Glucosamine amends CNS pathology in mucopolysaccharidosis IIIC mouse expressing misfolded HGSNATPan, Xuefang;Taherzadeh, Mahsa;Bose, Poulomee;Heon-Roberts, Rachel;Nguyen, Annie L.A.;Xu, TianMeng;Pará, Camila;Yamanaka, Yojiro;Priestman, David A.;Platt, Frances M.;Khan, Shaukat;Fnu, Nidhi;Tomatsu, Shunji;Morales, Carlos R.;Pshezhetsky, Alexey V.
doi: 10.1084/jem.20211860pmid: 35704026
The majority of mucopolysaccharidosis IIIC (MPS IIIC) patients have missense variants causing misfolding of heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), which are potentially treatable with pharmacological chaperones. To test this approach, we generated a novel HgsnatP304L mouse model expressing misfolded HGSNAT Pro304Leu variant. HgsnatP304L mice present deficits in short-term and working/spatial memory 2–4 mo earlier than previously described constitutive knockout Hgsnat-Geo mice. HgsnatP304L mice also show augmented severity of neuroimmune response, synaptic deficits, and neuronal storage of misfolded proteins and gangliosides compared with Hgsnat-Geo mice. Expression of misfolded human Pro311Leu HGSNAT protein in cultured hippocampal Hgsnat-Geo neurons further reduced levels of synaptic proteins. Memory deficits and majority of brain pathology were rescued in mice receiving HGSNAT chaperone, glucosamine. Our data for the first time demonstrate dominant-negative effects of misfolded HGSNAT Pro304Leu variant and show that they are treatable by oral administration of glucosamine. This suggests that patients affected with mutations preventing normal folding of the enzyme can benefit from chaperone therapy.
Charting the meningeal lymphatic networkDa Mesquita, Sandro
doi: 10.1084/jem.20220891pmid: 35789368
A genuine network of lymphatic vessels can be found in the dural layer of the meninges that ensheathe the brain and spinal cord of mammalians. In this issue, Jacob et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20220035) employ light sheet fluorescence imaging of intact mouse heads to provide a more comprehensive chart of the meningeal lymphatic vasculature and draw a parallel between lymphatic drainage of cerebrospinal fluid in mice and humans.
Differential IL-12 signaling induces human natural killer cell activating receptor-mediated ligand-specific expansionShemesh, Avishai;Pickering, Harry;Roybal, Kole T.;Lanier, Lewis L.
doi: 10.1084/jem.20212434pmid: 35758909
IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12–dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading to NK cell proliferation and expansion is not established. Here, we show that IL-12 alone can sustain human primary NK cell survival without providing IL-2 or IL-15 but was insufficient to promote human NK cell proliferation. IL-12 signaling analysis revealed STAT5 phosphorylation and weak mTOR activation, which was enhanced by activating NK receptor upregulation and crosslinking leading to STAT5-dependent, rapamycin-sensitive, or TGFβ-sensitive NK cell IL-12–dependent expansion, independently of IL-12 receptor upregulation. Prolonged IL-2 culture did not impair IL-12–dependent ligand-specific NK cell expansion. These findings demonstrate that activating NK receptor stimulation promotes differential IL-12 signaling, leading to human NK cell expansion, and suggest adopting strategies to provide IL-12 signaling in vivo for ligand-specific IL-2–primed NK cell–based therapies.
Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling moleculesLei, Xuqiu;Ketelut-Carneiro, Natalia;Shmuel-Galia, Liraz;Xu, Weili;Wilson, Ruth;Vierbuchen, Tim;Chen, Yongzhi;Reboldi, Andrea;Kang, Joonsoo;Edelblum, Karen L.;Ward, Doyle;Fitzgerald, Katherine A.
doi: 10.1084/jem.20212563pmid: 35792863
Hepatocyte nuclear factor 4 α (HNF4A) is a highly conserved nuclear receptor that has been associated with ulcerative colitis. In mice, HNF4A is indispensable for the maintenance of intestinal homeostasis, yet the underlying mechanisms are poorly characterized. Here, we demonstrate that the expression of HNF4A in intestinal epithelial cells (IECs) is required for the proper development and composition of the intraepithelial lymphocyte (IEL) compartment. HNF4A directly regulates expression of immune signaling molecules including butyrophilin-like (Btnl) 1, Btnl6, H2-T3, and Clec2e that control IEC–IEL crosstalk. HNF4A selectively enhances the expansion of natural IELs that are TCRγδ+ or TCRαβ+CD8αα+ to shape the composition of IEL compartment. In the small intestine, HNF4A cooperates with its paralog HNF4G, to drive expression of immune signaling molecules. Moreover, the HNF4A–BTNL regulatory axis is conserved in human IECs. Collectively, these findings underscore the importance of HNF4A as a conserved transcription factor controlling IEC–IEL crosstalk and suggest that HNF4A maintains intestinal homeostasis through regulation of the IEL compartment.
The dense-core plaques of Alzheimer’s disease are granulomasLemke, Greg;Huang, Youtong
doi: 10.1084/jem.20212477pmid: 35731195
Dense-core plaques, whose centers contain highly polymerized and compacted aggregates of amyloid β peptides, are one of the two defining histopathological features of Alzheimer’s disease. Recent findings indicate that these plaques do not form spontaneously but are instead constructed by microglia, the tissue macrophages of the central nervous system. We discuss cellular, structural, functional, and gene expression criteria by which the microglial assembly of dense-core plaques in the Alzheimer’s brain parallels the construction of granulomas by macrophages in other settings. We compare the genesis of these plaques to the macrophage assembly of mycobacterial granulomas, the defining histopathological features of tuberculosis. We suggest that if dense-core plaques are indeed granulomas, their simple disassembly may be contraindicated as an Alzheimer’s therapy.