E. Brodeur, Liang Chen, Yan Du, Holly Wobma, Evan E. Hsu, Meng Liu, Joyce C. Chang, Margaret H. Chang, Janet Chou, Megan Day-Lewis, Fatma Dedeoglu, Olha Halyabar, James A. Lederer, Tianwang Li, Mindy S. Lo, Meiping Lu, Esra Meidan, Jane W. Newburger, Adrienne G. Randolph, Mary Beth F. Son, Robert P. Sundel, Maria L. Taylor, Huaxiang Wu, Qing Zhou, Scott W. Canna, Kevin Wei, Lauren A. Henderson, Peter A. Nigrovic, Pui Y. Lee
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