Journal of Experimental Medicine

ELF4 is an ETS family transcription factor involved in immune regulation, and germline loss-of-function mutations in ELF4 have been known as "deficiency in ELF4, X-linked"(DEX). To date, ELF4-related disease has been exclusively associated with germline mutations. Here, we report a pediatric patient with recurrent mucocutaneous inflammation and periodic fever caused by a somatic truncating mutation in ELF4. By directly comparing ELF4-mutant and wild-type immune cells within the same individual using full-length single-cell RNA sequencing, we identified mutation-associated transcriptional alterations across multiple immune cell types. Pathway analyses revealed cell type-specific immune alterations, characterized by reduced antiviral and interferon-related signaling in NK cells and enhanced inflammatory pathways related to Th17 differentiation and inflammatory bowel disease in CD16+ monocytes. This study expands the disease spectrum of ELF4 deficiency by identifying somatic truncation of ELF4 as a genetic mechanism underlying autoinflammatory diseases and biased immune programs.

Mast cells (MCs) are tissue-resident sentinels of the innate immune system that play pivotal roles in host defense and inflammation. Perivascular MCs exert a particularly strong influence on the onset and dynamics of inflammation through the rapid, directional release of proinflammatory mediators into the circulation. Yet, the mechanisms governing their attachment to the vessel wall - a prerequisite for intravascular degranulation - remain poorly defined. Using a conditional knockout of integrin {beta}1 (Itgb1) in MCs, we investigated how perivascular positioning, degranulation, and vasoactive function contribute to inflammatory responses. In vivo imaging revealed that Itgb1 is essential for positioning MCs within the perivascular niche, particularly around arterioles. The absence of Itgb1 markedly reduced directional MC degranulation into blood vessels during skin inflammation. In vitro, Itgb1-deficient MCs displayed impaired degranulation kinetics together with altered SHIP1/PI3K-AKT signaling and calcium influx upon P2X7 ligation by ATP. During contact hypersensitivity, mice lacking Itgb1 in MCs exhibited strongly diminished ear swelling and reduced recruitment of multiple leukocyte subsets. Mechanistically, disordered MC positioning and attenuated degranulation impaired endothelial activation, resulting in decreased leukocyte adhesion and extravasation. These findings uncover a dual role for Itgb1 in regulating MC responsiveness and pro-inflammatory vasoactive function, establishing Itgb1-mediated perivascular MC positioning as a key prerequisite for effective leukocyte recruitment. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/723399v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@ada618org.highwire.dtl.DTLVardef@73a85forg.highwire.dtl.DTLVardef@1330cccorg.highwire.dtl.DTLVardef@8d3b3c_HPS_FORMAT_FIGEXP M_FIG C_FIG

TNF is a potent proinflammatory cytokine that can induce cell death by activating the kinase RIPK1. The adaptor proteins TANK and AZI2 protect against cell death by recruiting TBK1 to the TNF receptor signaling complex, thereby inhibiting RIPK1. While deficiency of either adaptor alone is well tolerated, combined loss of TANK and AZI2 results in partial embryonic lethality and severe TNF- and RIPK1-driven autoinflammation. Here, we show that TANK/AZI2-deficient mice exhibit a striking expansion of regulatory T cells (Tregs), most of which display an effector phenotype with high expression of immunosuppressive genes. Although thymic Treg generation is modestly increased, Tregs arise predominantly in the periphery through a largely cell-intrinsic mechanism. The marked accumulation of effector Tregs suggested that the T-cell compartment may limit TNF-driven pathology in this model. Supporting this, T cell ablation in TANK/AZI2-deficient mice markedly exacerbates disease progression and enhances TNF-driven, RIPK1-mediated inflammation. Similarly, T cells protect against acute TNF-induced systemic inflammatory response syndrome by limiting RIPK1-mediated cell death. Together, our findings identify TANK and AZI2 as negative regulators of Treg formation, demonstrate that T cells restrain TNF-driven inflammation by limiting RIPK1-dependent cell death, and suggest that this protective effect is mediated primarily by Tregs.

Natural killer (NK) cells undergo stepwise differentiation from multipotent progenitors within secondary lymphoid tissues. Despite the central importance of the tissue microenvironment in their development, little is known about cell-cell interactions that regulate human NK cell trafficking and maturation. Here, we identify the chemokine receptor CXCR4 and its lig- and CXCL12 as regulators of stromal-NK cell interactions required for NK cell maturation. We demonstrate that CXCR4 is expressed throughout human NK cell development in peripheral blood and tonsil, and CXCL12 is enriched in stromal niches containing developing NK cells. Pharmacologic blockade or genetic disruption of CXCR4 resulted in diminished adhesion to integrin ligands and high-resolution imaging demonstrated crosstalk between CXCR4 and integrins, providing a mechanistic basis for chemokine-dependent modulation of adhesion. Further, CXCR4 blockade resulted in altered contact-dependent motility on stromal cells and integrin ligands, with decreased stable stromal engagement and increased cell speed. Consistent with a requirement for these interactions, treatment with the CXCR4 antagonist plerixafor (AMD3100) impaired NK cell generation from CD34+ precursors. Analysis of NK cells from WHIM syndrome patients with CXCR4 gain-of-function mutations treated with plerixafor revealed similar defects in migration and adhesion, supporting the in-vivo relevance CXCR4-dependent regulation of NK cell adhesion and motility.

Secondary lymphoid tissue, including tonsil, supports human NK cell development, but the spatial organization and tissue niches that drive this differentiation remain undefined. Here, we used single cell analysis of cyclic immunofluorescence to generate a comprehensive atlas of human NK cell development in tissue. By integrating regional localization, chemokine signaling, cytokine availability, and cell phenotype, we show that NK cell differentiation follows a reproducible spatial trajectory defined by stage-specific cell-cell interactions. Notably, CD34+ NK cell progenitors are found in the interfollicular domain in proximity to high endothelial venules and preferentially interact with lymphatic endothelial cells, suggesting their route of progenitor entry into tissue. Mature NK cells are primarily found in the T-cell rich parafollicular domain, where they interact with other NK cells and T cell subsets. Local inflammation increases NK cell frequency in tissue through both proliferation of NK progenitors and recruitment of circulating mature NK cells. Finally, we identify a subset of tonsil stromal cells that support differentiation of NK cells in vitro and proliferation of NK precursors in situ. Together, these findings demonstrate that spatial localization defines human NK cell development and provide an in situ definition of niches that support human NK cell differentiation in tonsil.

Persistence of memory T lymphocytes, in the apparent absence of antigen, is a hallmark of immune memory and key to adaptive immunity to recurrent infections. The signaling pathways ensuring survival and quiescence of the memory T cells are largely enigmatic. Here we show, by inhibition in vivo, that persistence of surface CD69+KLF2-tissue-resident memory T cells of murine bone marrow and spleen is blocked by antibodies to the integrins VLA-4 and LFA-1, connecting the memory T cells to VCAM1 and ICAM1 of stromal cells. Persistence requires the PI3K/AKT signaling pathway, since it is blocked by Wortmannin, and it involves PI3K-dependent survival genes. Surface CD69-KLF2+ memory T cells of the bone marrow are also dependent on integrin-mediated contact to stromal cells. Their persistence critically depends on the NF-kB pathway, their PI3K signaling pathway is not relevant. Blocking Jak1 and 3 of the interleukin-7 and -15 signaling pathways does affect memory T cells of the spleen, but not those of the bone marrow. Thus, tissue-resident KLF2+ and KLF2-memory T cells, and memory T cells of spleen and bone marrow, use different signaling pathways, adapting them to their respective tissues and reflecting an unexpected heterogeneity in the molecular mechanisms of persistence.

Host cell metabolic pathways influence innate immune responses to intracellular pathogens, but the contribution of nucleotide metabolism to antimicrobial defense remains incompletely defined. Here, we identify the mitochondrial nucleoside monophosphate kinase CMPK2 as a regulator of macrophage responses to Mycobacterium tuberculosis (Mtb). Using a targeted genetic screen of candidate host factors, we found that depletion of CMPK2 enhances intracellular Mtb replication in human macrophages. This phenotype was confirmed using both shRNA-mediated knockdown and CRISPR-Cas9-mediated knockout approaches. CMPK2 expression increased following macrophage activation and Mtb infection. Transcriptomic profiling revealed that loss of CMPK2 is associated with broad alterations in gene expression, including reduced expression of genes linked to innate immune and inflammatory responses early after infection. In contrast, myeloid-specific deletion of Cmpk2 in mice did not significantly alter bacterial burden or survival following aerosol Mtb infection, indicating that the contribution of CMPK2 to host defense is context dependent. Together, these findings identify CMPK2 as a host factor that limits Mtb replication in human macrophages and shapes innate immune gene expression programs.

Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1, IL-1{beta}, TNF-{beta}) and TH2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes were cross-reactive (75%, 12/16 SARS-CoV-2 TCRs) for autoantigens related to prostaglandin biology and insulin metabolism, suggesting a breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 gene targets with self-antigen peptides also exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease driven by uncensored B and T cell autoreactivity. Understanding this pathogenic process has been hampered by lack of studies of secondary lymphoid organs in human SLE. Using minimally invasive lymph node fine needle aspirates (LN-FNAs), we profiled tissue-resident immune cells from 59 SLE patients and 34 healthy controls through high-dimensional 43-color flow cytometry, antigen-specific tetramer probing, and sc-RNA sequencing with paired VH/VL repertoire analysis. Our findings reveal hyperactive lymph node immunity in SLE characterized by spontaneous germinal center (GC) activation, plasma cell accumulation enriched in mature CD19- and CD138+ antibody-secreting cells, and increased frequencies of both GC-TFH and PD-1+CXCR5- T extra-follicular helper cells. SLE lymph nodes harbored large oligoclonal B cell families with altered isotype usage, dominated by IgG1 and IgG4. Critically, self-reactive 9G4+ and Ro60+ B cells showed defective tolerance checkpoint control, accumulating in activated naive, GC, and plasma cell compartments with distinctive PD-1+Tox+ expression absent in viral-specific responses. Single-cell repertoire analysis revealed VH4-34 clones in SLE BGC and BPC, that in contrast to HD, had not experienced clonal redemption. Instead, SLE VH4-34 clones displayed low somatic hypermutation and preserved the AVY hydrophobic patch associated with autoreactivity. Monoclonal antibody testing confirmed that unmutated AVY+ VH4-34 clones retained polyreactivity against naive B cells, apoptotic cells, and multiple self-antigens. Together, these results define "clonal damnation" as a key mechanism in SLE whereby autoreactive VH4-34 clones of pathogenic potential escape tolerance checkpoints, expand in germinal centers, and differentiate into tissue plasma cells while preserving germline-encoded self-reactivity. Combined, our study defines critical mechanisms of tolerance breakdown in lupus pathogenesis.

Alveologenesis during early postnatal life requires tight coordination between epithelial differentiation and immune regulation, yet how immune cells contribute to this process remains unclear. Regulatory T cells (Tregs) are established mediators of immune homeostasis and tissue repair in adult lung injury, but their role in lung development is unknown. Here, we identify a transient wave of highly proliferative, activated Tregs that accumulates in the neonatal lung during an early postnatal window. Using inducible Treg ablation, we show that loss of this neonatal Treg population disrupts alveologenesis, resulting in enlarged airspaces, and persistent structural abnormalities later in life. Treg depletion also induces interferon-associated inflammatory programmes, promotes neutrophil accumulation, and is accompanied by a sustained imbalance in alveolar epithelial populations. Notably, neutrophil depletion partially rescues both epithelial composition and alveolar structure, identifying neutrophils as key downstream effectors of Treg-mediated regulation. Together, these findings show that neonatal Tregs are required for normal alveologenesis by restraining neutrophil-driven inflammation and preserving epithelial balance. Our study reveals a previously unappreciated role for immune regulation in lung organogenesis.

Acute respiratory distress syndrome (ARDS) is a devastating complication of respiratory infections; however, the biological mechanisms that initiate its onset are poorly defined. Here we show that TNFRSF13B polymorphisms increase the risk of ARDS following SARS-CoV-2 infection up to 7.4-fold compared to the WT genotype. The increased risk was not due to immune-deficiency or impaired virus neutralization. On the contrary, TNFRSF13B mutant subjects mounted better antibody neutralization compared to subjects with WT TNFRSF13B. However, IgG from subjects expressing TNFRSF13B variants had less sialic acid, terminal galactose, and fucose than IgG from subjects with a WT genotype. Moreover, IgG from TNFRSF13B mutant subjects exhibited increased recruitment of complement factors. Thus, besides well-known actions governing plasma cell differentiation, TNFRSF13B impacts both affinity maturation and effector functions of IgG in ways that independently govern complement activation controlling inflammatory responses known to trigger ARDS.

B cell development relies on stringent checkpoints that ensure immune competence and eliminate autoreactive clones. Transitional B cells (B220CD93), which emerge from the bone marrow, migrate to the spleen and differentiate into follicular (FO) or marginal zone (MZ) B cells, a process governed by B cell receptor (BCR) signaling strength, metabolic fitness, and survival cues. Here, we identify Folliculin Interacting Protein 1 (Fnip1) as a key regulator of this developmental transition. Using conditional Fnip1-deficient mice (Fnip1fl/flCD21Cre), loss of Fnip1 results in a developmental arrest at the transitional B220CD93mid stage, severely limiting differentiation into FO and MZ B cells and leading to accumulation of a distinct enlarged CD19high, RAG negative B cells. Fnip1 modulates BCR signaling thresholds and metabolic programming by regulating the AMPK/FLCN/TFEB and CD19/PI3K/Akt/mTORC1 pathways through restricting TFEB access to the nucleus. Using the MD4/mHEL/sHEL tolerance model, we show that Fnip1 is dispensable for negative selection but is essential for maintaining peripheral tolerance. Together, our findings define Fnip1 as a metabolic gatekeeper that integrates nutrient-sensing pathways with BCR signaling to orchestrate transitional B cell fate decisions, promote peripheral tolerance, and maintain immune homeostasis.

ABSTRACTSHeterozygous gain-of-function (GOF) mutations in signal transducer and activator of transcription 1 (STAT1) cause an inborn error of immunity characterized by immune dysregulation, recurrent infections and various autoimmune manifestations. However, the precise pathogenic mechanism by which STAT1 GOF contributes to autoimmunity remains elusive. In our cohort, STAT1-GOF patients exhibit biased circulating follicular helper T (cTfh) populations with CXCR3+ Tfh1-like features. Using a Stat1 GOF mouse model that spontaneously developed autoimmunity, we found that overactivated STAT1 promotes Tfh differentiation and disrupted T cell-dependent humoral responses with skewed immunoglobulin class switching towards IgG2. Furthermore, STAT1 GOF directly targets to Tfh and Th1 cell signature genes and thereby drives the development of Tfh1 cells with excessive IFN-{gamma} production, which implicated in autoantibody production and the development of autoimmunity. Notably, IFN-{gamma} neutralization significantly alleviated autoimmune cellular responses and autoantibody levels in mutant mice, highlighting IFN-{gamma} blockade as a promising targeted therapy for the STAT1-GOF patients with autoimmunity. Our findings suggest that proper regulation of STAT1 activity within a reasonable magnitude is crucial for ensuring optimal host-protective humoral immunity. One-sentence summaryOveractivated STAT1 promotes Tfh1 differentiation to drive autoimmunity.

Age is a major determinant of disease severity following La Crosse virus (LACV) infection, yet the immunological mechanisms underlying heightened susceptibility in children remains poorly defined. Here, we show that acute LACV infection in weanling mice induces T cell dysfunction characterized by early PD-1 upregulation and impaired effector differentiation despite evidence of activation. This state is associated with reduced IL-2-dependent STAT5 signaling, indicating a failure to respond to available cytokine cues. Although regulatory T cells expand and exhibit elevated CD25 expression, their depletion increases IL-2 levels without restoring antiviral T cell responses or viral control. In contrast, PD-1 blockade partially restores T cell activation, and combined PD-1 blockade with CD25 targeting enables robust effector differentiation and improved viral control. These findings demonstrate that checkpoint signaling limits T cell responsiveness to IL-2, uncoupling activation from differentiation and driving age-dependent susceptibility to LACV infection.

Basal keratinocytes in the skin are essential for epidermal homeostasis and repair; however, how intrinsic alterations in these cells contribute to inflammatory skin pathology remains poorly understood. In this study, we employed a tamoxifen-inducible mouse model to express the human RUNX1-ETO fusion gene, a well-established oncogenic driver of acute myeloid leukemia, in epidermal basal keratinocytes. RUNX1-ETO induction in keratinocytes resulted in progressive skin inflammation in vivo, accompanied by splenomegaly, epidermal hyperplasia, increased cytokine production, and alterations in epidermal stem cell composition. Inflammatory lesions were prominent in the tail, ear, and plantar epidermis, whereas hair-bearing dorsal skin remained largely unaffected. RNA-seq analysis of FACS-isolated RUNX1-ETO+ basal keratinocytes revealed global changes in gene expression, characterized by the suppression of epidermal homeostatic and metabolic programs and the activation of inflammatory signaling pathways. In particular, RUNX1-ETO expression was associated with increased TNF/NF-{kappa}B and IL-6-STAT signaling, as well as interferon-associated inflammatory pathways, together with the induction of neutrophil-attracting chemokines and epithelial inflammatory mediators. Together, these findings indicate that RUNX1-ETO-mediated transcriptional dysregulation in basal keratinocytes promotes a pro-inflammatory cellular state that drives progressive skin inflammation.

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a primary immunodeficiency caused by gain-of-function in CXCR4 chemokine receptor (CXCR4GOF) in response to its chemokine ligand CXCL12. The patients suffering from this syndrome display lymphopenia and neutropenia, and most of them show exacerbated susceptibility to human papillomavirus pathogenesis. In a mouse model harboring a WHIM-associated CXCR4 mutation and expressing HPV16 oncoproteins in keratinocytes, we previously reported reduced circulating plasmacytoid dendritic cells (pDCs), mirroring patients blood, and impaired dendritic cell (DC) trafficking from the skin to lymphoid organs, with the few migrating DCs displaying an overactivated phenotype. Given the promising results of CXCR4-targeted therapies in WHIM patients, we investigated whether and how the orally available CXCR4-specific antagonist, X4-136, affects DC localization, activation, and trafficking at the subset level, as well as skin immune landscape. CXCR4GOF inhibition corrected defects in circulating myeloid cells and pDCs, as well as in lymph node-resident DCs. Furthermore, it rescued skin DC migration to lymph nodes in WHIM mice, in a context- and subset-dependent manner, by promoting their activation and relocation within the dermis. Taken together, these findings indicate that inhibiting CXCR4GOF may restore skin immunity in WHIM syndrome by rescuing DC counts and functions. Key pointsO_LICXC R4 gain-of-function inhibition promotes subset-selective dermal dendritic cell migration to lymph nodes in a WHIM syndrome mouse model. C_LIO_LIInhibiting CXCR4 corrects migratory WHIM dendritic cell hyperactivation with subset-specific effects tied to the inflammatory context. C_LI

Human cytomegalovirus (CMV) infection represents a significant risk factor for transplant recipients, including patients undergoing hematopoietic stem cell transplantation (HSCT). Interestingly, several studies have reported an association between early CMV reactivation and a reduced risk of leukemia relapse, particularly in acute myeloid leukemia (AML). Given that CMV profoundly shapes the natural killer (NK) cell compartment, a contribution of CMV-primed NK cells to this effect has been proposed. To explore this mechanism, we analyzed the relationship between NK cell functionality and CMV reactivation in the context of AML. Consistent with observations in peripheral blood, CMV-seropositive HSCT recipients displayed expanded NKG2Cpos NK cell populations within the bone marrow, characterized by high Granzyme B expression. CMV replication was associated with elevated plasma IFN{gamma} levels, which in vitro rendered AML cells more susceptible to apoptosis when co-cultured with peripheral blood mononuclear cells. Importantly, IFN{gamma} treatment modulated NK cell responses by inducing a variety of NK cell ligands including HLA-E on primary bone marrow-derived blasts and AML cell lines. In line with this, the activation of CMV-associated NKG2Cpos NK cells was enhanced upon stimulation with IFN{gamma}-pretreated AML cells. In summary, our findings demonstrate that CMV replication induces a transient increase in IFN{gamma} levels that influences both AML and NK cells, ultimately enhancing AML cell susceptibility to NK cell-mediated cytotoxicity initiated through the NKG2C-HLA-E axis. ImportancePrevious studies suggested that CMV reactivation after HSCT may reduce leukemia relapse in AML patients, but the underlying mechanism remained unclear. Here, we show that CMV replication induces IFN{gamma} release, which sensitizes AML cells to NK cell-mediated killing. This effect involves upregulation of HLA-E on AML cells and activation of expanded NKG2Cpos NK cells within the bone marrow. Our findings uncover a novel IFN{gamma}-dependent link between CMV replication and enhanced NK cell cytotoxicity in AML, suggesting that combining IFN{gamma} treatment with NK cell-based immunotherapy or NKG2A blockade could reduce post-HSCT relapse, even in CMV-negative patients.

Targeting Tregs is a potential strategy to improve cancer therapies. However, which Tregs accumulate in response to tumoral processes, and how tumors affect their phenotype, is poorly understood. Here we show that tumor Tregs are equivalent to effector tissue Tregs in steady state organs. We used a mouse model of intestinal neoplasia to demonstrate that one early event in carcinogenesis is sufficient to induce local accumulation of Tregs resembling human tumor Tregs. Treg accumulation was driven by TCR-dependent oligoclonal expansion of tissue Tregs with an effector Treg phenotype. Treg expansion was independent of CCR8, IL33R and CD137, which were previously linked to tumor Treg. In contrast, GATA3 was required for effector tissue Tregs and for their expansion in response to neoplasia. Our findings identify GATA3-dependent clonal expansion of effector tissue Tregs as a key event in promoting tumor growth. HighlightsO_LIAn early tumorigenic event alone drives accumulation of effector tissue Tregs C_LIO_LITregs in tumors are phenotypically akin to effector tissue Tregs C_LIO_LIThe accumulation of Tregs is driven by TCR-dependent oligoclonal expansion C_LIO_LIGATA3 controls tumor-promoting effector tissue Tregs C_LI

The clearance of apoptotic cells by macrophages, termed efferocytosis, reprograms macrophages to a resolution/repair phenotype, and pathologic defects in efferocytosis drive many chronic inflammatory diseases. Previous studies have elucidated numerous downstream pro-resolving pathways activated by efferocytosis, but whether there exists a common upstream trigger of these pathways remains unknown. Here, we report that efferocytosing macrophages surprisingly use a signaling module typically associated with inflammation to carry out this key initiating role in tissue resolution. The binding of apoptotic cells to the MerTK receptor triggers a rapid and transient activation of inhibitor of nuclear factor (NF) kappa-B kinase subunit beta (IKK{beta}), leading to NF{kappa}B and p38-signal transducer and activator of transcription 3 (STAT3) signaling and then activation of several key downstream pro-resolving pathways, including interleukin-10 (IL-10) production, continuing efferocytosis, and regulatory T (Treg) cell expansion. The upstream IKK{beta} pathway and the downstream resolution pathways are linked through several intermediary molecules, including the transcription factor Myc, the epigenetic modifier ten-eleven translocation-2 (TET2), and the immune checkpoint protein programmed cell death ligand 1 (PD-L1). Deletion of macrophage IKK{beta} in vivo blocks the above resolution pathways and compromises tissue repair in two efferocytosis-mediated repair settings: resolution of thymic injury after dexamethasone-induced thymocyte apoptosis; and, most importantly, atherosclerosis regression induced by low-density lipoprotein (LDL)-lowering, which is highly relevant to the prevention of cardiovascular disease in humans. These findings illustrate the existence of a unifying upstream signal for efferocytosis-induced resolution, which could suggest new therapeutic strategies to enhance multiple tissue resolution pathways and to optimize anti-inflammatory therapies by avoiding blocking IKK{beta}-NF{kappa}B/p38-mediated resolution.

RNA-binding proteins are key players in determining the fate of mRNA. One such RNA binding protein, Fragile X messenger ribonucleoprotein (FMRP), has an established role in RNA transcription, metabolism, translation, and degradation in the brain and reproductive system. Although FMRP is expressed in immune cells, little is known about how FMRP influences immune cell mRNA transcript outcomes. Here, we show that macrophage infection with the intracellular pathogen Listeria monocytogenes induces FMRP translocation from the cytoplasm to the nucleus. We show that infected macrophages lacking FMRP have impaired Il6 induction in response to L. monocytogenes infection. Finally, we show that macrophages lacking FMRP have increased susceptibility to inflammatory cell death. Together, these data implicate FMRP in modulating proinflammatory gene expression during bacterial infection.