Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box–binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn’s disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.
Cinzia Fionda, Giuseppe Sciumè
Mechanical stress from cardiomyocyte contraction causes misfolded sarcomeric protein replacement. Sarcomeric maintenance utilizes localized pools of mRNAs and translation machinery, yet the importance of localized translation remains unclear. In this issue of the JCI, Haddad et al. identify the Z-line as a critical site for localized translation of sarcomeric proteins, mediated by ribosomal protein SA (RPSA). RPSA localized ribosomes at Z-lines and was trafficked via microtubules. Cardiomyocyte-specific loss of RPSA in mice resulted in mislocalized protein translation and caused structural dilation from myocyte atrophy. These findings demonstrate the necessity of RPSA-dependent spatially localized translation for sarcomere maintenance and cardiac structure and function.
Abigail Nagle, Michael Regnier, Jennifer Davis
Multiple approaches have targeted voltage-gated sodium (Nav) channels for analgesia. In this issue of the JCI, Shin et al. identified a peptide aptamer, NaViPA1, carrying a short polybasic motif flanked by serine residues in a structurally disordered region of loop 1 in tetrodotoxin-sensitive (TTX-S) but not tetrodotoxin-resistant (TTX-R) channels. NaViPA1h inhibited TTX-S NaV channels and attenuated excitability of sensory neurons. Delivery of NaViPA1 in vivo via adeno-associated virions restricted its expression to peripheral sensory neurons and induced analgesia in rats. Targeting of short linear motifs in this manner may provide a gene therapy modality, with minimal side effects due to its peripherally-restricted biodistribution, which opens up a therapeutic strategy for hyperexcitability disorders, including pain.
Sulayman D. Dib-Hajj, Stephen G. Waxman
Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.
Sunder Sims-Lucas, Eric S. Goetzman, Thomas R. Kleyman
Obesity has reached pandemic proportion not only in the West but also in other countries around the world; it is now one of the leading causes of death worldwide. A Western diet is rich in saturated fats and provides more calories than necessary, contributing to the rise of the obesity rate. It also promotes the development of liver steatosis, insulin resistance, hyperglycemia, and hyperlipidemia. In this issue of the JCI, Goetzman and colleagues describe the effects of consuming dicarboxylic acids (DAs) as an alternative source of dietary fat. The 12-carbon dicarboxylic acid (DC12) was administered to mice at 20% of their daily caloric intake for nine weeks in place of triglycerides. Notably, the change in diet increased the metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. These findings highlight DAs as useful energy nutrients for combatting obesity and treating various metabolic disorders.
Lidia Castagneto-Gissey, Stefan R. Bornstein, Geltrude Mingrone
Designing strategies to target cell proliferation has been a priority of cancer researchers for decades. However, targeting the secretory programs of transformed cells can influence other cancer features such as cell survival, migration, and communication with the tumor stroma. In this issue of the JCI, Tan and colleagues describe functional cooperativity between the Golgi-resident proteins Golgi integral membrane protein 4 (GOLIM4) and ATPase secretory pathway Ca2+ transporting 1 (ATP2C1) in the coordination of a secretory program in 3q-amplified cancers. Targeting these tumors with manganese (Mn2+) promoted GOLIM4 degradation and imposed a secretory blockade that impaired tumor progression and stromal cell recruitment in mice. These findings highlight the secretory program as a therapeutic target in 3q-amplified malignancies and provide a promising strategy to treat tumor progression.
Luis Pardo, Jim C. Norman
Bone fracture healing is a complex process with distinct phases: the inflammatory phase, the soft and hard callus formation, and the remodeling phase. In older individuals, bone healing can be delayed or disturbed, leading to non-union fractures at worst. The initial healing phases require communication between immune cells and osteoprogenitor cells. However, senescence in these cell types impedes fracture healing by unknown mechanisms. In this issue of the JCI, Saul et al. showed that two distinct senescent p21-expressing cell populations, an osteochondroprogenitor cell and a neutrophil subpopulation, intrinsically impair fracture healing in mice irrespective of age. Genetic ablation of p21-positive cells accelerated fracture healing, while removal of a different senescent cell population, p16-positive cells, made no difference. Conceptually, this view of senescence in fracture healing with a spotlight on osteoimmune cross-talk provides a promising rationale for therapies to boost bone repair at all ages.
Lorenz C. Hofbauer, Ulrike Baschant, Christine Hofbauer
The occurrence of clonal hematopoiesis of indeterminate potential (CHIP), in which advantageous somatic mutations result in the clonal expansion of blood cells, increases with age, as do an increased risk of mortality and detrimental outcomes associated with CHIP. However, the role of CHIP in susceptibility to pulmonary infections, which also increase with age, is unclear. In this issue of the JCI, Quin and colleagues explored the role of CHIP in bacterial pneumonia. Using characterization of immune cells from human donors and mice lacking tet methylcytosine dioxygenase 2 (Tet2), the authors mechanistically link myeloid immune cell dysfunction to CHIP-mediated risk of bacterial pneumonia. The findings suggest that CHIP drives inflammaging and immune senescence, and provide Tet2 status in older adults as a potential prognostic tool for informing treatment options related to immune modulation.
Elsa N. Bou Ghanem
Although antibody-mediated lung damage is a major factor in transfusion-related acute lung injury (ALI), autoimmune lung disease (for example, coatomer subunit α [COPA] syndrome), and primary graft dysfunction following lung transplantation, the mechanism by which antigen-antibody complexes activate complement to induce lung damage remains unclear. In this issue of the JCI, Cleary and colleagues utilized several approaches to demonstrate that IgG forms hexamers with MHC class I alloantibodies. This hexamerization served as a key pathophysiological mechanism in alloimmune lung injury models and was mediated through the classical pathway of complement activation. Additionally, the authors provided avenues for exploring therapeutics for this currently hard-to-treat clinical entity that has several etiologies but a potentially focused mechanism.
Hrishikesh S. Kulkarni
The macula densa (MD) is a distinct cluster of approximately 20 specialized kidney epithelial cells that constitute a key component of the juxtaglomerular apparatus. Unlike other renal tubular epithelial cell populations with functions relating to reclamation or secretion of electrolytes and solutes, the MD acts as a cell sensor, exerting homeostatic actions in response to sodium and chloride changes within the tubular fluid. Electrolyte flux through apical sodium transporters in MD cells triggers release of paracrine mediators, affecting blood pressure and glomerular hemodynamics. In this issue of the JCI, Gyarmati and authors explored a program of MD that resulted in activation of regeneration pathways. Notably, regeneration was triggered by feeding mice a low-salt diet. Furthermore, the MD cells showed neuron-like properties that may contribute to their regulation of glomerular structure and function. These findings suggest that dietary sodium restriction and/or targeting MD signaling might attenuate glomerular injury.
Yun Xia, Thomas M. Coffman
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