IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation

Background Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma. Objective We sought to evaluate the effect of the prototypic type 2 cytokines IL-4 and IL-13 on human neutrophils. Methods Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (1) expression of IL-4 receptor subunits, (2) neutrophil extracellular trap (NET) formation, (3) migration toward CXCL8 in vitro and in humanized mice, and (4) CXCR1, CXCR2, and CXCR4 expression, as well as (5) in nonallergic versus allergic subjects. Results Human neutrophils expressed both types of IL-4 receptors, and their stimulation through IL-4 or IL-13 diminished their ability to form NETs and migrate toward CXCL8 in vitro. Likewise, in vivo chemotaxis in NOD-scid-Il2rg−/− mice was reduced in IL-4–stimulated human neutrophils compared with control values. These effects were accompanied by downregulation of the CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils on IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from nonallergic subjects to allergic donor serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13–stimulated neutrophils. Conclusion IL-4 receptor signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders

Neuroprotective tissue adaptation induced by IL-12 attenuates CNS inflammation

IL-12 is a well-established driver of type 1 immune responses. Paradoxically, in several autoimmune conditions including neuroinflammation, IL-12 reduces pathology and exhibits regulatory properties. Yet, the mechanism and the involved cellular players behind this immune regulation remain elusive. To identify the IL-12-responsive elements which prevent immunopathology, we generated mouse models lacking a functional IL-12 receptor either in all cells or in specific populations within the immune or central nervous system (CNS) compartments, and induced experimental autoimmune encephalomyelitis (EAE), which models human Multiple Sclerosis (MS). This revealed that the CNS tissue-protective features of IL-12 are mediated by cells of the neuroectoderm, and not immune cells. Importantly, sections of brain from patients with MS show comparable patterns of expression, indicating parallel mechanisms in humans. By combining spectral flow cytometry, bulk and single-nucleus RNA sequencing, we uncovered an IL-12-induced neuroprotective adaption of the neuroectoderm critically involved in maintaining CNS tissue integrity during inflammation

IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice

Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice

Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth

Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s

Regulation of neutrophils in type 2 immune responses

Type 2 immune responses contribute to the resistance to helminths and toxins as well as several physiological processes. Although they usually do not participate in type 2 immune responses, neutrophils have been shown in mice to enhance the anti-helminth response, but they also contribute to increased target tissue damage. Increased pathology and morbidity is also observed in type 2 immune-mediated disorders, such as allergic asthma, when neutrophils become a predominant subset of the infiltrate. How neutrophil recruitment is regulated during type 2 immune responses is now starting to become clear, with recent data showing that signaling via the prototypic type 2 cytokine interleukin-4 receptor mediates direct and indirect inhibitory actions on neutrophils in mice and humans

Cervical cancer screening among marginalized women:A cross-sectional intervention study

BACKGROUND: Many countries organize population-based cervical cancer screening programs (CSP). In the Netherlands, eligible women are invited by mail. Marginalized women living in unstable conditions and homeless women often fail to receive the invitation letter. These women also experience access barriers to regular healthcare. Consequently, despite presumably being at higher risk of developing cervical cancer due to prevalent risk factors, marginalized women are rarely screened for cervical cancer. The aim of the study was to identify the prevalence of (pre)cancerous abnormalities among marginalized women, and subsequently explore invitation approaches to enhance their screening participation. METHODS: A cross-sectional intervention study was conducted in Rotterdam, the Netherlands. Between February and May 2019, marginalized women aged 20–60 years were invited to participate in cervical screening. A participant was considered screen-positive when they tested positive for high-risk human papilloma virus (HR-HPV) and showed cytological abnormalities. Data of the study population were compared with regional data of the Dutch CSP. Various invitation approaches were used to recruit women. RESULTS: Out of 74 included women, 12 participants (16%) were found screen-positive, against 3.4% in women screened by the Dutch CSP. The prevalence ratio for the study population was 4.4 (95% CI 1.9–8.6) compared with women screened by the Dutch CSP. Using a direct, pro-active approach resulted in participation of 92% of the included women. CONCLUSION: Marginalized women have an increased risk of (pre)cancerous cervical abnormalities in screening, compared with women screened by the Dutch CSP. A direct pro-active approach was the most effective to stimulate screening participation. Enhancement of screening uptake for this population needs special effort

Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth.

Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s

Eating behavior and food purchases during the COVID-19 lockdown:A cross-sectional study among adults in the Netherlands

On March 15, 2020, the Dutch Government implemented COVID-19 lockdown measures. Although self-quarantine and social-distancing measures were implemented, restrictions were less severe compared to several other countries. The aim of this study was to assess changes in eating behavior and food purchases among a representative adult sample in the Netherlands (n = 1030), five weeks into lockdown. The results show that most participants did not change their eating behaviors (83.0%) or food purchases (73.3%). However, socio-demographic differences were observed among those that reported changes during lockdown. For example, participants with overweight (OR = 2.26, 95%CI = 1.24–4.11) and obesity (OR = 4.21, 95%CI = 2.13–8.32) were more likely to indicate to eat unhealthier during lockdown compared to participants with a healthy weight. Those with a high educational level (OR = 2.25, 95%-CI = 1.03–4.93) were also more likely to indicate to eat unhealthier during lockdown compared to those with a low educational level. Older participants were more likely to indicate to experience no differences in their eating behaviors compared to those of younger age, who were more likely to indicate that they ate healthier (OR = 1.03, 95%CI = 1.01–1.04) as well as unhealthier (OR = 1.04, 95%CI = 1.02–1.06) during lockdown. Participants with obesity were more likely to indicate to purchase more chips/snacks (OR = 2.79, 95%CI = 1.43–5.45) and more nonalcoholic beverages (OR = 2.74, 95%CI = 1.36–5.50) during lockdown in comparison with those with a healthy weight. Of those that used meal delivery services before, 174 (29.5%) indicated to use meal delivery services more frequently during lockdown. Although the results confirm the persistence of dietary routines, profound socio-demographic differences were observed for those that did report changes. Especially for individuals with overweight and obesity, the lockdown has taken its toll on healthy dietary choices. Further research should unravel underlying mechanisms for these observations.</p

Eating behavior and food purchases during the COVID-19 lockdown: A cross-sectional study among adults in the Netherlands

On March 15, 2020, the Dutch Government implemented COVID-19 lockdown measures. Although self-quarantine and social-distancing measures were implemented, restrictions were less severe compared to several other countries. The aim of this study was to assess changes in eating behavior and food purchases among a representative adult sample in the Netherlands (n = 1030), five weeks into lockdown. The results show that most participants did not change their eating behaviors (83.0%) or food purchases (73.3%). However, socio-demographic differences were observed among those that reported changes during lockdown. For example, participants with overweight (OR = 2.26, 95%CI = 1.24–4.11) and obesity (OR = 4.21, 95%CI = 2.13–8.32) were more likely to indicate to eat unhealthier during lockdown compared to participants with a healthy weight. Those with a high educational level (OR = 2.25, 95%-CI = 1.03–4.93) were also more likely to indicate to eat unhealthier during lockdown compared to those with a low educational level. Older participants were more likely to indicate to experience no differences in their eating behaviors compared to those of younger age, who were more likely to indicate that they ate healthier (OR = 1.03, 95%CI = 1.01–1.04) as well as unhealthier (OR = 1.04, 95%CI = 1.02–1.06) during lockdown. Participants with obesity were more likely to indicate to purchase more chips/snacks (OR = 2.79, 95%CI = 1.43–5.45) and more nonalcoholic beverages (OR = 2.74, 95%CI = 1.36–5.50) during lockdown in comparison with those with a healthy weight. Of those that used meal delivery services before, 174 (29.5%) indicated to use meal delivery services more frequently during lockdown. Although the results confirm the persistence of dietary routines, profound socio-demographic differences were observed for those that did report changes. Especially for individuals with overweight and obesity, the lockdown has taken its toll on healthy dietary choices. Further research should unravel underlying mechanisms for these observations

Eating behavior and food purchases during the COVID-19 lockdown: A cross-sectional study among adults in the Netherlands

On March 15, 2020, the Dutch Government implemented COVID-19 lockdown measures. Although self-quarantine and social-distancing measures were implemented, restrictions were less severe compared to several other countries. The aim of this study was to assess changes in eating behavior and food purchases among a representative adult sample in the Netherlands (n = 1030), five weeks into lockdown. The results show that most participants did not change their eating behaviors (83.0%) or food purchases (73.3%). However, socio-demographic differences were observed among those that reported changes during lockdown. For example, participants with overweight (OR = 2.26, 95%CI = 1.24-4.11) and obesity (OR = 4.21, 95%CI = 2.13-8.32) were more likely to indicate to eat unhealthier during lockdown compared to participants with a healthy weight. Those with a high educational level (OR = 2.25, 95%-CI = 1.03-4.93) were also more likely to indicate to eat unhealthier during lockdown compared to those with a low educational level. Older participants were more likely to indicate to experience no differences in their eating behaviors compared to those of younger age, who were more likely to indicate that they ate healthier (OR = 1.03, 95%CI = 1.01-1.04) as well as unhealthier (OR = 1.04, 95%CI = 1.02-1.06) during lockdown. Participants with obesity were more likely to indicate to purchase more chips/snacks (OR = 2.79, 95%CI = 1.43-5.45) and more nonalcoholic beverages (OR = 2.74, 95%CI = 1.36-5.50) during lockdown in comparison with those with a healthy weight. Of those that used meal delivery services before, 174 (29.5%) indicated to use meal delivery services more frequently during lockdown. Although the results confirm the persistence of dietary routines, profound socio-demographic differences were observed for those that did report changes. Especially for individuals with overweight and obesity, the lockdown has taken its toll on healthy dietary choices. Further research should unravel underlying mechanisms for these observations