Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden

Jang, Jessica C.; Chen, Gang; Wang, Spencer H.; Barnes, Mark; Chung, Josiah I; Camberis, Mali; Gros, Graham Le; Cooper, Philip J.; Steel, Cathy; Nutman, Thomas B.; Lazar, Mitchell A.; Nair, Meera G.

doi:10.1371/journal.ppat.1004579

Cited by 47 publications

(56 citation statements)

References 57 publications

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“…Delineating the role of both murine RELM␣ and RELM␤ in the context of infection and inflammation may allow a better understanding of human RELM␤ function. In previous studies, we have shown the importance of human resistin but not mouse resistin in influencing the immune response to N. brasiliensis (5). Transgenic mice expressing human resistin exhibited delayed parasite expulsion and increased parasite egg burdens, which mirrors our findings here showing that RELM␣ deficiency leads to im- proved parasite expulsion and decreased parasite fecundity.…”

Section: Discussionsupporting

confidence: 89%

“…Resistin-like molecules (RELMs) are secreted proteins with putative effector and immunoregulatory functions against helminth infections (3,4). In humans, significant increases in resistin expression occur in both filarial nematode and gastrointestinal nematode infections (5,6). In mice, RELM␣ and RELM␤, which share sequence homology with human RELM␤, are induced in response to Schistosoma mansoni and the gastrointestinal helminths Trichuris muris, Heligmosomoides polygyrus, and Nippostrongylus brasiliensis (7)(8)(9)(10)(11).…”

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confidence: 99%

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Comparison of RELMα and RELMβ Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection

et al. 2016

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bResistin-like molecules (RELMs) are highly expressed following helminth infection, where they impact both the host and helminth. While RELM␣ (Retnla) impairs helminth expulsion by inhibiting protective Th2 immunity, RELM␤ (Retnlb) can promote its expulsion. We employed Retnla ؊/؊ and Retnlb ؊/؊ mice to delineate the function of both proteins following infection with Nippostrongylus brasiliensis, a hookworm that infects the lung and intestine. Whereas wild-type (WT) and Retnlb ؊/؊ mice exhibited equivalent infection-induced inflammation, Retnla ؊/؊ mice suffered a heightened inflammatory response, including increased mortality, weight loss, and lung inflammation. In the intestine, Retnla ؊/؊ mice had low parasite egg burdens compared to those of WT mice, while Retnlb ؊/؊ mice exhibited high egg burdens, suggesting that RELM␣ and RELM␤ have functionally distinct effects on immunity and inflammation to N. brasiliensis. To test the importance of both proteins, we generated Retnla ؊/؊ Retnlb ؊/؊ mice. Infected Retnla ؊/؊ Retnlb ؊/؊ mice exhibited similar responses to Retnla ؊/؊ mice, including increased mortality and lung inflammation. This inflammatory response in Retnla ؊/؊ Retnlb ؊/؊ mice negatively impacted N. brasiliensis fitness, as demonstrated by significantly lower worm ATP levels and decreased intestinal worm burden and fecundity. Lung cytokine analysis revealed that Retnla ؊/؊ and Retnla ؊/؊ Retnlb ؊/؊ mice expressed significantly increased levels of interleukin-4 (IL-4). Finally, we generated Retnla ؊/؊ mice on the Rag ؊/؊ background and observed that the effects of RELM␣ were abrogated in the absence of adaptive immunity. Together, these data demonstrate that RELM␣ but not RELM␤ significantly impacts the immune response to N. brasiliensis infection by downregulating the Th2 adaptive immune response in the lung, which protects the host but allows improved parasite fitness. Soil-transmitted helminths (STHs) afflict over 2 billion individuals worldwide and can cause anemia and debilitating symptoms in the lung and intestine (1). Host protection against STHs is dependent on the balance between effector immune responses that promote worm expulsion and immunoregulatory pathways that control excessive infection-induced inflammation (2). Resistin-like molecules (RELMs) are secreted proteins with putative effector and immunoregulatory functions against helminth infections (3, 4). In humans, significant increases in resistin expression occur in both filarial nematode and gastrointestinal nematode infections (5, 6). In mice, RELM␣ and RELM␤, which share sequence homology with human RELM␤, are induced in response to Schistosoma mansoni and the gastrointestinal helminths Trichuris muris, Heligmosomoides polygyrus, and Nippostrongylus brasiliensis (7-11).Despite sharing sequence identity and expression patterns, the putative functions of RELM␣ and RELM␤ in helminth infection are different and involve both host-specific and parasite-specific effects. S. mansoni and N. brasiliensis infection led to increased RELM␣ expr...

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Comparison of RELMα and RELMβ Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection

et al. 2016

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“…Resistin is expressed in monocytes and epithelial cells (26), and thus could also be involved in host defense against pathogenic infections. The bactericidal activity of resistin and its expression in adipose tissue are also consistent with the known role of adipocytes in producing antimicrobial proteins that protect the host from bacterial infection (32).…”

Section: Discussionmentioning

confidence: 99%

“…The RELM family member resistin (RETN) is produced by adipocytes and has been proposed to be a hormone that functions in metabolic regulation (25). However, human resistin (hRETN) is also expressed in monocytes and epithelial cells (26), suggesting a possible antimicrobial function. hRETN has a high degree of homology with hRELMβ (51% identity overall), particularly in the C terminus (60% amino acid identity), leading us to postulate that hRETN might also have bactericidal activity.…”

Section: Relmβ Limits Entry Of Gram-negative Bacteria Into the Colon mentioning

confidence: 99%

Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium

Propheter

Chara

Harris

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

139

108

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The mammalian intestine is colonized by trillions of bacteria that perform essential metabolic functions for their hosts. The mutualistic nature of this relationship depends on maintaining spatial segregation between these bacteria and the intestinal epithelial surface. This segregation is achieved in part by the presence of a dense mucus layer at the epithelial surface and by the production of antimicrobial proteins that are secreted by epithelial cells into the mucus layer. Here, we show that resistin-like molecule β (RELMβ) is a bactericidal protein that limits contact between Gram-negative bacteria and the colonic epithelial surface. Mouse and human RELMβ selectively killed Gram-negative bacteria by forming size-selective pores that permeabilized bacterial membranes. In mice lacking RELMβ, Proteobacteria were present in the inner mucus layer and invaded mucosal tissues. Another RELM family member, human resistin, was also bactericidal, suggesting that bactericidal activity is a conserved function of the RELM family. Our findings thus identify the RELM family as a unique family of bactericidal proteins and show that RELMβ promotes host-bacterial mutualism by regulating the spatial segregation between the microbiota and the intestinal epithelium.antibacterial protein | microbiota | innate immunity | intestinal epithelium

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“…Resistin directly stimulates NF-κB-mediated inflammation, including the promoting expression and secretion of TNFα, IL-1β, IL-6 and IL-12 [71]. Recent data from our lab indicate that the immune stimulatory effect of human resistin is detrimental in helminth infection and impairs worm expulsion [75]. Transgenic mice expressing human resistin exhibited increased expression of resistin and infiltration of pro-inflammatory monocytes following infection with the helminth Nippostrongylus .…”

Section: Resistin and Resistin-like Moleculesmentioning

confidence: 99%

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

2015

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Catecholamines and adipokines function as hormones; catecholamines as neurotransmitters in the sympathetic nervous system, and adipokines as mediators of metabolic processes. It has become increasingly clear, however, that both also function as immunomodulators of innate and adaptive immune cells, including macrophages. Macrophages can respond to, as well as produce their own catecholamines. Dopamine, noradrenaline, and adrenaline are the most abundant catecholamines in the body, and can induce both pro-inflammatory and anti-inflammatory immune responses in macrophages, as well as non-immune processes such as thermogenesis. Though they are responsive to adipokines, particularly lipoproteins, leptin, and adiponectin, macrophages generally do synthesize their own adipokines, with the exception being resistin-like molecules. Adipokines contribute to adverse metabolic and immune response by stimulating lipid accumulation, foam cell formation and pro-inflammatory cytokine production in macrophages. Adipokines can also promote balance or resolution during metabolic and immune processes by promoting reverse lipid transport and expression of Th2 cytokines. This review will explore the mechanisms by which catecholamines and adipokines influence macrophage function in neural pathways, immunity and metabolism.

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Macrophage-Derived Human Resistin Is Induced in Multiple Helminth Infections and Promotes Inflammatory Monocytes and Increased Parasite Burden

Cited by 47 publications

References 57 publications

Comparison of RELMα and RELMβ Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection

Comparison of RELMα and RELMβ Single- and Double-Gene-Deficient Mice Reveals that RELMα Expression Dictates Inflammation and Worm Expulsion in Hookworm Infection

Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium

Non-traditional cytokines: How catecholamines and adipokines influence macrophages in immunity, metabolism and the central nervous system

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