Tissue-Resident CD169 + Macrophages Form a Crucial Front Line against Plasmodium Infection

Gupta, Pravesh; Lai, Sarah; Sheng, Jianpeng; Tetlak, Piotr; Balachander, Akhila; Claser, Carla; Rénia, Laurent; Karjalainen, Klaus; Ruedl, Christiane

doi:10.1016/j.celrep.2016.07.010

Cited by 74 publications

(79 citation statements)

References 55 publications

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“…Recently, tissue-resident CD169 + macrophages were shown to produce high levels of IL-10 during P. berghei ANKA infection in BALB/c mice and to restrict inflammatory responses (27). Concerning T cells, protection against ECM may also be due to balanced IFN-γ/IL-10 secretion in activated T cells versus regulatory T cells (Tregs).…”

Section: Discussionmentioning

confidence: 99%

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

et al. 2017

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The resolution of malaria infection is dependent on a balance between proinflammatory and regulatory immune responses. While early effector T cell responses are required for limiting parasitemia, these responses need to be switched off by regulatory mechanisms in a timely manner to avoid immune-mediated tissue damage. Interleukin-10 receptor (IL-10R) signaling is considered to be a vital component of regulatory responses, although its role in host resistance to severe immune pathology during acute malaria infections is not fully understood. In this study, we have determined the contribution of IL-10R signaling to the regulation of immune responses during Plasmodium berghei ANKA-induced experimental cerebral malaria (ECM). We show that antibody-mediated blockade of the IL-10R during P. berghei ANKA infection in ECM-resistant BALB/c mice leads to amplified T cell activation, higher serum gamma interferon (IFN-γ) concentrations, enhanced intravascular accumulation of both parasitized red blood cells and CD8+ T cells to the brain, and an increased incidence of ECM. Importantly, the pathogenic effects of IL-10R blockade during P. berghei ANKA infection were reversible by depletion of T cells and neutralization of IFN-γ. Our findings underscore the importance of IL-10R signaling in preventing T-cell- and cytokine-mediated pathology during potentially lethal malaria infections.

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Section: Discussionmentioning

confidence: 99%

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

et al. 2017

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“…Induction of KC death resulted in the recruitment of monocytes from the BM and these cells differentiated in KCs, filling in the empty niche [22]. DT-mediated depletion of CD169 + cells induced the ablation of CD11b lo Mϕ after DT treatment [21,23], and resulted in the recruitment of Ly6C hi monocytes expressing high levels of CD64 in the liver (Supporting Information Fig. 4B).…”

Section: Ablation Of Resident Cd11b Lo Mϕ During Infection Induces Thmentioning

confidence: 99%

Recruitment of hepatic macrophages from monocytes is independent of IL‐4Rα but is associated with ablation of resident macrophages in schistosomiasis

et al. 2019

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Alternatively activated Mϕs (AAMϕ) accumulate in hepatic granulomas during schistosomiasis and have been suggested to originate in the bone marrow. What is less understood is how these Mϕ responses are regulated after S. mansoni infection. Here, we investigated the role of IL-4 receptor α-chain (IL-4Rα)-signalling in the dynamics of liver Mϕ responses. We observed that IL-4Rα signalling was dispensable for the recruitment of Ly6C hi monocytes and for their conversion into F4/80 hi CD64 hi CD11b hi Mϕ. Moreover, while IL-4Rα provided an AAMϕ phenotype to liver F4/80 hi CD64 hi CD11b hi Mϕ that was associated with regulation of granuloma formation, it was dispensable for host survival. Resident F4/80 hi CD64 hi CD11b lo Mϕ did not upregulate the AAMϕ signature gene Ym1. Rather, resident Mϕ nearly disappeared by week 8 after infection and artificial ablation of resident Mϕ in CD169 DTR mice did not affect the response to S. mansoni infection. Interestingly, ablation of CD169 + cells in naive mice resulted in the accumulation of F4/80 hi CD64 hi CD11b hi Mϕ, which was amplified when ablation occurred during schistosomiasis. Altogether, our results suggest the ablation of resident KCs after S. mansoni infection to be associated with the recruitment and accumulation of F4/80 hi CD64 hi CD11b hi Mϕ with lyz2-dependent IL-4Rα contributing to the regulation of granuloma inflammation but being dispensable for host survival.Keywords: liver r monocytes r mouse model r Mϕ r schistosomiasis See accompanying Commentary by Rückerl and CookAdditional supporting information may be found online in the Supporting Information section at the end of the article. infected with Schistosoma mansoni develop a severe liver pathology with granulomatous inflammatory responses directed toward the parasite eggs. During chronic infections, type 2 inflammation in the liver results in fibrosis, which leads to portal hypertension, bleeding from collateral vessels and ultimately death [2][3][4]. Mϕ accumulate in the liver and are a key cellular component in granuloma formation and host protection [2,5].Mϕ are plastic cells that can be alternatively activated by IL-4 and IL-13 via the type I or type II IL-4 receptor, respectively [6].

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“…However, data from these studies suggests a potential role of macrophages and/or monocytes in promoting early parasite control during the acute phase of infection. This suggestion was first supported by the reduced parasitemia in splenectomised mice, which lacked both T and B-cells and then in during lethal blood-stage malaria [363]. Mice lacking these cells displayed elevated levels of sequestered parasites, increased hemozoin deposition and recruitment of inflammatory cells and enhanced immunopathology.…”

Section: Discussionmentioning

confidence: 65%

“…This is partly due to the lack of appropriate tools and reagents to examine these cell types in-vivo. elsewhere [363]. Probably, this was not the case in LDTR mice treated with DT.…”

Section: Chapter Six: Concluding Remarks and Future Directionsmentioning

confidence: 92%

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Immunological mechanisms controlling blood-stage parasites in mouse models of malaria

Sebina¹

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Controlling Plasmodium parasite numbers in vivo is crucial for protection against malaria.However, immunological mechanisms that mediate this process remain incompletely defined. For example, although robust antibody responses are essential for controlling parasites, host immune factors that influence the development of these responses are not well understood. A second example is our limited understanding of the role of the mononuclear phagocyte system (MPS) during infection. In part, this is due to the lack of appropriate in vivo tools. This thesis examined cellular and molecular factors that influenced control of parasites in mouse models of blood-stage Plasmodium infection. switching and the production of parasite-specific antibodies were established.

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Tissue-Resident CD169 + Macrophages Form a Crucial Front Line against Plasmodium Infection

Cited by 74 publications

References 55 publications

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

Recruitment of hepatic macrophages from monocytes is independent of IL‐4Rα but is associated with ablation of resident macrophages in schistosomiasis

Immunological mechanisms controlling blood-stage parasites in mouse models of malaria

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