CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation

Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage proliferation is promoted by macrophage colony-stimulating factor (M-CSF)-induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2-interacting protein-1 (CKIP-1) as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP-1 was phosphorylated at Serine 342 by constitutively active GSK3β, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degradation of CKIP-1. Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3β, leading to the stabilization of CKIP-1 and β-catenin proteins. β-catenin promotes the expression of proliferation genes including cyclin D and c-Myc. CKIP-1 interacts with TRAF6, a ubiquitin ligase required for K63-linked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6-mediated Akt activation. By this means, CKIP-1 inhibits macrophage proliferation specifically at the late stage after M-CSF stimulation. Furthermore, CKIP-1 deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1^−/− mice spontaneously develop a macrophage-dominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation.     

Chaperone–usher pathways: diversity and pilus assembly mechanism

Up to eight different types of secretion systems, and several more subtypes, have been described in Gram-negative bacteria. Here, we focus on the diversity and assembly mechanism of one of the best-studied secretion systems, the widespread chaperone–usher pathway known to assemble and secrete adhesive surface structures, called pili or fimbriae, which play essential roles in targeting bacterial pathogens to the host.     

Host–parasite interactions: resist or tolerate but never stop running

A conference exploring ‘The impact of the environment on innate immunity: the threat of diseases’ was held on 4–9 May 2009 in Obergurgl, Austria, thanks to the support from the European Science Foundation, Innsbruck University and the Austrian Science Foundation. The goals of the conference were to explore how the outcomes of host–parasite interactions depend on variation across individuals, their parasites and the environment in which they both find themselves. Central themes were the inherent costs of mounting an immune response, the ability of some organisms to pre-empt infection by ‘priming’ their immune systems, the fact that parasites learn to evade immune responses over time and the use of theory to predict when diseases will get out of hand. Many of the systems presented had clear impacts on human health, agriculture or the maintenance of complex ecosystems. There was common ground throughout in developing methodologies and embracing what one of the organizers termed the ‘interactome’ between hosts and those which would exploit them.     

Opposing effects of allogrooming on disease transmission in ant societies

To prevent epidemics, insect societies have evolved collective disease defences that are highly effective at curing exposed individuals and limiting disease transmission to healthy group members. Grooming is an important sanitary behaviour—either performed towards oneself (self-grooming) or towards others (allogrooming)—to remove infectious agents from the body surface of exposed individuals, but at the risk of disease contraction by the groomer. We use garden ants (Lasius neglectus) and the fungal pathogen Metarhizium as a model system to study how pathogen presence affects self-grooming and allogrooming between exposed and healthy individuals. We develop an epidemiological SIS model to explore how experimentally observed grooming patterns affect disease spread within the colony, thereby providing a direct link between the expression and direction of sanitary behaviours, and their effects on colony-level epidemiology. We find that fungus-exposed ants increase self-grooming, while simultaneously decreasing allogrooming. This behavioural modulation seems universally adaptive and is predicted to contain disease spread in a great variety of host–pathogen systems. In contrast, allogrooming directed towards pathogen-exposed individuals might both increase and decrease disease risk. Our model reveals that the effect of allogrooming depends on the balance between pathogen infectiousness and efficiency of social host defences, which are likely to vary across host–pathogen systems.     

Self-harm to preferentially harm the pathogens within: non-specific stressors in innate immunity

Therapies with increasing specificity against pathogens follow the immune system''s evolutionary course in maximizing host defence while minimizing self-harm. Nevertheless, even completely non-specific stressors, such as reactive molecular species, heat, nutrient and oxygen deprivation, and acidity can be used to preferentially harm pathogens. Strategic use of non-specific stressors requires exploiting differences in stress vulnerability between pathogens and hosts. Two basic vulnerabilities of pathogens are: (i) the inherent vulnerability to stress of growth and replication (more immediately crucial for pathogens than for host cells) and (ii) the degree of pathogen localization, permitting the host''s use of locally and regionally intense stress. Each of the various types of non-specific stressors is present during severe infections at all levels of localization: (i) ultra-locally within phagolysosomes, (ii) locally at the infected site, (iii) regionally around the infected site and (iv) systemically as part of the acute-phase response. We propose that hosts strategically use a coordinated system of non-specific stressors at local, regional and systemic levels to preferentially harm the pathogens within. With the rising concern over emergence of resistance to specific therapies, we suggest more scrutiny of strategies using less specific therapies in pathogen control. Hosts'' active use of multiple non-specific stressors is likely an evolutionarily basic defence whose retention underlies and supplements the well-recognized immune defences that directly target pathogens.     

Too much of a good thing: resource provisioning alters infectious disease dynamics in wildlife

Provisioning of abundant food resources in human-altered landscapes can have profound effects on wildlife ecology, with important implications for pathogen transmission. While empirical studies have quantified the effects of provisioning on host behaviour and immunology, the net interactive effect of these components on host–pathogen dynamics is unknown. We use simple compartmental models to investigate how provisioning-induced changes to host demography, contact behaviour and immune defence influence pathogen invasion and persistence. We show that pathogen invasion success and equilibrium prevalence depend critically on how provisioning affects host immune defence and that moderate levels of provisioning can lead to drastically different outcomes of pathogen extinction or maximizing prevalence. These results highlight the need for further empirical studies to fully understand how provisioning affects pathogen transmission in urbanized environments.     

ClC-2 inhibition prevents macrophage foam cell formation by suppressing Nlrp3 inflammasome activation

ABSTRACT

Macrophage foam cell formation and inflammation are a pathological hallmark of atherosclerosis. ClC-2 has been implicated in various pathological processes, including inflammation and lipid metabolic disorder. However, the functional role of ClC-2 in macrophage foam cell formation and inflammation is unclear. Here, we found that ClC-2 was dominantly expressed in macrophages of atherosclerotic plaque and increased in atherogenesis. Knockdown of ClC-2 inhibited ox-LDL -induced lipid uptake and deposition in macrophages. The increase in CD36 expression and the decrease in ABCA1 expression induced by ox-LDL were alleviated by ClC-2 downregulation. Further, ClC-2 lacking limited the ox-LDL-induced secretion of inflammatory cytokines and chemokine, and suppressed Nlrp3 inflammasome activation. Restoration of Nlrp3 expression reversed the effect of ClC-2 downregulation on macrophage lipid accumulation and inflammation. Collectively, our study demonstrates that ClC-2 knockdown ameliorates ox-LDL-induced macrophage foam cell formation and inflammation by inhibiting Nlrp3 inflammasome activation.     

PPARs调控巨噬细胞的活化与功能

巨噬细胞是先天性防御病原体的关键组分,它参与炎症的发生和消退,同时也参与了组织的修复。巨噬细胞的多种功能通过不同的活化状态完成,即从经典活化状态到替代性活化状态,再到失活状态。巨噬细胞活化的失调与代谢、炎症和免疫病变有关,调节蛋白控制巨噬细胞的活化可作为新的治疗靶点。主要综述过氧化物酶体增殖物激活受体（PPARs）调控巨噬细胞活化的作用。     

Suppression of inflammation by helminths: a role for the gut microbiota?

Multiple recent investigations have highlighted the promise of helminth-based therapies for the treatment of inflammatory disorders of the intestinal tract of humans, including inflammatory bowel disease and coeliac disease. However, the mechanisms by which helminths regulate immune responses, leading to the amelioration of symptoms of chronic inflammation are unknown. Given the pivotal roles of the intestinal microbiota in the pathogenesis of these disorders, it has been hypothesized that helminth-induced modifications of the gut commensal flora may be responsible for the therapeutic properties of gastrointestinal parasites. In this article, we review recent progress in the elucidation of host–parasite–microbiota interactions in both animal models of chronic inflammation and humans, and provide a working hypothesis of the role of the gut microbiota in helminth-induced suppression of inflammation.     

The blood parasite Haemoproteus reduces survival in a wild bird: a medication experiment

While avian chronic haemoparasite infections induce reproductive costs, infection has not previously been shown to affect survival. Here, we experimentally reduced, through medication, the intensity of infection by Haemoproteus parasites in wild-breeding female blue tits Cyanistes caeruleus. However, this treatment did not reduce the intensity of infection in males or the intensity of infection by Leucocytozoon. Medicated females, but not males, showed increased local survival until the next breeding season compared with control birds. To our knowledge, this is the first empirical evidence showing long-term direct survival costs of chronic Haemoproteus infections in wild birds.     

Polymorphisms at the innate immune receptor TLR2 are associated with Borrelia infection in a wild rodent population

The discovery of the key role of Toll-like receptors (TLRs) in initiating innate immune responses and modulating adaptive immunity has revolutionized our understanding of vertebrate defence against pathogens. Yet, despite their central role in pathogen recognition and defence initiation, there is little information on how variation in TLRs influences disease susceptibility in natural populations. Here, we assessed the extent of naturally occurring polymorphisms at TLR2 in wild bank voles (Myodes glareolus) and tested for associations between TLR2 variants and infection with Borrelia afzelii, a common tick-transmitted pathogen in rodents and one of the causative agents of human Lyme disease. Bank voles in our population had 15 different TLR2 haplotypes (10 different haplotypes at the amino acid level), which grouped in three well-separated clusters. In a large-scale capture–mark–recapture study, we show that voles carrying TLR2 haplotypes of one particular cluster (TLR2_c2) were almost three times less likely to be Borrelia infected than animals carrying other haplotypes. Moreover, neutrality tests suggested that TLR2 has been under positive selection. This is, to our knowledge, the first demonstration of an association between TLR polymorphism and parasitism in wildlife, and a striking example that genetic variation at innate immune receptors can have a large impact on host resistance.     

Adenosine‐A3 receptors in neutrophil microdomains promote the formation of bacteria‐tethering cytonemes

The A₃‐adenosine receptor (A₃AR) has recently emerged as a key regulator of neutrophil behaviour. Using a fluorescent A₃AR ligand, we show that A₃ARs aggregate in highly polarized immunomodulatory microdomains on human neutrophil membranes. In addition to regulating chemotaxis, A₃ARs promote the formation of filipodia‐like projections (cytonemes) that can extend up to 100 μm to tether and ‘reel in’ pathogens. Exposure to bacteria or an A₃AR agonist stimulates the formation of these projections and bacterial phagocytosis, whereas an A₃AR‐selective antagonist inhibits cytoneme formation. Our results shed new light on the behaviour of neutrophils and identify the A₃AR as a potential target for modulating their function.     

Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization

Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.