Highlights • Type 2 immunity is associated with both helminth infection and responses to injury. • Pathways involved in tissue repair and helminth immunity overlap. • The IL-4Rα is central to ...accelerating both repair and helminth control. • Adaptive immunity contributes to more rapid wound repair.
For decades, immunologists have studied the role of circulating immune cells in host protection, with a more recent appreciation of immune cells resident within the tissue microenvironment and the ...intercommunication between nonhematopoietic cells and immune cells. However, the extracellular matrix (ECM), which comprises at least a third of tissue structures, remains relatively underexplored in immunology. Similarly, matrix biologists often overlook regulation of complex structural matrices by the immune system. We are only beginning to understand the scale at which ECM structures determine immune cell localization and function. Additionally, we need to better understand how immune cells dictate ECM complexity. This review aims to highlight the potential for biological discovery at the interface of immunology and matrix biology.
Crystal-clear treatment for allergic disease Allen, Judith E; Sutherland, Tara E
Science (American Association for the Advancement of Science),
05/2019, Letnik:
364, Številka:
6442
Journal Article
Recenzirano
Protein crystals could be targeted therapeutically to treat allergic pathology
Charcot-Leyden crystals (CLCs) are protein crystals produced by human eosinophils, immune cells typically associated ...with allergy and parasitic worm (helminth) infection. These responses involve the “type 2” arm of the immune system, and CLCs are a hallmark of the more severe pathologies that can occur during type 2 inflammation, such as allergic asthma. Although described over 160 years ago, the biological relevance of CLCs to type 2 immunity has remained unknown. On page 751 of this issue, Persson
et al.
(
1
) confirm anecdotal evidence that CLCs are a key feature of severe asthma and chronic rhinosinusitis with nasal polyps. They demonstrate that the crystals, but not the soluble proteins, are powerful promoters of allergic inflammation and can be targeted with crystal-dissolving antibodies to reverse disease symptoms.
Ym1 and RELMα are established effector molecules closely synonymous with Th2-type inflammation and associated pathology. Here, we show that whilst largely dependent on IL-4Rα signaling during a type ...2 response, Ym1 and RELMα also have IL-4Rα-independent expression patterns in the lung. Notably, we found that Ym1 has opposing effects on type 2 immunity during nematode infection depending on whether it is expressed at the time of innate or adaptive responses. During the lung migratory stage of Nippostrongylus brasiliensis, Ym1 promoted the subsequent reparative type 2 response but once that response was established, IL-4Rα-dependent Ym1 was important for limiting the magnitude of type 2 cytokine production from both CD4+ T cells and innate lymphoid cells in the lung. Importantly, our study demonstrates that delivery of Ym1 to IL-4Rα deficient animals drives RELMα production and overcomes lung repair deficits in mice deficient in type 2 immunity. Together, Ym1 and RELMα, exhibit time and dose-dependent interactions that determines the outcome of lung repair during nematode infection.
The mammalian intestine is colonized by beneficial commensal bacteria and is a site of infection by pathogens, including helminth parasites. Helminths induce potent immunomodulatory effects, but ...whether these effects are mediated by direct regulation of host immunity or indirectly through eliciting changes in the microbiota is unknown. We tested this in the context of virus-helminth coinfection. Helminth coinfection resulted in impaired antiviral immunity and was associated with changes in the microbiota and STAT6-dependent helminth-induced alternative activation of macrophages. Notably, helminth-induced impairment of antiviral immunity was evident in germ-free mice, but neutralization of Ym1, a chitinase-like molecule that is associated with alternatively activated macrophages, could partially restore antiviral immunity. These data indicate that helminth-induced immunomodulation occurs independently of changes in the microbiota but is dependent on Ym1.
The type 2 immune response controls helminth infection and maintains tissue homeostasis but can lead to allergy and fibrosis if not adequately regulated. We have discovered local tissue-specific ...amplifiers of type 2–mediated macrophage activation. In the lung, surfactant protein A (SP-A) enhanced interleukin-4 (IL-4)–dependent macrophage proliferation and activation, accelerating parasite clearance and reducing pulmonary injury after infection with a lung-migrating helminth. In the peritoneal cavity and liver, C1q enhancement of type 2 macrophage activation was required for liver repair after bacterial infection, but resulted in fibrosis after peritoneal dialysis. IL-4 drives production of these structurally related defense collagens, SP-A and C1q, and the expression of their receptor, myosin 18A. These findings reveal the existence within different tissues of an amplification system needed for local type 2 responses.
Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found ...that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of γδ T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in γδ T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury. Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family.
Rapid reprogramming of the macrophage activation phenotype is considered important in the defense against consecutive infection with diverse infectious agents. However, in the setting of persistent, ...chronic infection the functional importance of macrophage-intrinsic adaptation to changing environments vs. recruitment of new macrophages remains unclear. Here we show that resident peritoneal macrophages expanded by infection with the nematode Heligmosomoides polygyrus bakeri altered their activation phenotype in response to infection with Salmonella enterica ser. Typhimurium in vitro and in vivo. The nematode-expanded resident F4/80high macrophages efficiently upregulated bacterial induced effector molecules (e.g. MHC-II, NOS2) similarly to newly recruited monocyte-derived macrophages. Nonetheless, recruitment of blood monocyte-derived macrophages to Salmonella infection occurred with equal magnitude in co-infected animals and caused displacement of the nematode-expanded, tissue resident-derived macrophages from the peritoneal cavity. Global gene expression analysis revealed that although nematode-expanded resident F4/80high macrophages made an anti-bacterial response, this was muted as compared to newly recruited F4/80low macrophages. However, the F4/80high macrophages adopted unique functional characteristics that included enhanced neutrophil-stimulating chemokine production. Thus, our data provide important evidence that plastic adaptation of MΦ activation does occur in vivo, but that cellular plasticity is outweighed by functional capabilities specific to the tissue origin of the cell.
Peritoneal dialysis (PD) is a more continuous alternative to haemodialysis, for patients with chronic kidney disease, with considerable initial benefits for survival, patient independence and ...healthcare costs. However, long-term PD is associated with significant pathology, negating the positive effects over haemodialysis. Importantly, peritonitis and activation of macrophages is closely associated with disease progression and treatment failure. However, recent advances in macrophage biology suggest opposite functions for macrophages of different cellular origins. While monocyte-derived macrophages promote disease progression in some models of fibrosis, tissue resident macrophages have rather been associated with protective roles. Thus, we aimed to identify the relative contribution of tissue resident macrophages to PD induced inflammation in mice. Unexpectedly, we found an incremental loss of homeostatic characteristics, anti-inflammatory and efferocytic functionality in peritoneal resident macrophages, accompanied by enhanced inflammatory responses to external stimuli. Moreover, presence of glucose degradation products within the dialysis fluid led to markedly enhanced inflammation and almost complete disappearance of tissue resident cells. Thus, alterations in tissue resident macrophages may render long-term PD patients sensitive to developing peritonitis and consequently fibrosis/sclerosis.
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