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Title: Eosinophils and IL-4 Support Nematode Growth Coincident with an Innate Response to Tissue Injury}
Article:
Abstract:
It has become increasingly clear that the functions of eosinophils extend beyond host defense and allergy to metabolism and tissue regeneration. These influences have strong potential to be relevant in worm infections in which eosinophils are prominent and parasites rely on the host for nutrients to support growth or reproduction. The aim of this study was to investigate the mechanism underlying the observation that eosinophils promote growth of Trichinella spiralis larvae in skeletal muscle. Our results indicate that IL-4 and eosinophils are necessary for normal larval growth and that eosinophils from IL-4 competent mice are sufficient to support growth. The eosinophil-mediated effect operates in the absence of adaptive immunity. Following invasion by newborn larvae, host gene expression in skeletal muscle was compatible with a regenerative response and a shift in the source of energy in infected tissue. The presence of eosinophils suppressed local inflammation while also influencing nutrient homeostasis in muscle. Redistribution of glucose transporter 4( GLUT4) and phosphorylation of Akt were observed in nurse cells, consistent with enhancement of glucose uptake and glycogen storage by larvae that is known to occur. The data are consistent with a mechanism in which eosinophils promote larval growth by an IL-4 dependent mechanism that limits local interferon-driven responses that otherwise alter nutrient metabolism in infected muscle. Our findings document a novel interaction between parasite and host in which worms have evolved a strategy to co-opt an innate host cell response in a way that facilitates their growth.
Introduction:
Genomic analysis of diverse members of the Nematoda has revealed that parasitism emerged in free-living nematodes as a result of multiple, independent evolutionary events[1]. The process of host adaptation is associated with loss of functions that enable a free-living lifestyle. Understanding these dependencies is instructive when devising therapeutic and prophylactic approaches to controlling parasitic disease. A central influence on successful parasitism is the host immune response. Animals often mount highly effective Th2 immune responses against worms; however, specific effector mechanisms vary by host, tissue and parasite. As counterpoint, helminths co-opt or evade the host immune response in ways that ensure completion of life cycle and transmission to the next host. In two examples, schistosomes manipulate innate immune signals and Th2 immunity to facilitate their development[2, 3] and Trichinella reproduces in the host intestine within 5 days of infection, in advance of a potent intestinal immune response that expels adult worms[4]. Eosinophilia is a hallmark of the host immune response to parasitic worms. Long considered to be cytotoxic effector cells that kill parasite larvae, recent studies in eosinophil-ablated mice have shown that the influence of eosinophils on worms varies from no effect, to protecting the host, to supporting the parasite[5–9]. In separate research on animal metabolism, new findings document a regulatory influence of eosinophils[10–13]. Control of energy metabolism by eosinophils has potential to influence the outcome of worm infection. After being released from female adult worms in the intestine, Trichinella spiralis( T. spiralis) newborn larvae( NBL) enter the circulatory system, migrate to a variety of tissues and eventually establish intracellular infection in skeletal muscle. Following invasion of skeletal muscle cells, NBL remain inactive for 4 days prior to initiating growth from 130 μm to 1 mm in length over the course of 20 days[14]. Our previous studies demonstrated that eosinophils are recruited to muscle when NBL arrive and that they positively regulate both survival and growth of larvae[5, 7, 9]. Larval survival is dependent on eosinophil-derived interleukin( IL)-10. This, in turn, drives production of CD4+IL-10+ cells that suppress local nitric oxide( NO) production by neutrophils and macrophages[9]. NO is toxic for newborn and growing larvae[5, 9]. A distinct mechanism that is independent of IL-10[5] supports growth of T. spiralis larvae. This was the focus of the current study. Our results reveal a requirement for IL-4/signal transducers and activators of transcription 6( STAT6) signaling in eosinophils for normal larval growth. In the absence of eosinophils, there is a sustained, local, interferon-driven inflammation that promotes a shift in metabolism in infected muscle. These findings provide evidence for a host-parasite relationship in which the recruitment of eosinophils promotes a nutrient-rich environment that facilitates larval growth.
Discussion:
The influence of eosinophils varies dramatically between primary and secondary infection with T. spiralis[9, 16]. In secondary infection, eosinophils cooperate with antibodies to limit the number of NBL that transit the lung and colonize skeletal muscle[9, 16]. During primary infection, eosinophils appear to protect the parasite rather than the host and we have reported previously that growth of T. spiralis larvae during primary infection is dependent on eosinophils[5, 7, 9]. Others have shown that filarial parasites regulate their development and reproduction in response to eosinophilia[17]. The dependency of worms on eosinophils for development or growth suggests a mechanism by which the host response provides resources to the parasite. Due to the size and motility of parasitic worms, tissue injury is a feature of infection. The response of skeletal muscle to injury is regenerative. Recent findings have linked eosinophils to skeletal muscle regeneration by showing them to be the dominant IL-4 producing cells at sites of muscle damage and furthermore, that IL-4 activates regenerative responses[11]. Consistent with these findings, we found that expression of genes involved in muscle regeneration feature prominently in the response to NBL invasion and that this response is influenced by eosinophils. Our observations support a model in which eosinophils would contribute to IL-4 dependent muscle regeneration in an innate response to the injury caused by invading NBL. Larval growth was supported when eosinophils were restored to ablated mice by transfer from IL-4 or STAT6-competent mice. Eosinophils express a functional IL-4 receptor[18] and it is possible that they must develop in the presence of IL-4 in order to produce other mediators or effector functions that support larval growth. For example, RELMα is induced in an IL-4-dependent manner in eosinophils during schistosome infection[19], and also plays critical roles in regulating host energy metabolism and glucose homeostasis[20, 21]. Our microarray analysis revealed that RELMα expression increases 1. 76 fold at 7 dpi compared to naïve muscle. Attribution of this change to eosinophils is not possible with the available data. The influence of RELMα and other IL-4 dependent eosinophil products on larval growth requires experimentation with gene knockouts that are inducible or otherwise targeted to eosinophils. Alternatively, eosinophils may deliver IL-4 to other cells. Infection of STAT6 chimeras showed that when STAT6 was limited to bone marrow cells, mice supported larval growth. This eliminates the possibility that fully differentiated myotubes invaded by NBL would support growth via STAT6 signaling. It is important to note reports providing evidence that, during muscle injury and regeneration, IL-4 is capable of stimulating IL-4Rα+ myoblast fusion and muscle fiber growth[22]. A proportion of myoblasts arise from cells recruited from bone marrow[23–25]. Similarly, IL-4Rα+ fibro/adipocyte progenitors( FAP) support myogenesis[11]. Furthermore, bone marrow-derived IL-4Rα+ CD11b+ myeloid effector cells are capable of limiting excessive inflammation via IL-4 induced STAT6 signaling[26]. Any of these cells provides a target for eosinophil-derived IL-4, with potential to promote nurse cell formation, recovery from muscle injury, or control of inflammation. Transfer of IL-4 competent eosinophils to appropriately targeted IL-4 receptor knockout mice will serve to test these mechanisms. Autophagy is another mechanism involved in maintaining skeletal muscle mass and regulating glucose homeostasis in muscle cells[27, 28]. Autophagy defends cells against intracellular pathogens[29] and is inhibited by Th2 cytokines, such as IL-4 and IL-13[29]. Furthermore, helminth products can induce autophagy[30]. After invading muscle cells, NBL establish an intracellular infection. We speculated that T. spiralis might induce the recruitment of IL-4 secreting eosinophils to sites of infection as a mechanism to prevent destruction of NBL by autophagy. Gene expression array analysis did not reveal any significant regulation of autophagy-related genes in the absence of eosinophils. Our findings do not support a role for autophagy in regulating larval growth in skeletal muscle. T. spiralis larvae store large quantities of glycogen[31] and nurse cells transport greater quantities of glucose than skeletal muscle cells[15]. In the absence of exogenous glucose, under aerobic or anaerobic conditions, larvae rapidly break down endogenous stores of glycogen[32]. Importantly, reduced larval glycogen correlates with impaired infectivity[33]. Consistent with a deficiency of larval glycogen, surviving larvae in eosinophil-ablated mice are less infectious than larvae from WT mice[7]. Other reports show that infection by T. spiralis induces host hypoglycemia and suggest that this is the result of an increase in glucose uptake by infected muscle cells via up-regulation of the insulin signaling pathway[34]. Recent reports demonstrated that IL-4 producing eosinophils are capable of promoting insulin sensitivity in adipose tissues[10, 13]. In skeletal muscle, the binding of IL-4 to its receptor activates the PI3K/Akt pathway and further promotes insulin stimulated glucose uptake via GLUT4 translocation[35]. Our bone marrow chimera experiments suggested that STAT6 in established myotubes is dispensable for larval growth; however, modification of the myotube by infiltrating cells from bone marrow may enable STAT6 signaling in the nurse cell. Nevertheless, this mechanism need not come into play, as IL-4 also engages insulin receptor substrate 2( IRS2) /PI3K signaling to mediate Akt activation[36, 37]. We found evidence for pathway activation and GLUT4 translocation in infected muscle cells, which supports a mechanism in which eosinophil-derived IL-4 promotes muscle larval growth directly by enhancing glucose uptake in host cells. Establishing this pathway as a mechanism that supports larval growth requires further experimentation. Alternatively, glucose uptake can be regulated indirectly by IL-4. Inflammation attenuates insulin sensitivity in multiple tissues[38, 39], More specifically, IFN-γ attenuates insulin sensitivity via sustained activation of the STAT1 pathway[40]. Gene expression data revealed activation of the STAT1 pathway in infected muscle( Cluster 2 in Fig 5), a profile that was sustained in eosinophil-ablated mice compared to WT( Fig 7). Thus, in the absence of eosinophils, sustained STAT1 activation may limit glucose uptake in nurse cells. Transcriptional signatures of both the TCA cycle and fatty acid metabolism are dramatically reduced in the absence of eosinophils. IL-4 has been shown to be important for promoting lipolysis and glucose homeostasis[41, 42]. In aggregate, the gene expression data suggest that eosinophils contribute to the maintenance of glucose and lipid metabolism in muscle at an early stage of larval infection. Our results are consistent with a mechanism in which larval growth is supported when eosinophils, or eosinophil-derived IL-4, limits STAT1 signaling that otherwise would inhibit glucose and lipid metabolism in muscle. Further experimentation with gene knockouts targeted to eosinophils, or the cells they influence, will be important to clarifying the mechanism. Our results document a process by which a parasitic worm appears to co-opt innate responses to injury in a way that supports its life cycle. Eosinophils are central to this process and operate in the context of innate immunity.
Eosinophilia is a central feature of Type 2 immunity induced by infection with parasitic worms . Although early work showed that eosinophils could adhere to and damage parasite larvae in vitro , a definitive role for eosinophils during worm infection remained elusive for many years . Recent studies uncovered novel roles of eosinophils in regulating metabolism and tissue remodeling , observations that suggest that eosinophils may function as regulatory cells and modulate such processes during helminth infections . We investigated the eosinophil-dependent mechanism that promotes growth of Trichinella spiralis larvae . We found that larval growth is independent of adaptive immunity and requires IL-4/STAT6 signaling in eosinophils . Gene transcription profiles in infected muscle suggested that eosinophils promote larval growth by suppressing local inflammation and enhancing nutrient uptake and metabolism . Our study provides new insights into the interactions between a parasitic worm and its host .