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Leishmania mexicana induces limited recruitment and activation of monocytes and monocyte-derived dendritic cells early during infection.

Petritus PM, Manzoni-de-Almeida D, Gimblet C, Gonzalez Lombana C, Scott P - PLoS Negl Trop Dis (2012)

Bottom Line: Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice.Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS.Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT
While C57BL/6 mice infected in the ear with L. major mount a vigorous Th1 response and resolve their lesions, the Th1 response in C57BL/6 mice infected with L. mexicana is more limited, resulting in chronic, non-healing lesions. The aim of this study was to determine if the limited immune response following infection with L. mexicana is related to a deficiency in the ability of monocyte-derived dendritic cells (mo-DCs) to prime a sufficient Th1 response. To address this issue we compared the early immune response following L. mexicana infection with that seen in L. major infected mice. Our data show that fewer monocytes are recruited to the lesions of L. mexicana infected mice as compared to mice infected with L. major. Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice. Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS. Additionally, injection of DCs into the ear at the time of infection with L. mexicana also led to a more robust Th1 response. Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

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Production of IL-10 during L. mexicana infection contributes to less recruitment of monocytes.Ears from naïve, L. mexicana infected or L. mexicana infected and α-IL-10R treated C57BL/6 mice were processed as above. (A) Histograms of monocytes on day 7 and 14 or mo-DCs on day 14 in the ear of naïve (grey shaded histogram), L. mexicana infected mice (black line, top) or L. mexicana infected and α-IL-10R treated mice (black line, bottom). Absolute numbers of monocytes and mo-DCs are also shown. Monocytes are previously gated on live, singlets that are CD11bhi CD11c−. Mo-DCs are previously gated on live, singlets that are CD11bhi CD11c+. (B) Levels of IFN-γ (ng/mL) from the supernatants of single cell suspensions from the dLN of each group that were stimulated for 72 hours with L. mexicana freeze-thaw antigen. (C) Percentage and absolute number of iNOS-producing cells in the ear of naïve, L. mexicana infected mice or L. mexicana infected and α-IL-10R treated mice on day 14. Cells are previously gated on live, singlets that are CD11bhi CD11c+. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3–5 mice per group. The results are representative of two experiments. * significantly higher (p<0.05) compared to L. mexicana infected mice in Fig. 6A and 6C (FACS plots) or p<0.05 between indicated groups in Fig. 6A, 6B and 6C (bar graphs).
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pntd-0001858-g006: Production of IL-10 during L. mexicana infection contributes to less recruitment of monocytes.Ears from naïve, L. mexicana infected or L. mexicana infected and α-IL-10R treated C57BL/6 mice were processed as above. (A) Histograms of monocytes on day 7 and 14 or mo-DCs on day 14 in the ear of naïve (grey shaded histogram), L. mexicana infected mice (black line, top) or L. mexicana infected and α-IL-10R treated mice (black line, bottom). Absolute numbers of monocytes and mo-DCs are also shown. Monocytes are previously gated on live, singlets that are CD11bhi CD11c−. Mo-DCs are previously gated on live, singlets that are CD11bhi CD11c+. (B) Levels of IFN-γ (ng/mL) from the supernatants of single cell suspensions from the dLN of each group that were stimulated for 72 hours with L. mexicana freeze-thaw antigen. (C) Percentage and absolute number of iNOS-producing cells in the ear of naïve, L. mexicana infected mice or L. mexicana infected and α-IL-10R treated mice on day 14. Cells are previously gated on live, singlets that are CD11bhi CD11c+. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3–5 mice per group. The results are representative of two experiments. * significantly higher (p<0.05) compared to L. mexicana infected mice in Fig. 6A and 6C (FACS plots) or p<0.05 between indicated groups in Fig. 6A, 6B and 6C (bar graphs).

Mentions: IL-10 has been described as having anti-inflammatory effects during infection by inhibiting cytokine production and antigen presentation [32], however, more recently it was shown that IL-10 also limits recruitment of CD11b+ Ly6C+ monocytes following T. brucei infection [33]. Since IL-10−/− mice infected with L. mexicana resolve their lesions [6], we wanted to investigate whether blocking interaction of IL-10 with its receptor would lead to increased monocyte recruitment. We infected C57BL/6 mice as before with L. mexicana and treated one group with α-IL-10R antibody. We evaluated monocyte recruitment to lesions on days 7 and 14 following infection and found that there was a greater percentage and number of monocytes recruited to L. mexicana lesions in mice treated with α-IL-10R (Fig. 6A). Similarly, the percentage and number of mo-DCs in the lesions of L. mexicana infected mice was also significantly increased when IL-10R was blocked (Fig. 6A). Moreover, there were increased levels of IFN-γ in the draining lymph nodes (Fig. 6B), as well as a greater percentage and number of iNOS-producing mo-DCs in the lesions of L. mexicana infected mice treated with α-IL-10R (Fig. 6C). These data suggest that IL-10 is a key factor contributing to the limited number of monocytes observed during L. mexicana infection since blocking the interaction of IL-10 with its receptor results in a dramatic increase in monocytes and mo-DCs in the lesion. Surprisingly, we did not see a difference in the parasite burden in treated and untreated L. mexicana infected mice at this early time point, in spite of the fact that we have previously shown that IL-10−/− mice eventually resolve their L. mexicana lesions [6]. Our assumption is that the effect on parasite burden is simply delayed and will develop later.


Leishmania mexicana induces limited recruitment and activation of monocytes and monocyte-derived dendritic cells early during infection.

Petritus PM, Manzoni-de-Almeida D, Gimblet C, Gonzalez Lombana C, Scott P - PLoS Negl Trop Dis (2012)

Production of IL-10 during L. mexicana infection contributes to less recruitment of monocytes.Ears from naïve, L. mexicana infected or L. mexicana infected and α-IL-10R treated C57BL/6 mice were processed as above. (A) Histograms of monocytes on day 7 and 14 or mo-DCs on day 14 in the ear of naïve (grey shaded histogram), L. mexicana infected mice (black line, top) or L. mexicana infected and α-IL-10R treated mice (black line, bottom). Absolute numbers of monocytes and mo-DCs are also shown. Monocytes are previously gated on live, singlets that are CD11bhi CD11c−. Mo-DCs are previously gated on live, singlets that are CD11bhi CD11c+. (B) Levels of IFN-γ (ng/mL) from the supernatants of single cell suspensions from the dLN of each group that were stimulated for 72 hours with L. mexicana freeze-thaw antigen. (C) Percentage and absolute number of iNOS-producing cells in the ear of naïve, L. mexicana infected mice or L. mexicana infected and α-IL-10R treated mice on day 14. Cells are previously gated on live, singlets that are CD11bhi CD11c+. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3–5 mice per group. The results are representative of two experiments. * significantly higher (p<0.05) compared to L. mexicana infected mice in Fig. 6A and 6C (FACS plots) or p<0.05 between indicated groups in Fig. 6A, 6B and 6C (bar graphs).
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pntd-0001858-g006: Production of IL-10 during L. mexicana infection contributes to less recruitment of monocytes.Ears from naïve, L. mexicana infected or L. mexicana infected and α-IL-10R treated C57BL/6 mice were processed as above. (A) Histograms of monocytes on day 7 and 14 or mo-DCs on day 14 in the ear of naïve (grey shaded histogram), L. mexicana infected mice (black line, top) or L. mexicana infected and α-IL-10R treated mice (black line, bottom). Absolute numbers of monocytes and mo-DCs are also shown. Monocytes are previously gated on live, singlets that are CD11bhi CD11c−. Mo-DCs are previously gated on live, singlets that are CD11bhi CD11c+. (B) Levels of IFN-γ (ng/mL) from the supernatants of single cell suspensions from the dLN of each group that were stimulated for 72 hours with L. mexicana freeze-thaw antigen. (C) Percentage and absolute number of iNOS-producing cells in the ear of naïve, L. mexicana infected mice or L. mexicana infected and α-IL-10R treated mice on day 14. Cells are previously gated on live, singlets that are CD11bhi CD11c+. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3–5 mice per group. The results are representative of two experiments. * significantly higher (p<0.05) compared to L. mexicana infected mice in Fig. 6A and 6C (FACS plots) or p<0.05 between indicated groups in Fig. 6A, 6B and 6C (bar graphs).
Mentions: IL-10 has been described as having anti-inflammatory effects during infection by inhibiting cytokine production and antigen presentation [32], however, more recently it was shown that IL-10 also limits recruitment of CD11b+ Ly6C+ monocytes following T. brucei infection [33]. Since IL-10−/− mice infected with L. mexicana resolve their lesions [6], we wanted to investigate whether blocking interaction of IL-10 with its receptor would lead to increased monocyte recruitment. We infected C57BL/6 mice as before with L. mexicana and treated one group with α-IL-10R antibody. We evaluated monocyte recruitment to lesions on days 7 and 14 following infection and found that there was a greater percentage and number of monocytes recruited to L. mexicana lesions in mice treated with α-IL-10R (Fig. 6A). Similarly, the percentage and number of mo-DCs in the lesions of L. mexicana infected mice was also significantly increased when IL-10R was blocked (Fig. 6A). Moreover, there were increased levels of IFN-γ in the draining lymph nodes (Fig. 6B), as well as a greater percentage and number of iNOS-producing mo-DCs in the lesions of L. mexicana infected mice treated with α-IL-10R (Fig. 6C). These data suggest that IL-10 is a key factor contributing to the limited number of monocytes observed during L. mexicana infection since blocking the interaction of IL-10 with its receptor results in a dramatic increase in monocytes and mo-DCs in the lesion. Surprisingly, we did not see a difference in the parasite burden in treated and untreated L. mexicana infected mice at this early time point, in spite of the fact that we have previously shown that IL-10−/− mice eventually resolve their L. mexicana lesions [6]. Our assumption is that the effect on parasite burden is simply delayed and will develop later.

Bottom Line: Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice.Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS.Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.

ABSTRACT
While C57BL/6 mice infected in the ear with L. major mount a vigorous Th1 response and resolve their lesions, the Th1 response in C57BL/6 mice infected with L. mexicana is more limited, resulting in chronic, non-healing lesions. The aim of this study was to determine if the limited immune response following infection with L. mexicana is related to a deficiency in the ability of monocyte-derived dendritic cells (mo-DCs) to prime a sufficient Th1 response. To address this issue we compared the early immune response following L. mexicana infection with that seen in L. major infected mice. Our data show that fewer monocytes are recruited to the lesions of L. mexicana infected mice as compared to mice infected with L. major. Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice. Treatment of L. mexicana infected mice with α-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-γ and iNOS. Additionally, injection of DCs into the ear at the time of infection with L. mexicana also led to a more robust Th1 response. Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response.

Show MeSH
Related in: MedlinePlus