CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis

Xu, Jintao; Ganguly, Anutosh; Zhao, Jessica; Ivey, Michel; López, Rafael; Osterholzer, John J.; Cho, Clifford S.; Olszewski, M.

doi:10.1128/mbio.01076-21

Cited by 14 publications

(13 citation statements)

References 57 publications

(89 reference statements)

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“…These studies therefore show that CXCR3 + Th1 T cells are not needed to help control fungal infection in the brain, at least in the context of an IRIS-like syndrome (152). Similarly, knockdown of CCR2 in mice was also shown to improve survival independently of fungal control in the CNS, although CCR2 was not involved in the direct recruitment of Th1 T cells to the CNS but acted indirectly by promoting the initial recruitment of inflammatory monocytes (153). Collectively, these studies indicate that T-cells have a complex role in CM, both for fungal clearance and mediating immunopathology, which is likely context-and time-dependent.…”

Section: T-cellsmentioning

confidence: 83%

Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis

et al. 2022

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Cryptococcal meningitis (CM) is the leading cause of central nervous system (CNS) fungal infections in humans, with the majority of cases reported from the African continent. This is partly due to the high burden of HIV infection in the region and reduced access to standard-of-care including optimal sterilising antifungal drug treatments. As such, CM is responsible for 10-15% of all HIV-related mortality, with a large proportion being preventable. Immunity to the causative agent of CM, Cryptococcus neoformans, is only partially understood. IFNγ producing CD4+ T-cells are required for the activation of myeloid cells, especially macrophages, to enable fungal killing and clearance. However, macrophages may also act as a reservoir of the fungal yeast cells, shielding them from host immune detection thus promoting latent infection or persistent chronic inflammation. In this chapter, we review the epidemiology and pathogenesis of CNS fungal infections in Africa, with a major focus on CM, and the antifungal immune pathways operating to protect against C. neoformans infection. We also highlight the areas of research and policy that require prioritisation to help reduce the burden of CNS fungal diseases in Africa.

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Section: T-cellsmentioning

confidence: 83%

Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis

et al. 2022

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“…CCR2 is a highly selective and high‐affinity receptor for CCL2 (Xu, Wang, et al, 2021). Its expression was found mainly on the surface of macrophages, monocytes, dendritic cells, and so on (Biagioli et al, 2020; Shibuya et al, 2022; Xu, Ganguly, et al, 2021). According to recent studies, the expression levels of liver CCL2 and CCR2 in obesity or NASH mice fed with HFD are significantly increased, and the infiltration of proinflammatory cells in the liver is markedly raised (Pulli et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Pure total flavonoids from citrus improve nonalcoholic steatohepatitis liver inflammatory responses by regulating the CCL2/CCR2‐PI3K‐Akt signal transduction pathway

et al. 2022

The Anatomical Record

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Background and AimNonalcoholic steatohepatitis (NASH) is a critical stage in the prognosis of nonalcoholic fatty liver disease (NAFLD). Pure total flavonoids from circus (PTFC) play essential roles in the improvement of NASH symptoms, but the underlying regulatory mechanism remains elusive. Our previous high‐throughput omics screening results indicate that the CCL2/CCR2‐PI3K‐Akt signaling pathway is a key pathway that regulates the liver inflammatory response. PTFC may regulate the CCL2/CCR2‐PI3K‐Akt signaling pathway to improve the liver inflammatory response.MethodsA mice model of NASH was established by a high‐fat diet, and PTFC was used as treatment. Hematoxylin‐eosin and oil red O staining were used to observe the pathological changes in the liver tissue. Western blotting and real‐time PCR were used to measure the mRNA and protein levels in the liver. The expression of proinflammatory cytokines in the peripheral blood and liver tissues was measured by liquid suspension array. An automatic biochemical method was used to examine serum transaminases and lipids levels, as well as liver lipids.ResultsCompared with the mice in the high‐fat diet group, mice in the HFD + PTFC group showed significantly improved liver histopathology, and levels of serum transaminase and lipids, liver lipids and serum proinflammatory cytokines. Moreover, the mRNA and protein expression and phosphorylation levels of key signaling molecules in the CCL2/CCR2‐PI3K‐Akt signal transduction pathway were obviously reduced by PTFC treatment.Conclusive RemarksPTFC can ameliorate NASH symptoms, and the mechanism may be related to regulating the CCL2/CCR2‐PI3K‐Akt signal transduction pathway to reduce the liver inflammatory response.

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“…The impaired recruitment of leukocytes to the brain in MIP-1α knockout mice correlated with an impaired clearance of C. neoformans in the brain [ 120 ], suggesting that the accumulation of leukocytes including inflammatory monocytes in the brain is required for fungal clearance. However, the brain’s inflammatory responses mediated by inflammatory monocytes/macrophages and other leukocytes must be tightly controlled to avoid neuropathology during brain infection with C. neoformans [ 97 , 121 ].…”

Section: Host Immune Responses To C Neoformans In ...mentioning

confidence: 99%

Cryptococcus neoformans Infection in the Central Nervous System: The Battle between Host and Pathogen

Chen

Shi

Strickland

et al. 2022

JoF

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Cryptococcus neoformans (C. neoformans) is a pathogenic fungus with a global distribution. Humans become infected by inhaling the fungus from the environment, and the fungus initially colonizes the lungs. If the immune system fails to contain C. neoformans in the lungs, the fungus can disseminate to the blood and invade the central nervous system, resulting in fatal meningoencephalitis particularly in immunocompromised individuals including HIV/AIDS patients. Following brain invasion, C. neoformans will encounter host defenses involving resident as well as recruited immune cells in the brain. To overcome host defenses, C. neoformans possesses multiple virulence factors capable of modulating immune responses. The outcome of the interactions between the host and C. neoformans will determine the disease progression. In this review, we describe the current understanding of how C. neoformans migrates to the brain across the blood–brain barrier, and how the host immune system responds to the invading organism in the brain. We will also discuss the virulence factors that C. neoformans uses to modulate host immune responses.

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CCR2 Signaling Promotes Brain Infiltration of Inflammatory Monocytes and Contributes to Neuropathology during Cryptococcal Meningoencephalitis

Cited by 14 publications

References 57 publications

Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis

Fungal CNS Infections in Africa: The Neuroimmunology of Cryptococcal Meningitis

Pure total flavonoids from citrus improve nonalcoholic steatohepatitis liver inflammatory responses by regulating the CCL2/CCR2‐PI3K‐Akt signal transduction pathway

Cryptococcus neoformans Infection in the Central Nervous System: The Battle between Host and Pathogen

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