Chemokine CC Receptor 2 Is Important for Acute Control of Cardiac Parasitism but Does Not Contribute to Cardiac Inflammation after Infection with<i>Trypanosoma cruzi</i>

Hardison, Jenny L.; Kuziel, William A.; Manning, Jerry E.; Lane, Thomas E.

doi:10.1086/503812

Cited by 24 publications

(21 citation statements)

References 14 publications

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“…CCR2 may act through mediating the release of monocytes from the bone marrow and not through their extravasation into sites of infection (38). Infection of CCR2 Ϫ/Ϫ mice with Trypanosoma cruzi resulted in increased cardiac parasitism but no increase in cardiac inflammation (20). Taken together, these studies and the current results suggest that macrophages are more critical for the efficient control of pathogen burden than for the development of inflammation.…”

Section: Ccr2supporting

confidence: 53%

Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

Montgomery¹,

Booth

Wang³

et al. 2007

Infect Immun

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Lyme arthritis, caused by the spirochete Borrelia burgdorferi, can be recurrent or prolonged, whereas Lyme carditis is mostly nonrecurring. A prominent difference between arthritis and carditis is the differential representation of phagocytes in these lesions: polymorphonuclear leukocytes (PMN) are more prevalent in the joint, and macrophages predominate in the heart lesion. We have previously shown differential efficiency of B. burgdorferi clearance by PMN and macrophages, and we now investigate whether these functional differences at the cellular level may contribute to the observed differences in organ-specific pathogenesis. When we infected mice lacking the neutrophil chemokine receptor (CXCR2 ؊/؊ mice) with spirochetes, we detected fewer PMN in joints and less-severe arthritis. Here we have investigated the effects of the absence of the macrophage chemokine receptor CCR2 on the development and resolution of Lyme carditis in resistant (C57BL/6J [B6]) and sensitive (C3H/HeJ [C3H]) strains of mice. In B6 CCR2؊/؊ mice, although inflammation in hearts is mild, we detected an increased burden of B. burgdorferi compared to that in wild-type (WT) mice, suggesting reduced clearance in the absence of macrophages. In contrast, C3H CCR2 ؊/؊ mice have severe inflammation but a decreased B. burgdorferi burden compared to that in WT C3H mice both at peak disease and during resolution. Histopathologic examination of infected hearts revealed that infected C3H CCR2؊/؊ animals have an increased presence of PMN, suggesting compensatory mechanisms of B. burgdorferi clearance in the hearts of infected C3H CCR2 ؊/؊ mice. The more efficient clearance of B. burgdorferi from hearts by CCR2 ؊/؊ versus WT C3H mice suggests a natural defect in the recruitment or function of macrophages in C3H mice, which may contribute to the sensitivity of this strain to B. burgdorferi infection.

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Section: Ccr2supporting

confidence: 53%

Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

Montgomery¹,

Booth

Wang³

et al. 2007

Infect Immun

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“…Chemokines and chemokine receptors from the CC family have been reported to be involved in the normal thymus development [68] as well as the control of T. cruzi and chronic heart alterations [69][70][71] . At the thymic level, our results show that the basal number of thymocytes and thymic cellular loss after infection were similar in CCL3-deficient mice compared to wild-type mice ( fig.…”

Section: Other Molecules Involved In T Cruzi Induce Thymic Atrophymentioning

confidence: 99%

Immunoendocrinology of the Thymus in Chagas Disease

Pérez

Silva-Barbosa²,

Roggero³

et al. 2011

Neuroimmunomodulation

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During immune response to infectious agents, the host develops an inflammatory response which could fail to eliminate the pathogen or may become dysregulated. In this case, the ongoing response acquires a new status and turns out to be detrimental. The same elements taking part in the establishment and regulation of the inflammatory response (cytokines, chemokines, regulatory T cells and counteracting compounds like glucocorticoids) may also mediate harmful effects. Thymic disturbances seen during Trypanosoma cruzi (T. cruzi) infection fit well with this conceptual framework. After infection, this organ suffers a severe atrophy due to apoptosis-induced thymocyte exhaustion, mainly affecting the immature double-positive (DP) CD4+CD8+ population. Thymus cellularity depletion, which occurs in the absence of main immunological mediators involved in anti-T. cruzi defense, seems to be linked to a systemic cytokine/hormonal imbalance, involving a dysregulated increase in Tumor Necrosis Factor alpha (TNF-α) and corticosterone hormone levels. Additionally, we have found an anomalous exit of potentially autoimmune DP cells to the periphery, in parallel to a shrinkage in the compartment of natural regulatory T cells. In this context, our data clearly point to the view that the thymus is a target organ of T. cruzi infection. Preserved thymus may be essential for the development of an effective immune response against T. cruzi, but this organ is severely affected by a dysregulated circuit of proinflammatory cytokines and glucocorticoids. Also, the alterations observed in the DP population might have potential implications for the autoimmune component of human Chagas disease.

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“…17,18 Consequently, mice deficient in CCR2 expression fail to recruit a population of inflammatory monocytes to the sites of infection and are susceptible to many infections. [19][20][21][22] Here, we have characterized CD11b high Ly6C ϩ cells that appear in the spleen of mice after an acute infection of P chabaudi. They resemble inflammatory monocytes and require the chemokine receptor CCR2 for their egress from the bone marrow.…”

mentioning

confidence: 99%

Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria

Sponaas

Rosário

Voisine

et al. 2009

Blood

146

141

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Host responses controlling blood-stage malaria include both innate and acquired immune effector mechanisms. During Plasmodium chabaudi infection in mice, a population of CD11b(high)Ly6C(+) monocytes are generated in bone marrow, most of which depend on the chemokine receptor CCR2 for migration from bone marrow to the spleen. In the absence of this receptor mice harbor higher parasitemias. Most importantly, splenic CD11b(high)Ly6C(+) cells from P chabaudi-infected wild-type mice significantly reduce acute-stage parasitemia in CCR2(-/-) mice. The CD11b(high)Ly6C(+) cells in this malaria infection display effector functions such as production of inducible nitric oxide synthase and reactive oxygen intermediates, and phagocytose P chabaudi parasites in vitro, and in a proportion of the cells, in vivo in the spleen, suggesting possible mechanisms of parasite killing. In contrast to monocyte-derived dendritic cells, CD11b(high)Ly6C(+) cells isolated from malaria-infected mice express low levels of major histocompatibility complex II and have limited ability to present the P chabaudi antigen, merozoite surface protein-1, to specific T-cell receptor transgenic CD4 T cells and fail to activate these T cells. We propose that these monocytes, which are rapidly produced in the bone marrow as part of the early defense mechanism against invading pathogens, are important for controlling blood-stage malaria parasites.

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Chemokine CC Receptor 2 Is Important for Acute Control of Cardiac Parasitism but Does Not Contribute to Cardiac Inflammation after Infection withTrypanosoma cruzi

Cited by 24 publications

References 14 publications

Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

Recruitment of Macrophages and Polymorphonuclear Leukocytes in Lyme Carditis

Immunoendocrinology of the Thymus in Chagas Disease

Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria

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