IL-4)) activation, linked to wound repair and type 2 pathology 3, 4, 5. Although pulmonary macrophage sub-populations inhabit dramatically different anatomical sites, such as the airways and tissue parenchyma, it is not yet clear how location influences their ability to respond to type 2 inflammation. In particular, reports of M(IL-4) marker expression on lung macrophages during type 2 inflammation 6, 7, 8, 9 have involved experimental approaches that may not clearly distinguish macrophages from other myeloid cells, raising the possibility that functional differences in key macrophage sub-populations have been inadvertently overlooked. As the predominant macrophage sub-population in airways, alveolar macrophages (AlvMs) are vital for maintaining lung health and function, having a central role in clearance of debris, surfactant and apoptotic cells 10. In the absence of AlvMs, fluid build-up leads to primary pulmonary alveolar proteinosis, severe lung dysfunction and respiratory failure 11. The majority of AlvMs are thought to be derived from embryonic precursors that seed the lung tissue before birth 12 , with recent evidence suggesting that the cytokines GM-CSF and TGF-β induce PPAR-γ, a crucial transcription factor for AlvM development 11, 13, 14. During inflammation, AlvMs mediate bacterial clearance and initiate neutrophil recruitment 15 , functions that can be regulated by cytokines such as IL-10 or TGF-β, and/or the engagement of cell surface receptors such as SIRPα or CD200 16. Because clear discrimination between AlvMs and other lung macrophage sub-populations is technically challenging 17 , far less is known about the function and origin of tissue residing interstitial macrophages (IntMs). Although IntMs may comprise up to three separate subpopulations 18 , earlier work may have mistakenly identified them as AlvMs, monocytes or dendritic cells (DCs). Mucosal environments like the lung play a major role in determining both development and function of macrophages 19 , though many of the factors that shape such processes remain unclear, particularly in type 2 inflammation. Lung macrophage upregulation of M(IL-4) markers during parasite-mediated type 2 responses is promoted by environmental factors such as surfactant protein A (SP-A) and engagement of TAM receptors during clearance of apoptotic cells 20, 21. Here we show that lung macrophage subsets, particularly AlvMs, were considerably less responsive to type 2 inflammation than macrophages from other tissues. We demonstrate that this muted phenotype was conferred by the lung environment, and was independent of potential negative regulators such as CD200-CD200R, surfactant protein D (SP-D), mucin 5b (Muc5b) or the host microbiota. Hypo-responsive AlvMs had an altered metabolic profile compared to IL-4-responsive peritoneal exudate cell macrophages (PECMs), and were unable to upregulate glycolysis in situ. Results AlvMs are unresponsive to IL-4 in vivo To better understand how pulmonary macrophages respond during type 2 inflammation, we utilized MerTK, CD64,...

Although the growth factor progranulin was discovered more than two decades ago, the functional receptor remains elusive. Here, we discovered that EphA2, a member of the large family of Ephrin receptor tyrosine kinases, is a functional signaling receptor for progranulin. Recombinant progranulin bound with high affinity to EphA2 in both solid phase and solution. Interaction of progranulin with EphA2 caused prolonged activation of the receptor, downstream stimulation of mitogen-activated protein kinase and Akt, and promotion of capillary morphogenesis. Furthermore, we found an autoregulatory mechanism of progranulin whereby a feed-forward loop occurred in an EphA2-dependent manner that was independent of the endocytic receptor sortilin. The discovery of a functional signaling receptor for progranulin offers a new avenue for understanding the underlying mode of action of progranulin in cancer progression, tumor angiogenesis, and perhaps neurodegenerative diseases.

SummaryGastrointestinal (GI) nematodes are a group of successful multicellular parasites that have evolved to coexist within the intestinal niche of multiple species. It is estimated that over 10% of the world's population are chronically infected by GI nematodes, making this group of parasitic nematodes a major burden to global health. Despite the large number of affected individuals, there are few effective treatments to eradicate these infections. Research into GI nematode infections has primarily focused on defining the immunological and pathological consequences on host protection. One important but neglected aspect of host protection is mucus, and the concept that mucus is just a simple barrier is no longer tenable. In fact, mucus is a highly regulated and dynamic‐secreted matrix, underpinned by a physical hydrated network of highly glycosylated mucins, which is increasingly recognized to have a key protective role against GI nematode infections. Unravelling the complex interplay between mucins, the underlying epithelium and immune cells during infection are a major challenge and are required to fully define the protective role of the mucus barrier. This review summarizes the current state of knowledge on mucins and the mucus barrier during GI nematode infections, with particular focus on murine models of infection.

Infection by soil transmitted parasitic helminths, such as Trichuris spp , are ubiquitous in humans and animals but the mechanisms determining persistence of chronic infections are poorly understood. Here we show that p43, the single most abundant protein in T. muris excretions/secretions, is non-immunogenic during infection and has an unusual sequence and structure containing subdomain homology to thrombospondin type 1 and interleukin (IL)−13 receptor (R) α2. Binding of p43 to IL-13, the key effector cytokine responsible for T. muris expulsion, inhibits IL-13 function both in vitro and in vivo. Tethering of p43 to matrix proteoglycans presents a bound source of p43 to facilitate interaction with IL-13, which may underpin chronic intestinal infection. Our results suggest that exploiting the biology of p43 may open up new approaches to modulating IL-13 function and control of Trichuris infections.

Macroautophagy is a fundamental and evolutionarily conserved catabolic process that eradicates damaged and aging macromolecules and organelles in eukaryotic cells. Decorin, an archetypical small leucine-rich proteoglycan, initiates a protracted autophagic program downstream of VEGF receptor 2 (VEGFR2) signaling that requires paternally expressed gene 3 (PEG3). We have discovered that PEG3 is an upstream transcriptional regulator of transcription factor EB (TFEB), a master transcription factor of lysosomal biogenesis, for decorin-evoked endothelial cell autophagy. We found a functional requirement of PEG3 for TFEB transcriptional induction and nuclear translocation in human umbilical vein endothelial and PAER2 cells. Mechanistically, inhibiting VEGFR2 or AMP-activated protein kinase (AMPK), a major decorin-activated energy sensor kinase, prevented decorin-evoked TFEB induction and nuclear localization. In conclusion, our findings indicate a non-canonical (nutrient- and energy-independent) mechanism underlying the pro-autophagic bioactivity of decorin via PEG3 and TFEB.

Trichuris trichiura (whipworm) is one of the four major soil-transmitted helminth infections of man, affecting an estimated 465 million people worldwide. An effective vaccine that induces long-lasting protective immunity against T. trichiura would alleviate the morbidity associated with this intestinal-dwelling parasite, however the lack of known host protective antigens has hindered vaccine development. Here, we show that vaccination with ES products stimulates long-lasting protection against chronic infection in male C57BL/6 mice. We also provide a framework for the identification of immunogenic proteins within T. muris ES, and identify eleven candidates with direct homologues in T. trichiura that warrant further study. Given the extensive homology between T. muris and T. trichiura at both the genomic and transcriptomic levels, this work has the potential to advance vaccine design for T. trichiura.

Whipworms are large metazoan parasites that inhabit multi-intracellular epithelial tunnels in the large intestine of their hosts, causing chronic disease in humans and other mammals. How first-stage larvae invade host epithelia and establish infection remains unclear. Here we investigate early infection events using both Trichuris muris infections of mice and murine caecaloids, the first in-vitro system for whipworm infection and organoid model for live helminths. We show that larvae degrade mucus layers to access epithelial cells. In early syncytial tunnels, larvae are completely intracellular, woven through multiple live dividing cells. Using single-cell RNA sequencing of infected mouse caecum, we reveal that progression of infection results in cell damage and an expansion of enterocytes expressing of Isg15, potentially instigating the host immune response to the whipworm and tissue repair. Our results unravel intestinal epithelium invasion by whipworms and reveal specific host-parasite interactions that allow the whipworm to establish its multi-intracellular niche.

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