Discovering dominant tumor immune archetypes in a pan-cancer census.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity.

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.

The NK cell-cancer cycle: advances and new challenges in NK cell-based immunotherapies.

Natural killer (NK) cells belong to the innate immune system and contribute to protecting the host through killing of infected, foreign, stressed or transformed cells. Additionally, via cellular cross-talk, NK cells orchestrate antitumor immune responses. Hence, significant efforts have been undertaken to exploit the therapeutic properties of NK cells in cancer. Current strategies in preclinical and clinical development include adoptive transfer therapies, direct stimulation, recruitment of NK cells into the tumor microenvironment (TME), blockade of inhibitory receptors that limit NK cell functions, and therapeutic modulation of the TME to enhance antitumor NK cell function. In this Review, we introduce the NK cell-cancer cycle to highlight recent advances in NK cell biology and to discuss the progress and problems of NK cell-based cancer immunotherapies.

Multiomics in the central Arctic Ocean for benchmarking biodiversity change.

Multiomics approaches need to be applied in the central Arctic Ocean to benchmark biodiversity change and to identify novel species and their genes. As part of MOSAiC, EcoOmics will therefore be essential for conservation and sustainable bioprospecting in one of the least explored ecosystems on Earth.

Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model.

For the past two decades, BTK a tyrosine kinase and member of the Tec family has been a drug target of significant interest due to its potential to selectively treat various B cell-mediated diseases such as CLL, MCL, RA, and MS. Owning to the challenges encountered in identifying drug candidates exhibiting the potency block B cell activation via BTK inhibition, the pharmaceutical industry has relied on the use of covalent/irreversible inhibitors to address this unmet medical need. Herein, we describe a medicinal chemistry campaign to identify structurally diverse reversible BTK inhibitors originating from HITS identified using a fragment base screen. The leads were optimized to improve the potency and in vivo ADME properties resulting in a structurally distinct chemical series used to develop and validate a novel in vivo CD69 and CD86 PD assay in rodents.

Persistence and Potential Atmospheric Ramifications of Ice-Nucleating Particles Released from Thawing Permafrost.

Permafrost underlies approximately a quarter of the Northern Hemisphere and is changing amidst a warming climate. Thawed permafrost can enter water bodies through top-down thaw, thermokarst erosion, and slumping. Recent work revealed that permafrost contains ice-nucleating particles (INPs) with concentrations comparable to midlatitude topsoil. These INPs may impact the surface energy budget of the Arctic by affecting mixed-phase clouds, if emitted into the atmosphere. In two 3-4-week experiments, we placed 30,000- and 1000-year-old ice-rich silt permafrost in a tank with artificial freshwater and monitored aerosol INP emissions and water INP concentrations as the water's salinity and temperature were varied to mimic aging and transport of thawed material into seawater. We also tracked aerosol and water INP composition through thermal treatments and peroxide digestions and bacterial community composition with DNA sequencing. We found that the older permafrost produced the highest and most stable airborne INP concentrations, with levels comparable to desert dust when normalized to particle surface area. Both samples showed that the transfer of INPs to air persisted during simulated transport to the ocean, demonstrating a potential to influence the Arctic INP budget. This suggests an urgent need for quantifying permafrost INP sources and airborne emission mechanisms in climate models.

The effect of population density on outcomes of major trauma patients in Ireland.

BACKGROUND: Time-sensitive emergencies in areas of low population density have statistically poorer outcomes. This includes incidents of major trauma. This study assesses the effect that population density at a receiving hospital of a major trauma patient has on survival. METHODS: Patients meeting Trauma Audit Research Network criteria for major trauma from 2016 to 2020 in Ireland were included in this retrospective observational study. Incident data were retrieved from the Major Trauma Audit, while data on population density were calculated from Irish state sources. The primary outcome measure of survival to discharge was compared to population density using logistic regression, adjusted for demographic and incident variables. Records were divided into population density tertiles to assess for between-group differences in potential predictor variables. RESULTS: Population density at a receiving hospital had no impact on mortality in Irish major trauma patients from our logistic regression model (OR = 1.01, 95% CI 0.98-1.05, p = 0.53). Factors that did have an impact were age, Charlson Comorbidity Index, Injury Severity Score, and the presence of an Orthopaedic Surgery service at the receiving hospital (all p < 0.001). Age and Charlson Comorbidity Index differed slightly by population density tertile; both were higher in areas of high population density (all p < 0.001). CONCLUSIONS: Survival to discharge in Irish major trauma patients does not differ substantially based on population density. This is an important finding as Ireland moves to a new trauma system, with features based on population distribution. An Orthopaedic Surgery service is an important feature of a major trauma receiving hospital and its presence improves outcomes.

Frailty and emergency abdominal surgery: A systematic review and meta-analysis.

INTRODUCTION: Patients aged ≥65 years currently account for approximately 55% of all emergent operations. However, these patients account for 75% of post-operative mortality. Older age has long been associated with adverse outcomes from emergency surgery. However, old age is a heterogenous state. Recent studies have indicated that frailty may more accurately reflect true biological age and perioperative risk than chronological age alone in patients undergoing elective surgery. Few studies have evaluated the impact of frailty on post-operative outcomes in this setting. METHODS: A systematic, electronic search for relevant publications was performed in November 2019 using Pubmed and Embase from 2009 to 2019. The latest search for articles was performed on February 16th, 2020. Articles were excluded if frailty was not measured using a frailty tool, or if patients did not undergo emergency general surgery (EGS). RESULTS: The prevalence of frailty amongst patients undergoing emergency abdominal surgery was 30.8%. The all-cause mortality rate was 15.68%. The mortality rate amongst the frail undergoing EGS was 24.7%. Frailty was associated with an increased mortality rate compared with the non-frail (odds ratio (OR) 4.3, 95% CI 2.25-8.19%, p < 0.05, I2 = 80%). CONCLUSIONS: There is strong evidence to suggest that frailty in the older population predicts post-operative mortality, complications, prolonged length of stay and the loss of independence. Collaborative working with medicine for the elderly physicians to target modifiable aspects of the frailty syndrome in the perioperative pathway may improve outcomes. Frailty scoring should be integrated into acute surgical assessment practice to aid decision-making and development of novel postoperative strategies.

The Use of Clinical Parameters as Adjuncts to Endoscopic Evaluation of Mural Thickening on Conventional Computed Tomography in Diagnosing Malignancy.

BACKGROUND: Mural thickening (MT) on computed tomography (CT) poses a diagnostic dilemma in the absence of clear reporting guidelines. The aim of this study was to analyse CT reports, identifying patients in whom gastrointestinal wall MT was observed, and to correlate these reports with subsequent endoscopic evaluation. METHODS: Patients with MT who had follow-up endoscopy were included in the study (n = 308). The cohort was subdivided into upper gastrointestinal mural thickening (UGIMT) & lower gastrointestinal mural thickening (LGIMT). RESULTS: In total, 55.71% (n = 122) of colonoscopies and 61.8% (n = 55) of gastroscopies were found to be normal. Haemoglobin (HB) level in combination with MT was a predictor of neoplasia in both arms (p = 0.04 UGIMT cohort, p < 0.001 LGIMT cohort). In addition to this, age was a significant correlative parameter in both UGIMT and LGIMT cohorts (p = 0.003, p < 0.001 respectively). Dysphagia and weight loss were associated with UGI malignancies (38 and 63% respectively) and rectal bleeding was correlative in 20% of patients with LGI malignancies. CONCLUSION: HB, advancing age, and red flag symptoms are potentially useful adjuncts to MT in predicting upper and lower gastrointestinal malignancies. We propose the adoption of a streamlined pathway to delineate patients who should undergo endoscopic investigation following CT identification of MT.

Impact of targeted trainer feedback via video review on trainee performance of laparoscopic cholecystectomy.

INTRODUCTION: Tools for improving operative performance for surgical trainees are increasingly desirable, particularly in the context of EWTD and 'run-through' training programmes. In addition, positive direct trainer feedback to trainees can improve skill acquisition and motivation, whilst negative feedback may have the opposite effect.1 We aimed to examine the impact of targeted trainer feedback based on video analysis on trainee confidence and objective operative performance in laparoscopic cholecystectomy. METHODS: Selected procedures designated as training cases were recorded. These were assessed by the trainers using the Independence-Scaled Procedural Assessment Score for laparoscopic cholecystectomy. Targeted feedback based on video review of selected procedures was then delivered by the trainers to the trainees. Trainees completed a self-reported questionnaire based on their response to this feedback. Subsequent to the feedback intervention, further training procedures were recorded and assessed. RESULTS: A total of 6 trainees and 4 trainers participated in the study. For the pre-intervention assessment 15 cases were recorded, with a further 13 for the post-intervention assessment (total n = 28). The overall scores for the procedures performed post video feedback were improved, with a trend towards statistical significance (p = 0.08). However, there was a statistically significant improvement in the scores for performance of the triangle of Calot dissection after the feedback intervention (p = 0.009). The response rate to the questionnaire was 100%, with all trainees agreeing that they felt more confident and competent after the feedback intervention. CONCLUSION: Targeted feedback to trainees based on post-procedure video review improves trainee confidence and may also improve performance. ACGME Core Competencies; Patient Care and Procedural Skills; Practice Based Learning and Improvement.

Oxidative opening of the aromatic ring: Tracing the natural history of a large superfamily of dioxygenase domains and their relatives.

A diverse collection of enzymes comprising the protocatechuate dioxygenases (PCADs) has been characterized in several extradiol aromatic compound degradation pathways. Structural studies have shown a relationship between PCADs and the more broadly-distributed, functionally enigmatic Memo domain linked to several human diseases. To better understand the evolution of this PCAD-Memo protein superfamily, we explored their structural and functional determinants to establish a unified evolutionary framework, identifying 15 clearly-delineable families, including a previously-underappreciated diversity in five Memo clade families. We place the superfamily's origin within the greater radiation of the nucleoside phosphorylase/hydrolase-peptide/amidohydrolase fold prior to the last universal common ancestor of all extant organisms. In addition to identifying active-site residues across the superfamily, we describe three distinct, structurally-variable regions emanating from the core scaffold often housing conserved residues specific to individual families. These were predicted to contribute to the active-site pocket, potentially in substrate specificity and allosteric regulation. We also identified several previously-undescribed conserved genome contexts, providing insight into potentially novel substrates in PCAD clade families. We extend known conserved contextual associations for the Memo clade beyond previously-described associations with the AMMECR1 domain and a radical S-adenosylmethionine family domain. These observations point to two distinct yet potentially overlapping contexts wherein the elusive molecular function of the Memo domain could be finally resolved, thereby linking it to nucleotide base and aliphatic isoprenoid modification. In total, this report throws light on the functions of large swaths of the experimentally-uncharacterized PCAD-Memo families.

The histopathological and molecular features of breast carcinoma with tumour budding-a systematic review and meta-analysis.

PURPOSE: Tumour budding (TB) is an adverse histological feature in many epithelial cancers. It is thought to represent epithelial-mesenchymal transition, a key step in the metastatic process. The significance of TB in breast carcinoma (BC) remains unclear. The aim of this study is to investigate the relationship between TB and other histological and molecular features of BC. METHODS: A systematic search was performed to identify studies that compared features of BC based on the presence or absence of high-grade TB. Dichotomous variables were pooled as odds ratios (OR) using the Der Simonian-Laird method. Quality assessment of the included studies was performed using the Newcastle-Ottawa scale (NOS). RESULTS: Seven studies with a total of 1040 patients (high-grade TB n = 519, 49.9%; low-grade/absent TB n = 521, 50.1%) were included. A moderate to high risk of bias was noted. The median NOS was 7 (range 6-8). High-grade TB was significantly associated with lymph node metastasis (OR 2.32, 95% c.i. 1.77 to 3.03, P < 0.001) and lymphovascular invasion (OR 3.08, 95% c.i. 2.13 to 4.47, P < 0.001). With regard to molecular subtypes, there was an increased likelihood of high-grade TB in oestrogen (OR 1.66, 95% c.i. 1.21 to 2.29, P = 0.002) and progesterone receptor-positive (OR 1.48, 95% c.i. 1.09 to 2.02, P = 0.01) tumours. In contrast, triple-negative breast cancer had a reduced incidence of high-grade TB (OR 0.46, 95% c.i. 0.30 to 0.72, P = 0.0006). CONCLUSION: High-grade TB is enriched in hormone receptor-positive BC and is associated with known adverse prognostic variables. TB may offer new insights into the metastatic process of BC.

The Utility of Neutrophil to Lymphocyte Ratio as a Predictor of Intervention in Acute Diverticulitis.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR) is a novel biomarker that has been recently studied in diverticulitis. The primary aim of this study was to assess the accuracy of NLR in predicting which patients had complicated diverticulitis and which patients required a radiological or surgical intervention. The accuracy of NLR was compared to C-reactive protein (CRP), white blood cell (WBC) count, neutrophil count and white cell to lymphocyte ratio (WLR). METHODS: Details of all patients admitted with acute diverticulitis over an 18-month period were collected prospectively. Median CRP, WBC, neutrophil count, WLR and NLR values at initial presentation were compared using the Mann-Whitney U test. The diagnostic accuracy of each test was assessed using receiver operating characteristic curve analysis. Optimal cut-off points were determined for each biomarker using Youden's Index (J). RESULTS: CRP, WBC, neutrophil count, WLR and NLR had variable accuracy in predicting complicated diverticulitis. NLR had the greatest accuracy of the 5 biomarkers in predicting the need for intervention with an area under the curve of 0.79 (p < 0.0001). The optimal cut-off point for NLR was 5.34 (J = 0.45). CONCLUSION: NLR was more accurate than CRP, WBC, neutrophil count and WLR in predicting the need for intervention. This cost-neutral, readily available biomarker can easily be calculated from the complete blood count and is a useful adjunct to CT.

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro.

Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensing stresses and strains in bone. Sclerostin, a product of the SOST gene, is produced postnatally primarily by osteocytes and is a negative regulator of bone formation. Recent studies show that SOST is mechanically regulated at both the mRNA and protein levels. During prolonged bed rest and immobilization, circulating sclerostin increases both in humans and in animal models, and its increase is associated with a decrease in parathyroid hormone. To investigate whether SOST/sclerostin up-regulation in mechanical unloading is a cell-autonomous response or a hormonal response to decreased parathyroid hormone levels, we subjected osteocytes to an in vitro unloading environment achieved by the NASA rotating wall vessel system. To perform these studies, we generated a novel osteocytic cell line (Ocy454) that produces high levels of SOST/sclerostin at early time points and in the absence of differentiation factors. Importantly, these osteocytes recapitulated the in vivo response to mechanical unloading with increased expression of SOST (3.4 ± 1.9-fold, p < 0.001), sclerostin (4.7 ± 0.1-fold, p < 0.001), and the receptor activator of nuclear factor κΒ ligand (RANKL)/osteoprotegerin (OPG) (2.5 ± 0.7-fold, p < 0.001) ratio. These data demonstrate for the first time a cell-autonomous increase in SOST/sclerostin and RANKL/OPG ratio in the setting of unloading. Thus, targeted osteocyte therapies could hold promise as novel osteoporosis and disuse-induced bone loss treatments by directly modulating the mechanosensing cells in bone.

Pseudomonas aeruginosa quorum-sensing molecule homoserine lactone modulates inflammatory signaling through PERK and eI-F2α.

Pseudomonas aeruginosa secrete N-(3-oxododecanoyl)-homoserine lactone (HSL-C12) as a quorum-sensing molecule to regulate bacterial gene expression. Because HSL-C12 is membrane permeant, multiple cell types in P. aeruginosa-infected airways may be exposed to HSL-C12, especially adjacent to biofilms where local (HSL-C12) may be high. Previous reports showed that HSL-C12 causes both pro- and anti-inflammatory effects. To characterize HSL-C12's pro- and anti-inflammatory effects in host cells, we measured protein synthesis, NF-κB activation, and KC (mouse IL-8) and IL-6 mRNA and protein secretion in wild-type mouse embryonic fibroblasts (MEF). To test the role of the endoplasmic reticulum stress inducer, PERK we compared these responses in PERK(-/-) and PERK-corrected PERK(-/-) MEF. During 4-h treatments of wild-type MEF, HSL-C12 potentially activated NF-κB p65 by preventing the resynthesis of IκB and increased transcription of KC and IL-6 genes (quantitative PCR). HSL-C12 also inhibited secretion of KC and/or IL-6 into the media (ELISA) both in control conditions and also during stimulation by TNF-α. HSL-C12 also activated PERK (as shown by increased phosphorylation of eI-F2α) and inhibited protein synthesis (as measured by incorporation of [(35)S]methionine by MEF). Comparisons of PERK(-/-) and PERK-corrected MEF showed that HSL-C12's effects were explained in part by activation of PERK→phosphorylation of eI-F2α→inhibition of protein synthesis→reduced IκBα production→activation of NF-κB→increased transcription of the KC gene but reduced translation and secretion of KC. HSL-C12 may be an important modulator of early (up to 4 h) inflammatory signaling in P. aeruginosa infections.

Degringolade, a SUMO-targeted ubiquitin ligase, inhibits Hairy/Groucho-mediated repression.

Transcriptional cofactors are essential for proper embryonic development. One such cofactor in Drosophila, Degringolade (Dgrn), encodes a RING finger/E3 ubiquitin ligase. Dgrn and its mammalian ortholog RNF4 are SUMO-targeted ubiquitin ligases (STUbLs). STUbLs bind to SUMOylated proteins via their SUMO interaction motif (SIM) domains and facilitate substrate ubiquitylation. In this study, we show that Dgrn is a negative regulator of the repressor Hairy and its corepressor Groucho (Gro/transducin-like enhancer (TLE)) during embryonic segmentation and neurogenesis, as dgrn heterozygosity suppresses Hairy mutant phenotypes and embryonic lethality. Mechanistically Dgrn functions as a molecular selector: it targets Hairy for SUMO-independent ubiquitylation that inhibits the recruitment of its corepressor Gro, without affecting the recruitment of its other cofactors or the stability of Hairy. Concomitantly, Dgrn specifically targets SUMOylated Gro for sequestration and antagonizes Gro functions in vivo. Our findings suggest that by targeting SUMOylated Gro, Dgrn serves as a molecular switch that regulates cofactor recruitment and function during development. As Gro/TLE proteins are conserved universal corepressors, this may be a general paradigm used to regulate the Gro/TLE corepressors in other developmental processes.

Reproductive outcome and survival of common bottlenose dolphins sampled in Barataria Bay, Louisiana, USA, following the Deepwater Horizon oil spill.

Common bottlenose dolphins (Tursiops truncatus) inhabit bays, sounds and estuaries across the Gulf of Mexico. Following the Deepwater Horizon oil spill, studies were initiated to assess potential effects on these ecologically important apex predators. A previous study reported disease conditions, including lung disease and impaired stress response, for 32 dolphins that were temporarily captured and given health assessments in Barataria Bay, Louisiana, USA. Ten of the sampled dolphins were determined to be pregnant, with expected due dates the following spring or summer. Here, we report findings after 47 months of follow-up monitoring of those sampled dolphins. Only 20% (95% CI: 2.50-55.6%) of the pregnant dolphins produced viable calves, as compared with a previously reported pregnancy success rate of 83% in a reference population. Fifty-seven per cent of pregnant females that did not successfully produce a calf had been previously diagnosed with moderate-severe lung disease. In addition, the estimated annual survival rate of the sampled cohort was low (86.8%, 95% CI: 80.0-92.7%) as compared with survival rates of 95.1% and 96.2% from two other previously studied bottlenose dolphin populations. Our findings confirm low reproductive success and high mortality in dolphins from a heavily oiled estuary when compared with other populations. Follow-up studies are needed to better understand the potential recovery of dolphins in Barataria Bay and, by extension, other Gulf coastal regions impacted by the spill.

Myelopoiesis is regulated by osteocytes through Gsα-dependent signaling.

Hematopoietic progenitors are regulated in their respective niches by cells of the bone marrow microenvironment. The bone marrow microenvironment is composed of a variety of cell types, and the relative contribution of each of these cells for hematopoietic lineage maintenance has remained largely unclear. Osteocytes, the most abundant yet least understood cells in bone, are thought to initiate adaptive bone remodeling responses via osteoblasts and osteoclasts. Here we report that these cells regulate hematopoiesis, constraining myelopoiesis through a Gsα-mediated mechanism that affects G-CSF production. Mice lacking Gsα in osteocytes showed a dramatic increase in myeloid cells in bone marrow, spleen, and peripheral blood. This hematopoietic phenomenon was neither intrinsic to the hematopoietic cells nor dependent on osteoblasts but was a consequence of an altered bone marrow microenvironment imposed by Gsα deficiency in osteocytes. Conditioned media from osteocyte-enriched bone explants significantly increased myeloid colony formation in vitro, which was blocked by G-CSF­neutralizing antibody, indicating a critical role of osteocyte-derived G-CSF in the myeloid expansion.

Exploring allosteric activation of LigAB from Sphingobium sp. strain SYK-6 through kinetics, mutagenesis and computational studies.

The protocatechuate 4,5-dioxygenase (LigAB) from Sphingobium sp. strain SYK-6 is the defining member of the Type II extradiol dioxygenase superfamily (a.k.a. PCA Dioxygenase Superfamily or PCADSF) and plays a key aromatic ring-opening role in the metabolism of several lignin derived aromatic compounds. In our search for alternate substrates and inhibitors of LigAB, we discovered allosteric rate enhancement in the presence of non-substrate protocatechuate-like aldehydes such as vanillin. LigAB has the broadest substrate utilization profile of all protocatechuate (PCA) 4,5-dioxygenase described in the literature, however, the rate enhancement is only observed with PCA, with vanillin increasing kcat for LigAB by 36%. Computational docking has identified a potential site of allosteric binding near the entrance to the active site. Examination of a multiple sequence alignment reveals that many of the residues contributing to this newly identified allosteric pocket are highly conserved within the LigB family of the PCADSF. Point mutants of Phe103α and Ala18ß, two residues located in the putative allosteric pocket, display altered rate enhancement as compared to LigAB-WT, providing support for the computationally identified allosteric binding site. Further investigation of this binding site may provide insight into the mechanism of this never before observed allosteric activation in extradiol dioxygenases.

IL-1α signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo.

Legionella pneumophila is an intracellular bacterial pathogen that is the cause of a severe pneumonia in humans called Legionnaires' disease. A key feature of L. pneumophila pathogenesis is the rapid influx of neutrophils into the lungs, which occurs in response to signaling via the IL-1R. Two distinct cytokines, IL-1α and IL-1ß, can stimulate the type I IL-1R. IL-1ß is produced upon activation of cytosolic sensors called inflammasomes that detect L. pneumophila in vitro and in vivo. Surprisingly, we find no essential role for IL-1ß in neutrophil recruitment to the lungs in response to L. pneumophila. Instead, we show that IL-1α is a critical initiator of neutrophil recruitment to the lungs of L. pneumophila-infected mice. We find that neutrophil recruitment in response to virulent L. pneumophila requires the production of IL-1α specifically by hematopoietic cells. In contrast to IL-1ß, the innate signaling pathways that lead to the production of IL-1α in response to L. pneumophila remain poorly defined. In particular, although we confirm a role for inflammasomes for initiation of IL-1ß signaling in vivo, we find no essential role for inflammasomes in production of IL-1α. Instead, we propose that a novel host pathway, perhaps involving inhibition of host protein synthesis, is responsible for IL-1α production in response to virulent L. pneumophila. Our results establish IL-1α as a critical initiator of the inflammatory response to L. pneumophila in vivo and point to an important role for IL-1α in providing an alternative to inflammasome-mediated immune responses in vivo.