C3a is a key complement activation fragment, yet its neutrophil-expressed receptor (C3aR) still has no clearly defined role. In this study, we used a neutrophil-dependent mouse model of intestinal ischemia-reperfusion (IR) injury to explore the role of C3aR in acute tissue injuries. C3aR deficiency worsened intestinal injury, which corresponded with increased numbers of tissue-infiltrating neutrophils. Circulating neutrophils were significantly increased in C3aR −/− mice after intestinal ischemia, and C3aR −/− mice also mobilized more circulating neutrophils after granulocyte colony-stimulating factor infusion compared with WT mice, indicating a specific role for C3aR in constraining neutrophil mobilization in response to intestinal injury. In support of this role, C3aR −/− mice reconstituted with WT bone marrow reversed IR pathology back to WT levels. Complement C5a receptor (C5aR) antagonism in C3aR −/− mice also rectified the worsened pathology after intestinal IR injury but had no effect on circulating neutrophils, highlighting the opposing roles of C3a and C5a in disease pathogenesis. Finally, we found that using a potent C3a agonist to activate C3aR in vivo reduced neutrophil mobilization and ameliorated intestinal IR pathology in WT, but not C3aR −/− , mice. This study identifies a role for C3aR in regulating neutrophil mobilization after acute intestinal injury and highlights C3aR agonism as a potential treatment option for acute, neutrophil-driven pathologies.

We identified a hitherto unrecognized function of IL-33 as a potent suppressor of innate antiviral immunity and demonstrate that IL-33 contributes significantly to the synergistic interplay between respiratory virus and allergen exposures in the onset and progression of asthma.

Background Allogeneic mesenchymal precursor cells (MPC) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and efficacy of this strategy. Methods and Results In this multi-center, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25M MPCs or medium during LVAD implantation. The primary safety endpoint was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days post-randomization). Key efficacy endpoints were functional status and ventricular function, while temporarily weaned from LVAD support (90 days post-randomization). Patients were followed until transplant or 12 months post-randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean LVEF 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (p=0.24); the posterior probability that MPCs increased the likelihood of successful weaning is 93%. At 90 days, 3 deaths occurred in control and none in MPC patients. Mean LVEF following successful wean was 24.0% (MPC=10) and 22.5% (Control=2) (p=0.56). At 12 months, 30% of MPC and 40% of control patients were successfully temporarily weaned from LVAD support (p=0.69) and 6 deaths occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months. Conclusions In this preliminary trial, administration of MPCs appeared to be safe and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support. Clinical Trial Registration Information ClinicalTrials.gov. Identifier: NCT01442129.

RSV bronchiolitis causes significant infant mortality. Bronchiolitis is characterised by airway epithelial cell (AEC) death, however the mode of death remains unknown. Objectives:To determine whether necroptosis contributes to RSV bronchiolitis pathogenesis via high mobility group box 1 (HMGB1) release. Methods:Nasopharyngeal samples were collected from children presenting to hospital with acute respiratory infection. Primary human AECs and neonatal mice were inoculated with RSV and murine pneumovirus respectively. Necroptosis was determined via viability assays and immunohistochemistry for receptor-interacting protein kinase-1 (RIPK1), mixed lineage kinase domain-like protein (MLKL) and caspase-3. Necroptosis was blocked using pharmacological inhibitors, and RIPK1 kinase-dead knock-in mice. Measurements and Main Results:HMGB1 levels were elevated in nasopharyngeal samples of children with acute RSV infection. RSV-induced epithelial cell death was associated with increased pRIPK1 and pMLKL, but not active caspase-3 expression. Inhibition of RIPK1 or MLKL attenuated RSVinduced HMGB1 translocation and release, and lowered viral load. MLKL inhibition increased active caspase-3 expression in a caspase-8/9-dependent manner. In susceptible mice, Pneumovirus infection up-regulated RIPK1 and MLKL expression in the airway epithelium at 8-10 days post infection; coinciding with AEC sloughing, HMGB1 release, and

Lynch et al. provide evidence of a causal relationship between RSV-bronchiolitis and asthma development and highlight a common but age-related Sema4a-mediated pathway by which pDCs and microbial colonization induce T reg cell expansion to confer protection against severe bronchiolitis and asthma.

No abstract

Prostaglandin D2 (PGD2) signals through PGD2 receptor 2 (DP2, also known as CRTH2) on type 2 effector cells to promote asthma pathogenesis; however, little is known about its role during respiratory syncytial virus (RSV) bronchiolitis, a major risk factor for asthma development. We show that RSV infection up-regulated hematopoietic prostaglandin D synthase expression and increased PGD2 release by cultured human primary airway epithelial cells (AECs). Moreover, PGD2 production was elevated in nasopharyngeal samples from young infants hospitalized with RSV bronchiolitis compared to healthy controls. In a neonatal mouse model of severe viral bronchiolitis, DP2 antagonism decreased viral load, immunopathology, and morbidity and ablated the predisposition for subsequent asthma onset in later life. This protective response was abolished upon dual DP1/DP2 antagonism and replicated with a specific DP1 agonist. Rather than mediating an effect via type 2 inflammation, the beneficial effects of DP2 blockade or DP1 agonism were associated with increased interferon-λ (IFN-λ) [interleukin-28A/B (IL-28A/B)] expression and were lost upon IL-28A neutralization. In RSV-infected AEC cultures, DP1 activation up-regulated IFN-λ production, which, in turn, increased IFN-stimulated gene expression, accelerating viral clearance. Our findings suggest that DP2 antagonists or DP1 agonists may be useful antivirals for the treatment of viral bronchiolitis and possibly as primary preventatives for asthma.

Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation; however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.