Sepsis and sepsis syndrome are leading causes of mortality throughout the world. It is widely held that sepsis represents a dysregulated innate immune response to an offending pathogen. This immune response is often initiated via microbial products signaling through TLRs expressed on host immune cells. There is increasing evidence that this innate response can be dramatically influenced by the cellular redox state, and thus a better understanding of oxidative regulation of innate immunity could lead to new treatments for sepsis. In this issue of the JCI, Thimmulappa et al. show that nuclear factor-erythroid 2–related factor 2 (Nrf2), a member of the “cap’n’collar” family of basic region–leucine zipper transcription factors, which has previously been shown to be involved in the transcription of antioxidant gene expression in response to xenobiotic stress, is also a critical regulator of cellular oxidative stress in sepsis (see the related article beginning on page 984).
Jay K. Kolls
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent for the development of an aggressive hematologic neoplasia termed adult T cell leukemia/lymphoma (ATLL). Although the virus infects T cell subsets that display either CD4 or CD8 cell surface markers, the leukemic cell is exclusively of the CD4+ subtype. In the article by Sibon et al. in this issue of the JCI, the authors demonstrate that the molecular basis for clonal expansion differs between these 2 infected T cell populations (see the related article beginning on page 974). The molecular events associated with a preleukemic state, such as genomic instability, polynucleation, and cell cycle redistribution, were only observed in CD4+ T cells. This finding provides a molecular-based mechanism for the restriction of the leukemic phenotype to the CD4+ T cell subtype.
O. John Semmes
Enhanced signaling in myocytes by the G protein Gq has been implicated in cardiac hypertrophy and the transition to heart failure. α1-Adrenergic receptors (α1-ARs) are members of the 7-transmembrane-spanning domain (7-TM) receptor family and signal via interaction with Gq in the heart. The specific effects of a loss of α1-AR signaling in the heart are explored by O’Connell et al. in this issue of the JCI (see the related article beginning on page 1005). Paradoxically, gene ablation of the α1A and α1B subtypes in mice results in a maladaptive form of reactive cardiac hypertrophy from pressure overload, with a predisposition to heart failure. Thus signaling to the α1-AR (compared with signaling from other receptors such as angiotensin receptors, which also couple to Gq) appears to be specifically required for a normal hypertrophic response. This represents another example of how receptors that share common G proteins have diversified, developing unique signaling programs. These findings may have particular clinical relevance because of the widespread use of α1-AR antagonists in the treatment of hypertension and symptomatic prostate enlargement.
Stephen B. Liggett
Male and female external genitalia appear identical early in gestation. Testosterone exposure at 8–12 weeks’ gestation causes male differentiation. Female fetuses virilize if their adrenals secrete excessive levels of androgens, as occurs in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. This can be ameliorated by administering dexamethasone to the mother. A study by Goto et al. in this issue of the JCI provides a rationale for this treatment by demonstrating that the fetal hypothalamic-pituitary-adrenal axis is fully functional when the genitalia differentiate (see the related article beginning on page 953). Dexamethasone suppresses this axis, reducing abnormal secretion of adrenal androgens. Their results also show that cortisol synthesis by the fetal adrenal decreases after this period, allowing the adrenal to secrete high levels of dehydroepiandrosterone, an androgen precursor. However, this does not virilize female fetuses because androgens are aromatized to estrogens in the placenta. Thus normal sexual differentiation requires exquisite timing of fetal cortisol and androgen secretion versus placental capacity for aromatization.
Perrin C. White
RA is a quintessential autoimmune disease with a growing number of cells, mediators, and pathways implicated in this tissue-injurious inflammation. Now Kuhn and colleagues have provided convincing evidence that autoantibodies reacting with citrullinated proteins, known for their sensitivity and specificity as biomarkers in RA, enhance tissue damage in collagen-induced arthritis (see the related article beginning on page 961). This study adds yet another soldier to the growing army of autoaggressive mechanisms that underlie RA. With great success researchers have dismantled the pathogenic subunits of RA, adding gene to gene, molecule to molecule, and pathway to pathway in an ever more complex scheme of dysfunction. The complexity of the emerging disease model leaves us speechless. It seems that with this wealth of data available, we need to develop a new theory for this disease. We may want to seek guidance from our colleagues in physics and mathematics who have successfully integrated their knowledge of elementary particles and the complexity of their interacting forces by formulating the string theory.
Cornelia M. Weyand, Jörg J. Goronzy
The aspartyl protease renin was first isolated from the kidney by Tigerstedt more than a century ago. In the kidney, renin secretion is tightly linked to sodium intake and renal perfusion pressure, reflecting the important role of the renin-angiotensin system (RAS) in controlling body fluid volume and blood pressure. The study by Mackins et al. in this issue of the JCI describes a novel source of renin: the mast cell (see the related article beginning on page 1063). This discovery suggests a distinct pathway for activation of the RAS that may have a particular impact on the pathogenesis of chronic tissue injury as well as more acute pathology such as arrhythmias in the heart.
Thu H. Le, Thomas M. Coffman
During vertebrate development, mesenchymal progenitors capable of forming bone, cartilage, muscle, fat, or tendon arise from either neural crest or somitic mesoderm. Transcriptional programs that specify mesenchymal cell fates are initiated and modified by paracrine cues provided by TGF-β superfamily members and mediated in part via the regulated assembly of Smad-containing multiprotein transcription factor complexes. In this issue of the JCI, Hoffmann and colleagues have identified that Smad8 activation drives tendon formation from C3H10T1/2 cells, a murine cell line that recapitulates many features of normal multipotent mesenchymal cells (see the related article beginning on page 940). Cells programmed to the tenocyte cell fate in vitro formed tenogenic grafts in vivo. These results add to the accumulating evidence that proliferating, multipotent mesenchymal progenitor cells can be programmed to yield multiple cell types — e.g., osteoblasts, myocytes, chondrocytes, and tenocytes — that may be useful in cell-based therapeutic approaches to musculoskeletal diseases.
Dwight A. Towler, Richard H. Gelberman
Genetic diseases often reveal the physiological roles of the affected proteins. The identification of mutations in the nuclear envelope proteins lamin A and lamin C as the cause of a diverse group of human diseases has expanded our understanding of the lamin proteins from being merely structural elements of the cell nucleus and has implicated them in novel cellular functions including signal transduction and gene expression. However, it now appears that the physiological relevance of one of the lamin proteins in organismal function has been overestimated. In this issue of the JCI, Fong et al. demonstrate that lamin A–deficient mice are phenotypically normal (see the related article beginning on page 743). The good news is these findings open the door to a new strategy for the therapeutic treatment of diseases caused by mutations in lamin A, such as muscular dystrophies and some types of premature aging syndromes.
Paola Scaffidi, Tom Misteli
Ca2+ plays a pivotal role in both excitation-contraction coupling (ECC) and activation of Ca2+-dependent signaling pathways. One of the remaining questions in cardiac biology is how Ca2+-dependent signaling pathways are regulated under conditions of continual Ca2+ transients that mediate cardiac contraction during each heartbeat. Ca2+-calmodulin–dependent protein kinase II (CaMKII) activation and its ability to regulate histone deacetylase 5 (HDAC5) nuclear shuttling represent a critical Ca2+-dependent signaling circuit for controlling cardiac hypertrophy and heart failure, yet the mechanism of activation by Ca2+ is not known. In this issue of the JCI, Wu et al. convincingly demonstrate that the inositol 1,4,5-trisphosphate receptor (InsP3R) is involved in local control of Ca2+ for activating CaMKII in the nuclear envelope of adult ventricular cardiac myocytes (see the related article beginning on page 675). The overall paradigm that is demonstrated is the best example of a molecular mechanism whereby signaling is directly regulated by a local Ca2+ pool that is disparate or geometrically insensitive to cytosolic Ca2+ underlying each contractile cycle.
Jeffery D. Molkentin
The anaphylatoxins complement component 3a and 5a (C3a and C5a, respectively) are classically seen as proinflammatory mediators of allergic asthma that recruit inflammatory cells, induce edema, and cause bronchoconstriction. A few years ago, controversy arose when it was shown that C5-deficient mice were more susceptible to experimental asthma compared with C5-sufficient mice. In a study by Köhl et al. in this issue of the JCI, it is shown in a series of truly “complementary” experiments that C5a receptor (C5aR) blockade promotes Th2 sensitization upon first exposure to inhaled allergen, whereas C5aR blockade during established inflammation suppresses the cardinal features of asthma (see the related article beginning on page 783). Blockade of C5aR alters the function of airway DCs, crucial for inducing and maintaining Th2 responses in the lung. Targeting C5aR as a treatment for established asthma could be beneficial, but might be accompanied by sensitization to novel antigens.
Bart N. Lambrecht
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