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The lung is constantly exposed to airborne pathogens and particles that can cause alveolar damage. Hence, appropriate repair responses are essential for gas exchange and life. Here, we deciphered the spatiotemporal trajectory and function of an atypical population of macrophages after lung injury. Post–influenza A virus (IAV) infection, short-lived monocyte-derived Ly6G-expressing macrophages (Ly6G+ Macs) were recruited to the alveoli of lung perilesional areas. Ly6G+ Macs engulfed immune cells, exhibited a high metabolic potential, and clustered with alveolar type 2 epithelial cells (AT2s) in zones of active epithelial regeneration. Ly6G+ Macs were partially dependent on granulocyte-macrophage colony-stimulating factor and interleukin-4 receptor signaling and were essential for AT2-dependent alveolar regeneration. Similar macrophages were recruited in other models of injury and in the airspaces of lungs from patients with suspected pneumonia. This study identifies perilesional alveolar Ly6G+ Macs as a spatially restricted, short-lived macrophage subset promoting epithelial regeneration postinjury, thus representing an attractive therapeutic target for treating lung damage. Editor's summary: Respiratory virus infections can cause long-lasting lung damage, but how specific lung myeloid cell populations contribute to postinfection recovery is not fully understood. Using a mouse model of influenza A virus infection, Ruscitti et al. identified a distinct population of Ly6G+ monocyte-derived macrophages that emerges during the early recovery phase after viral-triggered lung injury. Ly6G+ lung macrophages were short lived and highly phagocytic and populated the alveoli within perilesional areas undergoing regeneration. Genetically engineered mice lacking lung Ly6G+ macrophages displayed impaired epithelial regeneration after influenza infection. Together, these findings identify a previously unappreciated population of reparative lung macrophages that could be targeted therapeutically to treat lung damage. —Claire Olingy [ABSTRACT FROM AUTHOR]

This article discusses the immunotherapeutic effects of specific and nonspecific mRNA-lipid nanoparticles (LNPs) in a mouse model of house dust mite (HDM)-induced airway inflammation. The study found that the mRNA-LNP vaccines were able to reduce key allergic parameters such as IL-5, specific IgE, and eosinophilia. However, the mRNA-LNP vaccines also switched HDM-specific airway eosinophilia into airway neutrophilia. The authors speculate that this may be due to the development of allergen-specific Th17 cells induced by the mRNA-LNP vaccines. Further research is needed to understand the distinct immunological pathways mediated by HDM-specific and nonspecific mRNA-LNP vaccines. [Extracted from the article]

Lung macrophages constitute a sophisticated surveillance and defense system that contributes to tissue homeostasis and host defense and allows the host to cope with the myriad of insults and antigens to which the lung mucosa is exposed. As opposed to alveolar macrophages, lung interstitial macrophages (IMs) express high levels of Type 2 major histocompatibility complex (MHC-II), a hallmark of antigen-presenting cells. Here, we showed that lung IMs, like dendritic cells, possess the machinery to present soluble antigens in an MHC-II–restricted way. Using ex vivo ovalbumin (OVA)-specific T cell proliferation assays, we found that OVA-pulsed IMs could trigger OVA-specific CD4+ T cell proliferation and Foxp3 expression through MHC-II–, IL-10–, and transforming growth factor β–dependent mechanisms. Moreover, we showed that IMs efficiently captured locally instilled antigens in vivo, did not migrate to the draining lymph nodes, and enhanced local interactions with CD4+ T cells in a model of OVA-induced allergic asthma. These results support that IMs can present antigens to CD4+ T cells and trigger regulatory T cells, which might attenuate lung immune responses and have functional consequences for lung immunity and T cell–mediated disorders. [ABSTRACT FROM AUTHOR]

Simple Summary: Since they have a unique phenotype, with an approximately 20% increase in muscle mass, we hypothesized that Belgian blue (BB) cows may have hematologic and biochemical characteristics that are significantly different from those of other cattle breeds. However, most available reference intervals in cattle are derived from dairy cows, mainly Holstein Friesian (HF) cows. Therefore, the aim of our study was to measure and compare biochemical and hematologic parameters in clinically healthy BB and HF cows. We studied 183 clinically healthy adult BB and HF cows. Our results confirmed that BB and HF represent different populations from a laboratory perspective. Therefore, we propose the first breed-specific reference intervals for BB, which are essential to improve the health management of this breed. Belgian blue (BB) cattle have an 11-bp deletion in myostatin that causes skeletal muscle hyperplasia and increased muscle mass, leading to a 'double-muscled' phenotype. Preliminary data suggest that this phenotype may be associated with breed-specific hematologic and biochemical values. Therefore, in this study, we sought to compare hematologic and serum biochemical parameters in healthy BB and Holstein Friesian (HF) cows and to propose breed-specific reference intervals for BB cows. Hematologic parameters, total protein, creatinine, creatine kinase (CK) and aspartate transaminase (AST) activities, albumin, and globulins were measured in 183 clinically healthy adult BB and HF cows. There were significant differences between BB and HF cows in 17 of 27 measured parameters. BB cows had significantly higher creatinine concentration and CK and AST activities (p < 0.001). RBCs, hemoglobin, hematocrit (p < 0.001), MCV and lymphocytes (p < 0.05) were also significantly higher in BB cows compared with HF cows. The average N/L ratio was greater than 1 in both breeds. These results suggest that BB and HF cows have significantly different clinically relevant hematologic and serum biochemical values, and, therefore, breed-specific reference intervals should be used. [ABSTRACT FROM AUTHOR]

Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations., Author(s): Marie Toussaint [1, 2]; David J Jackson [1, 2, 3, 4]; Dawid Swieboda [1, 2]; Anabel Guedán [1, 2]; Theodora-Dorita Tsourouktsoglou [5]; Yee Man Ching [1, 2]; Coraline Radermecker [...]

Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis. However, the mechanisms that regulate epidermal barrier function are incompletely understood. Here we have found that keratinocyte- specific deletion of the gene encoding RAB guanine nucleotide exchange factor 1 (RABGEF1, also known as RABEX-5) severely impairs epidermal barrier function in mice and induces an allergic cutaneous and systemic phenotype. RABGEF1-deficient keratinocytes exhibited aberrant activation of the intrinsic IL-1R/MYD88/NF-κB signaling pathway and MYD88- dependent abnormalities in expression of structural proteins that contribute to skin barrier function. Moreover, ablation of MYD88 signaling in RABGEF1-deficient keratinocytes or deletion of Il1r1 restored skin homeostasis and prevented development of skin inflammation. We further demonstrated that epidermal RABGEF1 expression is reduced in skin lesions of humans diagnosed with either atopic dermatitis or allergic contact dermatitis as well as in an inducible mouse model of allergic dermatitis. Our findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function in mice, and suggest that dysregulation of RABGEF1 expression may contribute to epidermal barrier dysfunction in allergic skin disorders in mice and humans. Thus, RABGEF1-mediated regulation of IL-1R/MYD88 signaling might represent a potential therapeutic target., Introduction The mammalian epidermis forms a barrier to external insults, and homeostasis at cutaneous surfaces depends on tightly regulated interactions among the environment, epidermal keratinocytes, and host immune responses (1). [...]

Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-[F.sup.int]CD62[L.sup.+][CD101.sup.lo] cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-[F.sup.hi]CD62[L.sup.-][CD101.sup.hi] cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-[8.sup.+]CD62[L.sup.+]IL- [3R.sup.lo] cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec- [8.sup.+]CD62[L.sup.lo]IL-[3R.sup.hi] cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions., Introduction Eosinophils are terminally differentiated granulocytes that develop in the BM under the control of key transcription factors, mainly GATA1, C/EBPa, PU.1, and XBP1 (1-6). They are characterized by the [...]