Helminth protein enhances wound healing by inhibiting fibrosis and promoting tissue regeneration.

Skin wound healing due to full thickness wounds typically results in fibrosis and scarring, where parenchyma tissue is replaced with connective tissue. A major advance in wound healing research would be to instead promote tissue regeneration. Helminth parasites express excretory/secretory (ES) molecules, which can modulate mammalian host responses.

Targeting helminths: The expanding world of type 2 immune effector mechanisms.

In this new review, Rick Maizels and Bill Gause summarize how type 2 immune responses combat helminth parasites through novel mechanisms, coordinating multiple innate and adaptive cell and molecular players that can eliminate infection and repair-resultant tissue damage.

Protocol for immunofluorescence staining of murine helminth-infected intestinal and lung tissues.

Preserving structurally intact tissue through proper tissue fixation and cryopreservation minimizes tissue autolysis, desiccation, and enzymatic degradation. In this protocol, we describe the use of an optimized fresh freezing technique that cryopreserves the tissue and favors the retention of the natural protein structure of antigens. We also detail the use of cold, low-concentration paraformaldehyde (PFA) fixation to enhance tissue morphology and detection of fluorescent proteins, such as GFP and TdTomato, in tissues of genetically engineered mice.

The Impact of Helminth Coinfection on Innate and Adaptive Immune Resistance and Disease Tolerance during Toxoplasmosis.

More than 2 billion people worldwide are infected with helminths. Thus, it is possible for individuals to experience concomitant infection with helminth and intracellular microbes. Although the helminth-induced type 2 response can suppress type 1 proinflammatory responses required for the immunity against intracellular pathogens in the context of a coinfection, conflicting evidence suggest that helminth infection can enhance antimicrobial immunity.

Maternal IL-33 critically regulates tissue remodeling and type 2 immune responses in the uterus during early pregnancy in mice.

The pregnant uterus is an immunologically rich organ, with dynamic changes in the inflammatory milieu and immune cell function underlying key stages of pregnancy. Recent studies have implicated dysregulated expression of the interleukin-1 (IL-1) family cytokine, IL-33, and its receptor, ST2, in poor pregnancy outcomes in women, including recurrent pregnancy loss, preeclampsia, and preterm labor. How IL-33 supports pregnancy progression in vivo is not well understood.

Adenosine metabolized from extracellular ATP promotes type 2 immunity through triggering AAR signaling in intestinal epithelial cells.

Intestinal nematode parasites can cross the epithelial barrier, causing tissue damage and release of danger-associated molecular patterns (DAMPs) that may promote host protective type 2 immunity. We investigate whether adenosine binding to the A adenosine receptor (AAR) on intestinal epithelial cells (IECs) plays an important role. Specific blockade of IEC AAR inhibits the host protective memory response to the enteric helminth, Heligmosomoides polygyrus bakeri (Hpb), including disruption of granuloma development at the host-parasite interface.

A adenosine receptor activation prevents neutrophil aging and promotes polarization from N1 towards N2 phenotype.

Extracellular adenosine is a biologically active signaling molecule that accumulates at sites of metabolic stress in sepsis. Extracellular adenosine has potent immunosuppressive effects by binding to and activating G protein-coupled A adenosine receptors (AARs) on the surface of neutrophils. AAR signaling reproduces many of the phenotypic changes in neutrophils that are characteristic of sepsis, including decreased degranulation, impaired chemotaxis, and diminished ability to ingest and kill bacteria.

Helminth resistance is mediated by differential activation of recruited monocyte-derived alveolar macrophages and arginine depletion.

Macrophages are known to mediate anti-helminth responses, but it remains uncertain which subsets are involved or how macrophages actually kill helminths. Here, we show rapid monocyte recruitment to the lung after infection with the nematode parasite Nippostrongylus brasiliensis. In this inflamed tissue microenvironment, these monocytes differentiate into an alveolar macrophage (AM)-like phenotype, expressing both SiglecF and CD11c, surround invading parasitic larvae, and preferentially kill parasites in vitro.

Inosine monophosphate and inosine differentially regulate endotoxemia and bacterial sepsis.

Inosine monophosphate (IMP) is the intracellular precursor for both adenosine monophosphate and guanosine monophosphate and thus plays a central role in intracellular purine metabolism. IMP can also serve as an extracellular signaling molecule, and can regulate diverse processes such as taste sensation, neutrophil function, and ischemia-reperfusion injury. How IMP regulates inflammation induced by bacterial products or bacteria is unknown.

Mining Helminths for Novel Therapeutics.

Helminths are an emerging source of therapeutics for dysregulated inflammatory diseases. Excretory/secretory (ES) molecules, released during infection, are responsible for many of these immunomodulatory effects and are likely to have evolved as a means for parasite survival in the host. While the mechanisms of action of these molecules have not been fully defined, evidence demonstrates that they target various pathways in the immune response, ranging from initiation to effector cell modulation.

Early Events Triggering the Initiation of a Type 2 Immune Response.

Type 2 immune responses are typically associated with protection against helminth infections and also with harmful inflammation in response to allergens. Recent advances have revealed that type 2 immunity also contributes to sterile inflammation, cancer, and microbial infections. However, the early events that initiate type 2 immune responses remain poorly defined.

Axl and Mertk Receptors Cooperate to Promote Breast Cancer Progression by Combined Oncogenic Signaling and Evasion of Host Antitumor Immunity.

Despite the promising clinical benefit of targeted and immune checkpoint blocking therapeutics, current strategies have limited success in breast cancer, indicating that additional inhibitory pathways are required to complement existing therapeutics. TAM receptors (Tyro-3, Axl, and Mertk) are often correlated with poor prognosis because of their capacities to sustain an immunosuppressive environment. Here, we ablate Axl on tumor cells using CRISPR/Cas9 gene editing, and by targeting Mertk in the tumor microenvironment (TME), we observed distinct functions of TAM as oncogenic kinases, as well as inhibitory immune receptors.

Heterogeneity in the initiation, development and function of type 2 immunity.

Type 2 immune responses operate under varying conditions in distinct tissue environments and are crucial for protection against helminth infections and for the maintenance of tissue homeostasis. Here we explore how different layers of heterogeneity influence type 2 immunity. Distinct insults, such as allergens or infections, can induce type 2 immune responses through diverse mechanisms, and this can have heterogeneous consequences, ranging from acute or chronic inflammation to deficits in immune regulation and tissue repair.

The NET Effect of Neutrophils during Helminth Infection.

Recent studies show that neutrophils mediate both tissue damage and host protection in response to multicellular parasites. In this issue of Cell Host & Microbe, Bouchery et al. demonstrate the importance of neutrophil extracellular traps in helminth damage after primary infections.

Sterile particle-induced inflammation is mediated by macrophages releasing IL-33 through a Bruton's tyrosine kinase-dependent pathway.

Initiation of the innate sterile inflammatory response that can develop in response to microparticle exposure is little understood. Here, we report that a potent type 2 immune response associated with the accumulation of neutrophils, eosinophils and alternatively activated (M2) macrophages was observed in response to sterile microparticles similar in size to wear debris associated with prosthetic implants. Although elevations in interleukin-33 (IL-33) and type 2 cytokines occurred independently of caspase-1 inflammasome signalling, the response was dependent on Bruton's tyrosine kinase (BTK).

B Cells Produce the Tissue-Protective Protein RELMα during Helminth Infection, which Inhibits IL-17 Expression and Limits Emphysema.

Emphysema results in destruction of alveolar walls and enlargement of lung airspaces and has been shown to develop during helminth infections through IL-4R-independent mechanisms. We examined whether interleukin 17A (IL-17A) may instead modulate development of emphysematous pathology in mice infected with the helminth parasite Nippostrongylus brasiliensis. We found that transient elevations in IL-17A shortly after helminth infection triggered subsequent emphysema that destroyed alveolar structures.

Helminth Infections Induce Tissue Tolerance Mitigating Immunopathology but Enhancing Microbial Pathogen Susceptibility.

Helminths are ubiquitous and have chronically infected vertebrates throughout their evolution. As such helminths have likely exerted considerable selection pressure on our immune systems. The large size of multicellular helminths and their limited replicative capacity in the host necessarily elicits different host protective mechanisms than the immune response evoked by microbial pathogens such as bacteria, viruses and intracellular parasites.

Pla2g1b Places Worms in Peril.

The determinants of helminth resistance are not well understood. In this issue of Cell Host & Microbe, Entwistle et al. (2017) provide intriguing evidence that a phospholipase A2 (Pla2gb1) produced by epithelial cells can impair larval development in helminths, providing a novel mechanism contributing to intestinal nematode resistance.

Cutting Edge: Helminth Coinfection Blocks Effector Differentiation of CD8 T Cells through Alternate Host Th2- and IL-10-Mediated Responses.

Concurrent helminth infection potently inhibits T cell immunity; however, whether helminthes prevent T cell priming or skew clonal recruitment and effector differentiation is not known. Using coinfection with two natural mouse pathogens, Heligmosomoides polygyrus and Toxoplasma gondii, to investigate the negative impact of helminthes on the CD8 T cell response, we demonstrate helminth-induced suppression of IL-12-dependent differentiation of killer-like receptor G1 effector CD8 T cells and IFN-γ production. Nevertheless, reversal of helminth suppression of the innate IL-12 response of CD8α dendritic cells, which occurred in STAT6-deficient mice, was not sufficient to normalize CD8 T cell differentiation.

Macrobiota - helminths as active participants and partners of the microbiota in host intestinal homeostasis.

Important insights have recently been gained in our understanding of the intricate relationship in the intestinal milieu between the vertebrate host mucosal immune response, commensal bacteria, and helminths. Helminths are metazoan worms (macrobiota) and trigger immune responses that include potent regulatory components capable of controlling harmful inflammation, protecting barrier function and mitigating tissue damage. They can secrete a variety of products that directly affect immune regulatory function but they also have the capacity to influence the composition of microbiota, which can also then impact immune function.

Helminth infection promotes colonization resistance via type 2 immunity.

Increasing incidence of inflammatory bowel diseases, such as Crohn's disease, in developed nations is associated with changes to the microbial environment, such as decreased prevalence of helminth colonization and alterations to the gut microbiota. We find that helminth infection protects mice deficient in the Crohn's disease susceptibility gene Nod2 from intestinal abnormalities by inhibiting colonization by an inflammatory Bacteroides species. Resistance to Bacteroides colonization was dependent on type 2 immunity, which promoted the establishment of a protective microbiota enriched in Clostridiales.

Innate cell communication kick-starts pathogen-specific immunity.

Innate cells are responsible for the rapid recognition of infection and mediate essential mechanisms of pathogen elimination, and also facilitate adaptive immune responses. We review here the numerous intricate interactions among innate cells that initiate protective immunity. The efficient eradication of pathogens depends on the coordinated actions of multiple cells, including innate cells and epithelial cells.

Emerging functions of amphiregulin in orchestrating immunity, inflammation, and tissue repair.

Type 2 inflammatory responses can be elicited by diverse stimuli, including toxins, venoms, allergens, and infectious agents, and play critical roles in resistance and tolerance associated with infection, wound healing, tissue repair, and tumor development. Emerging data suggest that in addition to characteristic type 2-associated cytokines, the epidermal growth factor (EGF)-like molecule Amphiregulin (AREG) might be a critical component of type 2-mediated resistance and tolerance. Notably, numerous studies demonstrate that in addition to the established role of epithelial- and mesenchymal-derived AREG, multiple leukocyte populations including mast cells, basophils, group 2 innate lymphoid cells (ILC2s), and a subset of tissue-resident regulatory CD4(+) T cells can express AREG.