Local macrophage clean-up: Infection, especially by helminths or bacteria, can cause tissue damage (see the Perspective by Bouchery and Harris). Minutti et al. studied mouse models of helminth infection and fibrosis. They expressed surfactant protein A (a member of the complement component C1q family) in the lung, which enhanced interleukin-4 (IL-4)-mediated proliferation and activation of alveolar macrophages. This activation accelerated helminth clearance and reduced lung injury. In the peritoneum, C1q boosted macrophage activation for liver repair after bacterial infection. By a different approach, Bosurgi et al. discovered that after wounding caused by migrating helminths in the lung or during inflammation in the gut of mice, IL-4 and IL-13 act only in the presence of apoptotic cells to promote tissue repair by local macrophages. Science , this issue p. 1076 , p. 1072 ; see also p. 1014

Influenza A viruses cause life-threatening pneumonia and lung injury in the lower respiratory tract. Application of high GM-CSF levels prior to infection has been shown to reduce morbidity and mortality from pathogenic influenza infection in mice, but the mechanisms of protection and treatment efficacy have not been established. Mice were infected intranasally with influenza A virus (PR8 strain). Supra-physiologic levels of GM-CSF were induced in the airways using the double transgenic GM-CSF (DTGM) or littermate control mice starting on 3 days post-infection (dpi). Assessment of respiratory mechanical parameters was performed using the flexiVent rodent ventilator. RNA sequence analysis was performed on FACS-sorted airway macrophage subsets at 8 dpi. Supra-physiologic levels of GM-CSF conferred a survival benefit, arrested the deterioration of lung mechanics, and reduced the abundance of protein exudates in bronchoalveolar (BAL) fluid to near baseline levels. Transcriptome analysis, and subsequent validation ELISA assays, revealed that excess GM-CSF re-directs macrophages from an “M1-like” to a more “M2-like” activation state as revealed by alterations in the ratios of CXCL9 and CCL17 in BAL fluid, respectively. Ingenuity pathway analysis predicted that GM-CSF surplus during IAV infection elicits expression of anti-inflammatory mediators and moderates M1 macrophage pro-inflammatory signaling by Type II interferon (IFN-γ). Our data indicate that application of high levels of GM-CSF in the lung after influenza A virus infection alters pathogenic “M1-like” macrophage inflammation. These results indicate a possible therapeutic strategy for respiratory virus-associated pneumonia and acute lung injury.

Sepsis-induced immunosuppression is a key factor contributing to the morbidity and mortality of critically ill patients, and polymorphonuclear neutrophil dysfunction is believed to be a hallmark of this immunosuppression. Circulating myeloid cells produce the cytokine resistin (RETN), which has been associated with poor outcomes in sepsis/septic shock and can directly inhibit neutrophil function. We previously demonstrated that resistin caused a dose-dependent impairment in neutrophil migration, reactive oxygen species production, and bacterial clearance in neutrophil cell lines. However, the relative antimicrobial responses of other innate immune cells to Gram-positive and Gram-negative infections in the presence of elevated levels of resistin have not been evaluated. We hypothesized that resistin directly contributes to sepsis-induced immunosuppression by selectively targeting the neutrophil component of the innate cellular immune system. Thus, the goal of the present study was to compare the effect of resistin on bacterial killing using monocultures or co-cultures of monocyte and neutrophil cell lines, as well as to extend our findings to primary immune cells. Our results indicate that human resistin impairs the ability of neutrophils to kill the Gram-negative bacterium Pseudomonas aeruginosa and the Gram-positive bacterium Staphylococcus aureus. In contrast, with the exception of macrophages incubated with P. aeruginosa, resistin did not affect the ability of macrophages or monocytes to kill either Gram-positive or Gram-negative organisms. Furthermore, co-incubation of neutrophils with increasing proportions of monocytes did not enhance bacterial killing. Resistin blocked bactericidal activity through partial reduction of F-actin polymerization and suppression of the oxidative burst in neutrophils. Our studies indicate that resistin selectively impairs neutrophil bacterial killing. These findings further support the notion that resistin can mimic cell type-dependent immunosuppressive effects. This is consistent with its putative role in the pathogenesis of bacterial sepsis.

New influenza A viruses that emerge frequently elicit composite inflammatory responses to both infection and structural damage of alveolar-capillary barrier cells that hinders regeneration of respiratory function. The host factors that relinquish restoration of lung health to enduring lung injury are insufficiently understood. Here, we investigated the role of endophilin B2 (B2) in susceptibility to severe influenza infection. WT and B2-deficient mice were infected with H1N1 PR8 by intranasal administration and course of influenza pneumonia, inflammatory, and tissue responses were monitored over time. Disruption of B2 enhanced recovery from severe influenza infection as indicated by swift body weight recovery and significantly better survival of endophilin B2-deficient mice compared to WT mice. Compared to WT mice, the B2-deficient lungs exhibited induction of genes that express surfactant proteins, ABCA3, GM-CSF, podoplanin, and caveolin mRNA after 7 days, temporal induction of CCAAT/enhancer binding protein CEBPα, β, and δ mRNAs 3–14 days after infection, and differences in alveolar extracellular matrix integrity and respiratory mechanics. Flow cytometry and gene expression studies demonstrated robust recovery of alveolar macrophages and recruitment of CD4+ lymphocytes in B2-deficient lungs. Targeting of endophilin B2 alleviates adverse effects of IAV infection on respiratory and immune cells enabling restoration of alveolar homeostasis.

Persistent high levels of proinflammatory and Th1 responses contribute to cerebral malaria (CM). Suppression of inflammatory responses and promotion of Th2 responses prevent pathogenesis. IL-4 commonly promotes Th2 responses and inhibits inflammatory and Th1 responses. Therefore, IL-4 is widely considered as a beneficial cytokine via its Th2-promoting role that is predicted to provide protection against severe malaria by inhibiting inflammatory responses. However, IL-4 may also induce inflammatory responses, as the result of IL-4 action depends on the timing and levels of its production, and the tissue environment in which it is produced. Recently, we showed that dendritic cells (DCs) produce IL-4 early during malaria infection in response to a parasite protein, and that this IL-4 response may contribute to severe malaria (Wu et al. (2018) J. Biol. Chem. 293, 10425-10434). However, the mechanism by which IL-4 produced by DCs contributing to lethal malaria is unknown. Using P. berghei ANKA-infected C57BL/6 mice, a CM model, we show here that mice lacking IL-4Rα only in CD8α+ DCs are protected against CM pathogenesis and survive, whereas WT mice develop CM and die. Compared to WT mice, mice lacking IL-4Rα in CD11c+ or CD8α+ DCs showed reduced inflammatory responses leading to decreased Th1 and cytotoxic CD8+ T cell responses, lower infiltration of CD8+ T cells to the brain, and negligible brain pathology. The novel results presented here reveal a paradoxical role of IL-4Rα signaling in CM pathogenesis that promotes CD8α+ DC-mediated inflammatory responses that generate damaging Th1 and cytotoxic CD8+ T cell responses.

Bloodstream infections are major contributing factors of morbidity and mortality among children. Precise and timely identification of causative agents can improve the clinical management and outcome of the infection, potentially saving lives. Electrochemical biosensors previously described by Gao et al. (2017) have the potential to deliver greater speed and discrimination. However, to date there are no data that determine whether the age of the host would cause bacteria to demonstrate different growth characteristics, or whether pediatric samples would behave differently using this electrochemical biosensor. The importance of this knowledge gap is clear: the preclinical testing phase of this line of research is limited by the relative lack of pediatric healthy blood volunteers to complete this work. Therefore, in this study we have applied this novel technology to diagnose bacteria spiked into pediatric blood and compared directly with adult blood samples. Only 180 µL of blood was utilized from both adult and pediatric volunteers and inoculated with Escherichia coli 67, and the signals generated at different time points were compared. We were able to demonstrate that the signals generated by adult and pediatric blood were not significantly different with this detection technology.