Intracellular immune sensing promotes inflammation via gasdermin D-driven release of a lectin alarmin.

Inflammatory caspase sensing of cytosolic lipopolysaccharide (LPS) triggers pyroptosis and the concurrent release of damage-associated molecular patterns (DAMPs). Collectively, DAMPs are key determinants that shape the aftermath of inflammatory cell death. However, the identity and function of the individual DAMPs released are poorly defined. Our proteomics study revealed that cytosolic LPS sensing triggered the release of galectin-1, a ß-galactoside-binding lectin. Galectin-1 release is a common feature of inflammatory cell death, including necroptosis. In vivo studies using galectin-1-deficient mice, recombinant galectin-1 and galectin-1-neutralizing antibody showed that galectin-1 promotes inflammation and plays a detrimental role in LPS-induced lethality. Mechanistically, galectin-1 inhibition of CD45 (Ptprc) underlies its unfavorable role in endotoxin shock. Finally, we found increased galectin-1 in sera from human patients with sepsis. Overall, we uncovered galectin-1 as a bona fide DAMP released as a consequence of cytosolic LPS sensing, identifying a new outcome of inflammatory cell death.

Bacterial Outer Membrane Vesicles Mediate Cytosolic Localization of LPS and Caspase-11 Activation.

Sensing of lipopolysaccharide (LPS) in the cytosol triggers caspase-11 activation and is central to host defense against Gram-negative bacterial infections and to the pathogenesis of sepsis. Most Gram-negative bacteria that activate caspase-11, however, are not cytosolic, and the mechanism by which LPS from these bacteria gains access to caspase-11 in the cytosol remains elusive. Here, we identify outer membrane vesicles (OMVs) produced by Gram-negative bacteria as a vehicle that delivers LPS into the cytosol triggering caspase-11-dependent effector responses in vitro and in vivo. OMVs are internalized via endocytosis, and LPS is released into the cytosol from early endosomes. The use of hypovesiculating bacterial mutants, compromised in their ability to generate OMVs, reveals the importance of OMVs in mediating the cytosolic localization of LPS. Collectively, these findings demonstrate a critical role for OMVs in enabling the cytosolic entry of LPS and, consequently, caspase-11 activation during Gram-negative bacterial infections.

Gasdermin D Restrains Type I Interferon Response to Cytosolic DNA by Disrupting Ionic Homeostasis.

Inflammasome-activated caspase-1 cleaves gasdermin D to unmask its pore-forming activity, the predominant consequence of which is pyroptosis. Here, we report an additional biological role for gasdermin D in limiting cytosolic DNA surveillance. Cytosolic DNA is sensed by Aim2 and cyclic GMP-AMP synthase (cGAS) leading to inflammasome and type I interferon responses, respectively. We found that gasdermin D activated by the Aim2 inflammasome suppressed cGAS-driven type I interferon response to cytosolic DNA and Francisella novicida in macrophages. Similarly, interferon-ß (IFN-ß) response to F. novicida infection was elevated in gasdermin D-deficient mice. Gasdermin D-mediated negative regulation of IFN-ß occurred in a pyroptosis-, interleukin-1 (IL-1)-, and IL-18-independent manner. Mechanistically, gasdermin D depleted intracellular potassium (K+) via membrane pores, and this K+ efflux was necessary and sufficient to inhibit cGAS-dependent IFN-ß response. Thus, our findings have uncovered an additional interferon regulatory module involving gasdermin D and K+ efflux.

Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection.

BACKGROUND & AIMS: Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs). METHODS: PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide LPS, and IFN or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP. RESULTS: E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced LPS-mediated tumor necrosis factor production without toll-like receptor 4 tolerance induction. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1ß upon bacterial infection. Proteomic screen in mouse macrophages revealed progranulin as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin-D in a type-I IFN and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP. CONCLUSIONS: Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP. IMPACT AND IMPLICATIONS: Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.

AIM2 in health and disease: Inflammasome and beyond.

Nucleic acid sensing is a critical mechanism by which the immune system monitors for pathogen invasion. A set of germline-encoded innate immune receptors detect microbial DNA in various compartments of the cell, such as endosomes, the cytosol, and the nucleus. Sensing of microbial DNA through these receptors stimulates, in most cases, interferon regulatory factor-dependent type I IFN synthesis followed by JAK/STAT-dependent interferon-stimulated gene expression. In contrast, the detection of DNA in the cytosol by AIM2 assembles a macromolecular complex called the inflammasome, which unleashes the proteolytic activity of a cysteine protease caspase-1. Caspase-1 cleaves and activates the pro-inflammatory cytokines such as IL-1ß and IL-18 and a pore-forming protein, gasdermin D, which triggers pyroptosis, an inflammatory form of cell death. Research over the past decade has revealed that AIM2 plays essential roles not only in host defense against pathogens but also in inflammatory diseases, autoimmunity, and cancer in inflammasome-dependent and inflammasome-independent manners. This review discusses the latest advancements in our understanding of AIM2 biology and its functions in health and disease.

Distinct Differences in Gastroesophageal Junction and Gastric Adenocarcinoma in 2194 Patients: In Memory of Rebecca A. Carr, February 24, 1988-January 19, 2021.

OBJECTIVE: We sought to compare gastroesophageal junction (GEJ) cancer and gastric cancer (GC) and identify clinicopathological and oncological differences. SUMMARY BACKGROUND DATA: GEJ cancer and GC are frequently studied together. Although the treatment approach for each often differs, clinico-pathological and oncological differences between the 2 have not been fully evaluated. METHODS: We retrospectively identified patients with GEJ cancer or GC who underwent R0 resection at our center between January 2000 and December 2016. Clinicopathological characteristics, disease-specific survival (DSS), and site of first recurrence were compared. RESULTS: In total, 2194 patients were analyzed: 1060 (48.3%) with GEJ cancer and 1134 (51.7%) with GC. Patients with GEJ cancer were younger (64 vs 66 years; P < 0.001), more often received neoadjuvant treatment (70.9% vs 30.2%; P < 0.001), and had lower pathological T and N status. Five-year DSS was 62.2% in patients with GEJ cancer and 74.6% in patients with GC ( P < 0.001). After adjustment for clinicopathological factors, DSS remained worse in patients with GEJ cancer (hazard ratio, 1.78; 95% confidence interval, 1.40-2.26; P < 0.001). The cumulative incidence of recurrence was approximately 10% higher in patients with GEJ cancer ( P < 0.001). The site of first recurrence was more likely to be hematogenous in patients with GEJ cancer (60.1% vs 31.4%; P < 0.001) and peritoneal in patients with GC (52.9% vs 12.5%; P < 0.001). CONCLUSIONS: GEJ adenocarcinoma is more aggressive, with a higher incidence of recurrence and worse DSS, compared with gastric adenocarcinoma. Distinct differences between GEJ cancer and GC, especially in patterns of recurrence, may affect evaluation of optimal treatment strategies.

Self-administered non-invasive vagus nerve stimulation therapy for severe pharmacoresistant restless legs syndrome: outcomes at 6 months.

Severe pharmacoresistant restless legs syndrome (RLS) is difficult to manage and a source of suffering to patients. We studied the effectiveness at 6 months of an innovative treatment: transauricular vagus nerve stimulation (taVNS) in the left cymba concha in a case series of 15 patients, 53% male, mean (SD) age 62.7 (12.3) years with severe pharmacoresistant RLS (mean [SD] International Restless Legs Rating Scale [IRLS] score of 31.9 [2.9]) at baseline. Following an 8-week non-randomised hospital-based study with eight 1-h sessions of taVNS, patients were trained to administer taVNS at home and were followed up for 6 months. The primary outcome measure was the IRLS score, secondary outcome measures were quality of life, mood disorders using the Hospital Anxiety and Depression scale (HAD) subscales for depression (HADD) and anxiety (HADA). At the 6-month follow-up 13/15 patients continued to use weekly taVNS. Symptom severity decreased (mean [SD] IRLS score 22.2 [9.32] at 6 months, p = 0.0005). Four of the 15 patients had an IRLS score of <20 at 6 months and two an IRLS score of 5. Quality of life significantly improved compared to baseline (mean [SD] score at baseline 49.3 [18.1] versus 65.66 [22.58] at 6 months, p = 0.0005) as did anxiety and depression symptoms (mean [SD] HADA score at baseline 8.9 [5.4] versus 7.53 [4.42] at 6 months, p = 0.029; and HADD score at baseline 5.2 [4.5] versus 4.73 [4.44] at 6 months, p = 0.03). Treatment was well tolerated, and no adverse events were reported. Our case series shows a potential role for self-administered taVNS in patients with severe pharmacoresistant RLS. Randomised controlled trials are needed to confirm the utility of taVNS.

Gastric Cancer Etiology and Management in Asia and the West.

Regional variation in treatment paradigms for gastric adenocarcinoma has attracted a great deal of interest. Between Asia and the West, major differences have been identified in tumor biology, implementation of screening programs, extent of surgical lymphadenectomy, and routine use of neoadjuvant versus adjuvant treatment strategies. Minimally invasive techniques, including both laparoscopic and robotic platforms, have been studied in both regions, with attention to safety, feasibility, and long-term oncologic outcomes. The purpose of this review is to discuss advances in the understanding of the etiology and underlying biology of gastric cancer, as well as the current state of management, focusing on the differences between Asia and the West.

Robotic Gastrectomy for Gastric Adenocarcinoma in the USA: Insights and Oncologic Outcomes in 220 Patients.

BACKGROUND: While multiple Asian and a few Western retrospective series have demonstrated the feasibility and safety of robotic-assisted gastrectomy for gastric cancer, its reliability for thorough resection, especially for locoregional disease, has not yet been firmly established, and reported learning curves vary widely. To support wider implementation of robotic gastrectomy, we evaluated the learning curve for this approach, assessed its oncologic feasibility, and created a selection model predicting the likelihood of conversion to open surgery in a US patient population. PATIENTS AND METHODS: We retrospectively reviewed data on all consecutive patients who underwent robotic gastrectomy at a high-volume institution between May 2012 and March 2019. RESULTS: Of the 220 patients with gastric cancer selected to undergo curative-intent robotic gastrectomy, surgery was completed using robotics in 159 (72.3%). The median number of removed lymph nodes was 28, and ≥ 15 lymph nodes were removed in 94% of procedures. Surgical time decreased steadily over the first 60-80 cases. Complications were generally minor: 7% of patients experienced complications of grade 3 or higher, with an anastomotic leak rate of 2% and mortality rate 0.9%. Factors predicting conversion to open surgery included neoadjuvant chemotherapy, BMI ≥ 31 kg/m2, and tumor size ≥ 6 cm. CONCLUSIONS: These findings support the safety and oncologic feasibility of robotic gastrectomy for selected patients with gastric cancer. Proficiency can be achieved by 20 cases and mastery by 60-80 cases. Ideal candidates for this approach are patients with few comorbidities, BMI < 31 kg/m2, and tumors < 6 cm.

Predicting malignancy in patients with adrenal tumors using 18 F-FDG-PET/CT SUVmax.

BACKGROUND AND OBJECTIVES: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG-PET/CT) parameters may help distinguish malignant from benign adrenal tumors, but few have been externally validated or determined based on definitive pathological confirmation. We determined and validated a threshold for 18 F-FDG-PET/CT maximum standard uptake value (SUVmax) in patients who underwent adrenalectomy for a nonfunctional tumor. METHODS: Database review identified patients with 18 F-FDG-PET/CT images available (training cohort), or only SUVmax values (validation cohort). Discriminative accuracy was assessed by area under the curve (AUC), and the optimal cutoff value estimated by maximally selected Wilcoxon rank statistics. RESULTS: Of identified patients (n = 171), 86 had adrenal metastases, 20 adrenal cortical carcinoma, and 27 adrenal cortical adenoma. In the training cohort (n = 96), SUVmax was significantly higher in malignant versus benign tumors (median 8.3 vs. 3.0, p < .001), with an AUC of 0.857. Tumor size did not differ. The optimal cutoff SUVmax was 4.6 (p < .01). In the validation cohort (n = 75), this cutoff had a sensitivity of 75% and specificity 55%. CONCLUSIONS: 18 F-FDG-PET/CT SUVmax was associated with malignancy. Validation indicated that SUVmax ≥ 4.6 was suggestive of malignancy, while lower values did not reliably predict benign tumor.

Cancer surveillance imaging: Does repeated iodinated contrast exposure impact long-term kidney function?

BACKGROUND: Contrast-induced nephropathy is a well-recognized acute complication in cancer patients, but the long-term effects of repeated contrast exposure are not known. We analyzed the association of the number of contrast-enhanced computed tomography (CECT) examinations and other clinical factors with decline in estimated glomerular filtration rate (eGFR) in colorectal cancer survivors. MATERIALS AND METHODS: We retrospectively queried a prospective surgical colorectal cancer database to identify patients with stage I or II cancer who underwent resection in 2007 - 2013 and were alive for at least 3 years. eGFR was calculated before and 3 years after the surgery with ≥ 20% decline relative to baseline defined as significant and used as the primary outcome. The association of clinical factors with the primary outcome was analyzed using logistic regression. RESULTS: Only 256 patients with the median follow-up of 65 months had sufficient clinical data for analysis. Median eGFR decline at follow-up was 3.0 mL/min/1.73m2 or 4% change from baseline. 47 patients (18%) had ≥ 20% reduction in eGFR, which was not associated with the number of CECT examinations. Multivariable analysis demonstrated that increasing age (OR, 1.03; 95% CI, 1.00 - 1.06), presence of diabetes (OR, 2.33; 95% CI, 1.18 - 4.61), and longer operation time (OR, 1.04; 95% CI, 1.01 - 1.07) were independently associated with a higher likelihood of ≥ 20% eGFR decline at 3 years. CONCLUSION: Older age, diabetes, and longer operating time, but not cumulative contrast exposure were found to be associated with worse long-term renal outcomes following surgical resection in patients with early-stage colorectal cancer who survived 3 years.

Adrenal Metastasectomy in the Presence and Absence of Extraadrenal Metastatic Disease.

OBJECTIVE: To determine if there are differences in overall survival (OS) or event-free survival (EFS) in patients with and without concomitant extra-adrenal metastases undergoing adrenal metastasectomy. BACKGROUND: There is growing interest in the use of local therapies in patients with oligometastatic disease. Previously published series have indicated that long-term survival is possible with resection. Adrenalectomy has been used to treat adrenal metastases in select patients. METHODS: Patients who underwent adrenal metastasectomy from 1994 to 2015 were identified from a prospectively maintained institutional database of adrenalectomy patients, excluding adrenalectomies due to tumor extension or for palliation. Sites of disease, treatment history, and survival data were extracted from chart review. RESULTS: One hundred seventy-four patients were included. Tumor histology included 68 nonsmall cell lung cancer, 34 renal cancer, 18 colorectal cancer, 11 melanoma cancer, 10 hepatocellular cancer, 8 sarcoma cancer, and 25 other cancers. The median follow-up among survivors was 5.2 (1-21) years. OS at 3 and 5 years was 50% and 40%, respectively. Patients with (n = 83) and without (n = 91) extra-adrenal metastases did not differ with respect to age, adrenal tumor size, or margin status. Median OS (3.3 years for patients with concomitant extra-adrenal metastases and 3.0 years for patients with isolated adrenal metastases; P = 0.816) and EFS (9.39 vs 9.59 months; P = 0.87) were similar. Factors negatively associated with OS included adrenal tumor size (P < 0.01), renal primary versus other (P < 0.01), and adrenal margin status (P < 0.01). CONCLUSIONS: In selected patients undergoing adrenal metastasectomy, there were no significant differences in OS or EFS between patients with and without concomitant extra-adrenal metastases.

Comparison of gastric cancer survival after R0 resection in the US and China.

BACKGROUND AND OBJECTIVES: Gastric cancer (GC) outcomes differ between Asian and Western countries, even when controlling for contributing factors, but whether this difference holds true for China remains inadequately studied. We sought to compare the presentation, treatment, and outcomes of patients with GC undergoing curative intent (R0) resection between the US and China, and to ascertain whether geography/ institution is an independent predictor of disease-specific survival (DSS). METHODS: Data were analyzed from patients with GC undergoing R0 resection at high-volume cancer centers in the US (Memorial Sloan Kettering Cancer Center [MSKCC], n = 1378) and China (Fujian Medical University Union Hospital [FMUUH], n = 4262) between 2000 and 2014. Factors associated with DSS were examined by multivariate analysis. RESULTS: The 5-year DSS ( P < 0.001) for all patients was better at MSKCC than at FMUUH, even among patients not receiving preoperative chemotherapy ( P < 0.001), but stratification by substage eliminated this difference ( P > 0.05). Factors independently associated with DSS included age, histology, tumor size, T category, N category, gastrectomy type, and preoperative chemotherapy, but not institution. CONCLUSIONS: Although the presentation of patients with GC between MSKCC and FMUUH differs, survival of patients with curatively resected GC, when matched for clinical stage, is comparable.

Comparison of Young Patients with Gastric Cancer in the United States and China.

BACKGROUND: This study aimed to compare the clinicopathologic characteristics and stage-specific prognosis of young patients with gastric cancer (GC) after curative resection (R0) in the United States and China. METHODS: Data were collected on young patients (age ≤40 years) undergoing R0 resection at one U.S. (n = 79) and one Chinese (n = 257) institution. Patient, surgical, and pathologic variables and stage-specific survival rates were compared. Factors associated with 5-year disease-specific survival (DSS) were determined via multivariate analysis. RESULTS: Tumor location was most often proximal in U.S. patients and distal in Chinese patients. The Chinese patients had more advanced-stage tumors, with a greater number of positive lymph nodes identified. Preoperative chemotherapy was administered more often in the United States. The 5-year overall survival (p = 0.07) and DSS (p = 0.07) did not differ statistically between the U.S. and Chinese cohorts. Among the patients with early GC receiving surgery alone, DSS did not differ significantly between the two cohorts (p = 0.44). Among the patients with advanced GC, DSS was comparable between the U.S. patients receiving preoperative chemotherapy plus surgery and the Chinese patients receiving surgery plus postoperative chemotherapy (p = 0.85). Lauren classification, depth of invasion, number of metastatic lymph nodes, and type of gastrectomy, but not country, were independent predictors of DSS. CONCLUSIONS: Tumor features and therapeutic strategies among young patients with GC differ between the United States and China. Survival is comparable between young patients with advanced GC receiving preoperative chemotherapy plus surgery in the United States and those receiving surgery plus postoperative chemotherapy in China, suggesting that the outcomes for young patients with GC are stage dependent but not country specific.

Differences in the multimodal treatment of gastric cancer: East versus west.

There has been a great deal of interest about varying treatment paradigms of gastric cancer in Eastern and Western countries. Differences in tumor biology, screening initiatives, surgical approach, extent of lymphadenectomy, and neoadjuvant versus adjuvant chemotherapy regimens have been studied and documented in the literature. The purpose of this review is to give an updated report on the current status and management differences in the treatment of gastric cancer between Eastern and Western countries.

Black Fungus of the Foot: An Unusual Presentation of COVID-19-Associated Mucormycosis.

Mucormycosis, also known as black fungus, is a rare but aggressive fungal disease with high morbidity and mortality rates that tends to affect patients who are severely immunocompromised. Early recognition of the infection and prompt intervention is critical for treatment success. In recent years the coronavirus disease of 2019 (COVID-19) pandemic has resulted in a surge in the number of cases of mucormycosis. This study aims to report an unfortunate event involving an immunocompromised elderly man with mucormycosis of the foot who died as a result of sepsis caused by COVID-19. It is important to have a high clinical suspicion for mucormycosis when a clinical lesion develops, and to appropriately perform biopsy the lesion in question, particularly in the context of COVID-19. Raising awareness of COVID-19-associated mucormycosis may allow for early detection of the disease, thus enabling the initiation of rapid treatment, ultimately saving lives.

Impact of primary tumor resection in the management of metastatic well-differentiated neuroendocrine tumors of the small bowel and pancreas.

Patients with gastroenteropancreatic (GEP) neuroendocrine tumors (NET) often present with advanced disease. Primary tumor resection (PTR) in the setting of unresectable metastatic disease is controversial. Most studies evaluating the impact of PTR on overall survival (OS) have been performed using large population-based databases, with limited treatment related data. This study aims to determine whether PTR improves OS and progression-free survival (PFS) in patients with metastatic well-differentiated GEP-NET. This is a retrospective single-institution study of patients with metastatic well-differentiated GEP-NET between 1978 and 2021. The primary outcome was OS. The secondary outcome was PFS. Chi-squared tests and Cox regression were used to perform univariate and multivariate analyses (MVA). OS and PFS were estimated using the Kaplan-Meier method and log-rank test. Between 1978 and 2021, 505 patients presented with metastatic NET, 151 of whom had well-differentiated GEP-NET. PTR was performed in 31 PNET and 77 SBNET patients. PTR was associated with improved median OS for PNET (136 vs. 61 months, p = .003) and SBNET (not reached vs. 79 months, p<.001). On MVA, only higher grade (HR 3.70, 95%CI 1.49-9.17) and PTR (HR 0.21, 95%CI 0.08-0.53) influenced OS. PTR resulted in longer median PFS for patients with SBNET (46 vs. 28 months, p = .03) and a trend toward longer median PFS for patients with PNET (20 vs. 13 months, p = .07). In patients with metastatic well-differentiated GEP-NET, PTR is associated with improved OS and may be associated with improved PFS and should be considered in a multidisciplinary setting. Future prospective studies are needed to validate these findings.

The Evolving Landscape of Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) represent a heterogeneous group of tumors, with variable presentation based on the location of origin and degree of metastatic spread. There are no randomized control trials to guide surgical management; however, surgery remains the mainstay of treatment for most gastroenteropancreatic NETs based on retrospective studies. Metastatic disease is common at the time of presentation, particularly in the liver. There is a role for cytoreduction for improvement of both symptoms and survival. Robust prospective randomized data exists to support the use of medical therapies to improve progression-free and overall survival in patients with advanced, metastatic, and unresectable NETs.

CD169+ macrophage intrinsic IL-10 production regulates immune homeostasis during sepsis.

Macrophages facilitate critical functions in regulating pathogen clearance and immune homeostasis in tissues. The remarkable functional diversity exhibited by macrophage subsets is dependent on tissue environment and the nature of the pathological insult. Our current knowledge of the mechanisms that regulate the multifaceted counter-inflammatory responses mediated by macrophages remains incomplete. Here, we report that CD169+ macrophage subsets are necessary for protection under excessive inflammatory conditions. We show that in the absence of these macrophages, even under mild septic conditions, mice fail to survive and exhibit increased production of inflammatory cytokines. Mechanistically, CD169+ macrophages control inflammatory responses via interleukin-10 (IL-10), as CD169+ macrophage-specific deletion of IL-10 was lethal during septic conditions, and recombinant IL-10 treatment reduced lipopolysaccharide (LPS)-induced lethality in mice lacking CD169+ macrophages. Collectively, our findings show a pivotal homeostatic role for CD169+ macrophages and suggest they may serve as an important target for therapy under damaging inflammatory conditions.