Gyarmati et al. identify the central roles of glomerular mechanical forces as well as endothelial and immune cell activation early in Alport syndrome. The cover image shows intravital multiphoton microscopy imaging of immune cell features in a late-stage Alport syndrome model.
Lung alveolar type 2 (AT2) cells are progenitors for alveolar type 1 (AT1) cells. Although many factors regulate AT2 cell plasticity, the role of mitochondrial calcium (mCa2+) uptake in controlling AT2 cells remains unclear. We previously identified that the microRNA family, miR-302, supports lung epithelial progenitor cell proliferation and less differentiated phenotypes during development. Here we report that a sustained elevation of miR-302 in adult AT2 cells decreases AT2-to-AT1 cell differentiation during the Streptococcus pneumoniae induced lung injury repair. We identified that miR-302 targets and represses the expression of mitochondrial Ca2+ uptake 1 (MICU1), which regulates mCa2+ uptake through the mCa2+ uniporter channel by acting as a gatekeeper at low cytosolic Ca2+ levels. Our results reveal a marked increase in MICU1 protein expression and decreased mCa2+ uptake during AT2-to-AT1 cell differentiation in the adult lung. Deletion of Micu1 in AT2 cells reduces AT2-to-AT1 cell differentiation during steady-state tissue maintenance and alveolar epithelial regeneration following bacterial pneumonia. These studies indicate that mCa2+ uptake is extensively modulated during AT2-to-AT1 cell differentiation and that MICU1-dependent mCa2+ uniporter channel gating is a prominent mechanism modulating AT2-to-AT1 cell differentiation.
Mir Ali, Xiaoying Zhang, Ryan LaCanna, Dhanendra Tomar, John W. Elrod, Ying Tian
Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of LS. Depleting leukocytes with a colony-stimulating factor 1 receptor inhibitor disrupts disease progression, including suppression of CNS lesion formation and a substantial extension of survival. Leukocyte depletion rescues diverse symptoms including seizures, respiratory center function, hyperlactemia, and neurologic sequelae. These data reveal a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement is causal in disease. This work has significant implications for the mechanisms of mitochondrial disease and may lead to novel therapeutic strategies.
Julia C. Stokes, Rebecca L. Bornstein, Katerina James, Kyung Yeon Park, Kira A. Spencer, Katie Vo, John C. Snell, Brittany M. Johnson, Philip G. Morgan, Margaret M. Sedensky, Nathan A. Baertsch, Simon C. Johnson
BACKGROUND. Prostate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intra-focal heterogeneity. We sought to characterize the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors. METHODS. From the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ERG, SPINK1, PTEN, and SPOP molecular status. We utilized dual ERG/SPINK1 immunohistochemistry, fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, and high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status. Analysis of biochemical recurrence-free of patients with collision tumors was conducted using Kaplan-Meier method. RESULTS. Based on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens. CONCLUSION. Interfocal molecular heterogeneity was identified in ~60% of multifocal RP specimens and collision tumors were present in ~10%. We present this phenomenon as a model for the intra-focal heterogeneity observed in previous studies and propose future genomic studies screen for collision tumors to better characterize molecular heterogeneity.
Jacqueline Fontugne, Peter Y. Cai, Hussein Alnajar, Bhavneet Bhinder, Kyung Park, Huihui Ye, Shaham Beg, Verena Sailer, Javed Siddiqui, Mirjam Blattner-Johnson, Jaclyn A. Croyle, Zohal Noorzad, Carla Calagua, Theresa Y. MacDonald, Ulrika Axcrona, Mari Bogaard, Karol Axcrona, Douglas S. Scherr, Martin G. Sanda, Bjarne Johannessen, Arul M. Chinnaiyan, Olivier Elemento, Rolf I. Skotheim, Mark A. Rubin, Christopher E. Barbieri, Juan M. Mosquera
Why Multisystem Inflammatory Syndrome in Children (MIS-C) develops after SARS-CoV-2 infection in a subset of children is unknown. We hypothesized that aberrant virus52 specific T-cell responses contribute to MIS-C pathogenesis. We quantified SARS-CoV-2 reactive T-cells, serologic responses against major viral proteins, and cytokine responses from plasma and peripheral blood mononuclear cells in children with convalescent COVID-19, acute MIS-C, and healthy controls. Children with MIS-C had significantly lower virus-specific CD4+ and CD8+ T-cell responses to major SARS-CoV-2 antigens compared with children convalescing from COVID-19. Further, T-cell responses in participants with MIS-C were similar to or lower than those in healthy controls. Serologic responses against spike receptor binding domain (RBD), full-length spike, and nucleocapsid were similar among convalescent COVID-19 and MIS-C, suggesting functional B cell responses. Cytokine profiling demonstrated predominant Th1 polarization of CD4+ T-cells from children with convalescent COVID-19 and MIS-C, although cytokine production was reduced in MIS-C. Our findings support a role for constrained induction of anti-SARS-CoV-2-specific T-cells in the pathogenesis of MIS-C.
Vidisha Singh, Veronica Obregon-Perko, Stacey A. Lapp, Anna M. Horner, Alyssa Brooks, Lisa Macoy, Laila Hussaini, Austin Lu, Theda Gibson, Guido Silvestri, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Evan J. Anderson, Christina A. Rostad, Ann Chahroudi
Impaired glucose metabolism is observed in obesity and type 2 diabetes. Glucose controls gene expression through the transcription factor ChREBP in liver and adipose tissues. Mlxipl encodes two isoforms, ChREBPα, the full-length form which translocation into the nucleus is under the control of glucose and, ChREBPβ, a constitutively nuclear shorter form. ChREBPβ gene expression in white adipose tissue is strongly associated with insulin sensitivity. Here, we investigated the consequences of ChREBPβ deficiency on insulin action and energy balance. ChREBPβ-deficient male and female C57BL6/J and FVB/N mice were produced using CRISPR-Cas9-mediated gene editing. Unlike global ChREBP deficiency, lack of ChREBPβ showed modest effects on gene expression in adipose tissues and liver, with variations seen chiefly in brown adipose tissue. In mice fed chow and high fat diets, lack of ChREBPβ had moderate effects on body composition and insulin sensitivity. ChREBPβ deficiency did not prevent the whitening of brown adipose tissue reported in total ChREBP knock out mice at thermoneutrality. These findings reveal that ChREBPβ is dispensable for metabolic adaptations to nutritional and thermic challenges.
Emeline Recazens, Geneviève Tavernier, Jérémy Dufau, Camille Bergoglio, Fadila Benhamed, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Sylvie Caspar-Bauguil, Alice Brion, Laurent Monbrun, Renaud Dentin, Clara Ferrier, Mélanie Leroux, Pierre-Damien Denechaud, Cedric Moro, Jean-Paul Concordet, Catherine Postic, Etienne Mouisel, Dominique Langin
JCI This Month is a digest of the research, reviews, and other features published each month.