ON THE COVER
Baranska et al. report that myeloid cells of the ear dermis are dominated by macrophages that have ingested melanosomes from neighboring melanocytes and denoted as melanophages. The cover illustrates the cytosol of those melanophages that is crowded with elongated melanin granules. Vacuoles and cytoplasm were pseudocolored in blue to better visualize membranebound melanosomes. The image was provided by the authors and modified by the JEM editorial office. See page 1115.
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Death, eaters, and dark marks
A study by Baranska in this issue of JEM identifies and elucidates the homeostasis of murine macrophages responsible for engulfing melanin and tattoo pigment, demonstrating that dark marks in the dermis can endure a cycle of cell death, renewal, and reuptake by bone marrow (BM)–derived precursors.
TAK1ng control: TAK1 restrains NLRP3 activation
In this issue of JEM, Malireddi et al. demonstrate that macrophage-specific loss of TAK1 causes spontaneous NLRP3 inflammasome activation, driven by unregulated TNF secretion and signaling. This has implications for therapeutically targeting TAK1, enhancing its potential function as an anticancer drug treatment.
Primary atopic disorders
Important insights from monogenic disorders into the immunopathogenesis of allergic diseases and reactions are discussed.
Brief Definitive Report
TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation
The NLRP3 inflammasome protects the host against microbial infections. In this study, Malireddi et al. demonstrate the critical role of TAK1 in restricting RIPK1 signaling to inhibit spontaneous NLRP3 inflammasome activation and cell death, which may be targeted for treatment of myeloid proliferation.
Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection
Nair et al. define a key role for Irg1 in minimizing the pathological immune response associated with Mtb infection. Using Irg1−/− and Irg1fl/fl conditional mice, detailed immune cell analysis, and transcriptional profiling, their data supports a model where Irg1 expression in myeloid cell subsets tempers inflammation and controls the recruitment and infection of neutrophils during Mtb infection.
ApoE facilitates the microglial response to amyloid plaque pathology
Increasing evidence suggests that apoE influences the innate immune response in neurodegeneration. Here, Ulrich et al. report that apoE influences amyloid plaque morphology and the microglial response to amyloid plaques, along with plaque-associated neuronal toxicity.
Regulation of amyloid-β dynamics and pathology by the circadian clock
Circadian dysfunction is common in Alzheimer’s disease, but its role in disease pathogenesis is unknown. Kress et al. demonstrate that the circadian clock regulates daily rhythms in amyloid-β and that genetic disruption of clock function accelerates amyloid plaque accumulation in mice.
IL-7–dependent maintenance of ILC3s is required for normal entry of lymphocytes into lymph nodes
Yang et al. identify a new function for IL-7 in permitting efficient entry of T and B lymphocytes into lymph nodes. Maintenance of ILC3s by IL-7 is implicated because ILC3-deficient chimeras exhibit similar trafficking defects.
STAT-3–independent production of IL-17 by mouse innate-like αβ T cells controls ocular infection
St. Leger et al. identify and examine innate-like αβ T cells that circumvent canonical STAT-3 phosphorylation to produce protective IL-17. These cells can exist in the ocular mucosa and protect the ocular surface from pathogenic Staphylococcus aureus infection.
4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses
Tumor-infiltrating T cells experience metabolic repression that hinders their function and thus response to immunotherapy. Menk et al. show that ligation of 4-1BB, a TNFR family costimulatory molecule, can promote increased metabolic sufficiency, which enables intratumoral T cell function and response to immunotherapy.
Signaling function of PRC2 is essential for TCR-driven T cell responses
PRC2 is a known chromatin regulator. Here the authors show novel cytosolic components of PRC2 and that PRC2 inactivation results in attenuation of MAPK/Erk signaling and impaired T cell activation. Systemic PRC2 inhibition in vivo cures the autoimmune syndrome caused by regulatory T cell depletion.
Unveiling skin macrophage dynamics explains both tattoo persistence and strenuous removal
Using a mouse model allowing inducible ablation of tissue-resident macrophages, Baranska et al. determine that skin macrophages are the only cells capable of capturing and retaining tattoo pigment particles and show that long-term tattoo persistence relies on macrophage renewal rather than on macrophage longevity.
Growth of Mycobacterium tuberculosis in vivo segregates with host macrophage metabolism and ontogeny
This study by Huang et al. demonstrates that lung macrophages of differing ontogeny respond divergently to Mycobacterium tuberculosis infection in vivo. Alveolar macrophages and interstitial macrophages adopt different metabolic states that promote or control M. tuberculosis growth, respectively.
ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates
Guan et al. identify genetic cooperativity between the transcription factor ZEB1 and the miR-200 family in memory CD8+ T cell development, which contrasts with that observed in the EMT. This study also shows that ZEB1 and its closely related homologue, ZEB2, play functionally distinct roles in CD8+ T cell differentiation.
Peripherally derived T regulatory and γδ T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy
Xu et al. provide the first study in patients with intractable epilepsy showing a direct correlation between the phenotype, activation state, cytokine profiles, and ability to cause neuronal apoptosis of brain-infiltrating peripherally derived immune cells with seizure severity using an unbiased flow cytometric approach.
CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss
Using a high-throughput small molecule screen, Teitz et al. identify kenpaullone, a cyclin-dependent kinase 2 inhibitor, which when delivered locally confers protection against cisplatin- and noise-induced hearing loss in zebrafish, mice, and rats and reduces mitochondrial ROS production and cochlear cell death.
ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling
Schmidt et al. show that loss of the membrane-bound metalloprotease ADAM17 led to impaired intestinal cancer development in the murine APCmin/+ model, which also depended on IL-6 trans-signaling via the soluble IL-6R and could be blocked by the specific IL-6 trans-signaling inhibitor sgp130Fc.
Plasma cell output from germinal centers is regulated by signals from Tfh and stromal cells
Plasmablasts generated in germinal centers (GC) emerge at the GC–T zone interface (GTI). Zhang et al. demonstrate two major regulators of this process: Tfh-derived IL-21 and APRIL produced by CD157high fibroblastic reticular cells located in the GTI.
Rab6-dependent retrograde traffic of LAT controls immune synapse formation and T cell activation
Carpier et al. show that LAT trafficking to the immune synapse depends on endosome-to-Golgi/TGN retrograde transport and is controlled by Rab6 and Syntaxin-16. Moreover, they show that this retrograde pathway controls the TCR-induced activation of T lymphocytes.