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Using single-cell analysis of whole blood and intestinal tissue, Olaloye et al. identify a population of inflammatory monocytes that are potentially pathogenic in necrotizing enterocolitis. They identify distinct phenotypes of necrotizing enterocolitis based on the nature of neutrophils (immature, newly emigrated, and aged) and highlight a population of CD16+CD163+ monocytes/Mϕ involved in multiple aspects of inflammation that could be targeted for therapeutics development.

Following myocardial infarction, tissue ischemia leads to activation of hypoxia-inducible factors. DeBerge et al. demonstrate that HIF-1α and HIF-2α activation in myeloid cells antagonizes cardiac repair pathways through cleavage of cardioprotective MerTK and suppression of anti-inflammatory mitochondrial metabolism, respectively.

Fukuda et al. demonstrate that AIM2 expression in DCs within human melanoma is a poor prognostic sign and that AIM2-deficient DC vaccination enhances melanoma immunotherapeutic responses by promoting STING-induced IFN secretion as well as limiting IL-1β and IL-18 production.

hnRNPC prevents release of inverted-repeat Alu double-stranded RNA into the cytosol by masking cryptic splice sites. Herzner et al. found that deficiency in hnRNPC led to dysregulation of splicing and increased abundance of intronic double-stranded RNA, which together with ADAR deficiency resulted in a synergistic increase in spontaneous MDA5-dependent IFN responses.

This work shows that Engrailed 1 (EN1) is a key mediator of TGFβ-induced myofibroblast differentiation and fibrotic tissue remodeling. Mechanistically, EN1 induces a profibrotic gene expression profile by modulating the activity of SP transcription factors to coordinate the microtubule–stress fiber cytoskeletal rearrangements required for fibroblast activation in a ROCK-dependent manner.

Type 2 cytokines promote epithelial changes that help to expel worms during intestinal helminth infection. Oyesola et al. show that prostaglandin D2 and its receptor CRTH2 are novel negative regulators of this response, dampening the Type 2 cytokine–mediated program.

BMP-Sox9 signaling drives tumor cells to transdifferentiate into astrocytes, which contributes to the recurrence of SHH-driven medulloblastoma, a common type of pediatric brain tumor.

The regulatory mechanisms controlling natural killer (NK) cell maturation remain unknown. In this article, Tan et al. report that Zhx2 acts as a key negative regulator of NK cell maturation by controlling IL-15 signaling and transcription of Zeb2.

Mowat et al. show that anti-tumor immunity in dMMR CRCs relies on recruitment and retention of systemic CD8+ T cells. This is driven by extensive genomic instability that upregulates CCL5 and CXCL10 in the CRC cells by endogenously activating cGAS/STING and type I IFN signaling.

The authors uncover a new interaction pattern between macrophage and adipocyte: that macrophage-derived uPA activates adipocyte-secreted PDGF-D, which finally accelerates AngII-induced cardiac remodeling in obese mice. Targeting the uPA/PDGF-D pathway might be a potential therapeutic tool for prevention of hypertensive cardiac injury during obesity.

The host-derived regulatory network that controls mucus secretion and thereby changes gut microbiota has not been fully illustrated. Here, we identify that Forkhead box protein O1 (Foxo1) is critical for gut commensalism and intestinal barrier integrity by regulating goblet cell function.

Genetically diverse IgM+ peripheral B cells reside in the lung microvasculature and dampen neutrophil-mediated lung inflammation via lipoxins. Podstawka et al. reveal that transitional B cells marginate in the lung capillaries, where they dampen neutrophil inflammation. These discoveries help elucidate regulatory mechanisms that attenuate acute lung inflammation, which, when unchecked, can lead to acute respiratory distress syndrome and pulmonary failure.

This study describes decreased production of reactive oxygen species by phagocytes of PKCδ-deficient patients as a possible mechanism by which inherited human PKCδ deficiency contributes to susceptibility to infectious diseases.

Vendramin et al. demonstrate that the integrated stress response in melanoma promotes cell plasticity and drives therapy resistance by boosting mitochondrial translation. Therefore, repurposing of mitoribosome-targeting antibiotics offers a salvage strategy for the treatment of patients with limited therapeutic options.

Using an immunocompetent mouse model of ZIKV infection, Cavazzoni et al. describe an immunodominant anti-NS1 humoral response characterized by autoreactive germinal center B cells, both cross-reactive and non-cross-reactive with NS1, exhibiting a paucity of somatic hypermutations, suggesting a broad breakage of self-tolerance in this viral infection model.

Technical Advances and Resources

Skin index-sorted single-cell RNA sequencing reveals the transcriptional landscape of macrophages and dendritic cells in atopic and psoriatic skin and identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriatic skin.

Transient genetic depletion of essential proteins in Mycobacterium tuberculosis leads to the establishment of latent infection in mice that reproducibly reactivates in a stable proportion of infected mice, mimicking aspects of latent tuberculosis and tuberculosis relapse in humans.

Through scRNA-seq and ATAC-seq, Pisu et al. characterize specific lung macrophage subsets that either restrict or promote M. tuberculosis growth. Comparable macrophage populations are present in the human airways, and cells show evidence of epigenetic imprinting.

Review

Neuro-Immune Interactions Focus

Astrocytes are glial cells of the central nervous system (CNS) that are strategically positioned to control CNS immunity in the context of health and disease. Here, Sanmarco, Polonio, Wheeler, and Quintana review progress in elucidating astrocyte–immune interactions in multiple sclerosis.

Neuro-Immune Interactions Focus

scRNA-seq analyses of microglial responses to AD pathology in patients and mouse models have provided fundamental insights but also exposed some heterogeneity and discrepancies. Here, we identify consistent microglial response patterns and discuss parallels and incongruities between humans and mice.

Viewpoint

Here, we will summarize the historical and current understanding of the stepwise assembly and function of factors that regulate ifnb gene transcription.

Ahn and Wang discuss the translational potential of the bat model for treating human diseases.

Insights

A recent study published in JEM describes the adipocyte–macrophage collaboration to foster cardiac fibrosis through the actions of angiotensin II in obesity.

The NS1 protein of flaviviruses is taking center stage. Recent work has made it an attractive target for development of vaccines and immunotherapeutics. Cavazzoni and colleagues now reveal a dark side to NS1, linking it to the development of self-reactive antibodies.

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