Cytokine release syndrome (CRS) is a life-threatening complication of several new immunotherapies used to treat cancers and autoimmune diseases
. Here we report that atrial natriuretic peptide can ...protect mice from CRS induced by such agents by reducing the levels of circulating catecholamines. Catecholamines were found to orchestrate an immunodysregulation resulting from oncolytic bacteria and lipopolysaccharide through a self-amplifying loop in macrophages. Myeloid-specific deletion of tyrosine hydroxylase inhibited this circuit. Cytokine release induced by T-cell-activating therapeutic agents was also accompanied by a catecholamine surge and inhibition of catecholamine synthesis reduced cytokine release in vitro and in mice. Pharmacologic catecholamine blockade with metyrosine protected mice from lethal complications of CRS resulting from infections and various biotherapeutic agents including oncolytic bacteria, T-cell-targeting antibodies and CAR-T cells. Our study identifies catecholamines as an essential component of the cytokine release that can be modulated by specific blockers without impairing the therapeutic response.
Circadian clocks regulate numerous physiological processes that vary across the day-night (diurnal) cycle, but if and how the circadian clock regulates the adaptive immune system is mostly unclear. ...lnterleukin-17–producing CD4⁺ T helper (T H 17) cells are proinflammatory immune cells that protect against bacterial and fungal infections at mucosal surfaces. Their lineage specification is regulated by the orphan nuclear receptor RORγt We show that the transcription factor NFIL3 suppresses T H 17 cell development by directly binding and repressing the Rorγt promoter. NFIL3 links T H 17 cell development to the circadian clock network through the transcription factor REV-ERBα. Accordingly, T H 17 lineage specification varies diurnally and is altered in Rev-erbα- ⁻ - mice. Light-cycle disruption elevated intestinal T H 17 cell frequencies and increased susceptibility to inflammatory disease. Thus, lineage specification of a key immune cell is under direct circadian control.
Natural killer (NK) cells belong to the innate immune system; they can control virus infections and developing tumors by cytotoxicity and producing inflammatory cytokines. Most studies of mouse NK ...cells, however, have focused on conventional NK (cNK) cells in the spleen. Recently, we described two populations of liver NK cells, tissue-resident NK (trNK) cells and those resembling splenic cNK cells. However, their lineage relationship was unclear; trNK cells could be developing cNK cells, related to thymic NK cells, or a lineage distinct from both cNK and thymic NK cells. Herein we used detailed transcriptomic, flow cytometric, and functional analysis and transcription factor-deficient mice to determine that liver trNK cells form a distinct lineage from cNK and thymic NK cells. Taken together with analysis of trNK cells in other tissues, there are at least four distinct lineages of NK cells: cNK, thymic, liver (and skin) trNK, and uterine trNK cells. DOI: http://dx.doi.org/10.7554/eLife.01659.001.
Inhalation of crystalline silica and asbestos is known to cause the progressive pulmonary fibrotic disorders silicosis and asbestosis, respectively. Although alveolar macrophages are believed to ...initiate these inflammatory responses, the mechanism by which this occurs has been unclear. Here we show that the inflammatory response and subsequent development of pulmonary fibrosis after inhalation of silica is dependent on the Nalp3 inflammasome. Stimulation of macrophages with silica results in the activation of caspase-1 in a Nalp3-dependent manner. Macrophages deficient in components of the Nalp3 inflammasome were incapable of secreting the proinflammatory cytokines interleukin (IL)-1β and IL-18 in response to silica. Similarly, asbestos was capable of activating caspase-1 in a Nalp3-dependent manner. Activation of the Nalp3 inflammasome by silica required both an efflux of intracellular potassium and the generation of reactive oxygen species. This study demonstrates a key role for the Nalp3 inflammasome in the pathogenesis of pneumoconiosis.
Development of the natural killer (NK) cell lineage is dependent on the transcription factor Nfil3 (or E4BP4), which is thought to act downstream of IL-15 signaling. Nfil3-deficient mice lack NK ...cells, whereas other lymphocyte lineages (B, T, and NKT cells) remain largely intact. We report the appearance of Ly49H-expressing NK cells in Nfil3(-/-) mice infected with mouse cytomegalovirus (MCMV) or recombinant viruses expressing the viral m157 glycoprotein. Nfil3(-/-) NK cells at the peak of antigen-driven expansion were functionally similar to NK cells from infected wild-type mice with respect to IFN-γ production and cytotoxicity, and could comparably produce long-lived memory NK cells that persisted in lymphoid and nonlymphoid tissues for >60 d. We demonstrate that generation and maintenance of NK cell memory is an Nfil3-independent but IL-15-dependent process. Furthermore, specific ablation of Nfil3 in either immature NK cells in the bone marrow or mature peripheral NK cells had no observable effect on NK cell lineage maintenance or homeostasis. Thus, expression of Nfil3 is crucial only early in the development of NK cells, and signals through activating receptors and proinflammatory cytokines during viral infection can bypass the requirement for Nfil3, promoting the proliferation and long-term survival of virus-specific NK cells.
The Center for Hearing Science, 1
Department of Biomedical Engineering, The Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205; and 2 Department of Otolaryngology/Head and Neck
...Surgery, and The Curriculum in Neurobiology, University of North
Carolina, Chapel Hill, North Carolina 27599
Using kinetic data from three different K + currents in acutely isolated neurons, a single electrical compartment representing the soma of a ventral cochlear nucleus (VCN) neuron was created. The K + currents include a fast transient current ( I A ), a slow-inactivating low-threshold current ( I LT ), and a noninactivating high-threshold current ( I HT ). The model also includes a fast-inactivating Na + current, a hyperpolarization-activated cation current ( I h ), and 150 auditory nerve synapses. With this model, the role I A , I LT , and I HT play in shaping the discharge patterns of VCN cells is explored. Simulation results indicate that I HT mainly functions to repolarize the membrane during an action potential, and I A functions to modulate the rate of repetitive firing. I LT is found to be responsible for the phasic discharge pattern observed in Type II cells (bushy cells). However, by adjusting the strength of I LT , both phasic and regular discharge patterns are observed, demonstrating that a critical level of I LT is necessary to produce the Type II response. Simulated Type II cells have a significantly faster membrane time constant in comparison to Type I cells (stellate cells) and are therefore better suited to preserve temporal information in their auditory nerve inputs by acting as precise coincidence detectors and having a short refractory period. Finally, we demonstrate that modulation of I h , which changes the resting membrane potential, is a more effective means of modulating the activation level of I LT than simply modulating I LT itself. This result may explain why I LT and I h are often coexpressed throughout the nervous system.
Address for reprint requests: Paul B. Manis, Dept. Otolaryngology/Head and Neck Surgery, 1123 Bioinformatics Bldg., CB#7070, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7070 (E-mail: pmanis{at}med.unc.edu ).
IL-4 signaling promotes IgE class switching through STAT6 activation and the induction of Ig germ-line ε (GLε) transcription. Previously, we and others identified a transcription factor, Nfil3, as a ...gene induced by IL-4 stimulation in B cells. However, the precise roles of nuclear factor, IL-3-regulated (NFIL3) in IL-4 signaling are unknown. Here, we report that NFIL3 is important for IgE class switching. NFIL3-deficient mice show impaired IgE class switching, and this defect is B-cell intrinsic. The induction of GLε transcripts after LPS and IL-4 stimulation is significantly reduced in NFIL3-deficient B cells. Expression of NFIL3 in NFIL3-deficient B cells restores the impairment of IgE production, and overexpression of NFIL3 in the presence of cycloheximide induces GLε transcripts. Moreover, NFIL3 binds to Iε promoter in vivo. Together, these results identify NFIL3 as a key regulator of IL-4-induced GLε transcription in response to IL-4 and subsequent IgE class switching.
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