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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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Fewer CD11bhi Ly6C+ cells in the ear following L. mexicana infection compared to L. major.Ears from naïve, as well as L. major or L. mexicana infected C57BL/6 mice were processed to single cell suspensions. (A) Percentage of CD11bhi cells present in the ear of naïve or infected mice on day 3 and 14. Cells are previously gated on total, single live cells. Histograms of monocytes (B) or mo-DCs (C) in the ear of naïve (grey shaded histogram) or infected mice (black line) on day 3 and 14 and absolute number of monocytes (B) or mo-DCs (C) from naïve, day 3 and day 14 infected mice. Monocytes are pre-gated on CD11bhi CD11c− cells and mo-DCs are previously gated on CD11bhi CD11c+ cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly lower (p<0.05) compared to L. major infected mice in Fig. 1A or p<0.05 between indicated groups in Fig. 1B and C.
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pntd-0001858-g001: Fewer CD11bhi Ly6C+ cells in the ear following L. mexicana infection compared to L. major.Ears from naïve, as well as L. major or L. mexicana infected C57BL/6 mice were processed to single cell suspensions. (A) Percentage of CD11bhi cells present in the ear of naïve or infected mice on day 3 and 14. Cells are previously gated on total, single live cells. Histograms of monocytes (B) or mo-DCs (C) in the ear of naïve (grey shaded histogram) or infected mice (black line) on day 3 and 14 and absolute number of monocytes (B) or mo-DCs (C) from naïve, day 3 and day 14 infected mice. Monocytes are pre-gated on CD11bhi CD11c− cells and mo-DCs are previously gated on CD11bhi CD11c+ cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly lower (p<0.05) compared to L. major infected mice in Fig. 1A or p<0.05 between indicated groups in Fig. 1B and C.

Mentions: The development of a protective response following L. major infection is associated with the recruitment of monocytes into the lesion, which are believed to differentiate into mo-DCs (defined as CD11bhi, CD11c+, Ly6C+) to prime a strong Th1 response [24]. Since L. mexicana infection promotes chronic, non-healing lesions and a minimal Th1 response, we hypothesized that fewer monocytes would be recruited to lesions following infection with L. mexicana compared to L. major. To test this, we infected C57BL/6 mice with either L. major or L. mexicana parasites and assessed the cellular composition of the lesions at 3 and 14 days post-infection. Expression of CD11b, a subunit of αMβ2 (also known as Mac-1 and CR3), was used to detect infiltrating leukocyte populations, including monocytes, macrophages, and granulocytes [28]. At 3 days post-infection, there was a significant increase in the percentage of CD11bhi cells in dermal lesions from L. major infected mice compared to normal skin (Fig. 1A). In contrast, no increase in CD11bhi cells was observed in lesions from L. mexicana infected mice. Moreover, the difference in percentage of CD11bhi cells between L. major and L. mexicana lesions was still evident two weeks after infection (Fig. 1A). In contrast, neutrophil (CD11bhi Ly6G+) frequency increased equally in lesions of both L. major and L. mexicana infected mice by day 14 as compared to normal skin (data not shown). Consistent with the observed alterations in CD11bhi cells, there was an increase in inflammatory monocytes (CD11bhi CD11c− Ly6C+) in the lesions from 3-day and 14-day L. major infected mice as compared with normal skin (Fig. 1B) while no such increase was observed following L. mexicana infection (Fig. 1B). By day 14, mo-DCs (CD11bhi CD11c+ Ly6C+) were evident in lesions of both L. major and L. mexicana infected mice, however, mo-DCs were preferentially represented in L. major lesions (Fig. 1C). Taken together, these results suggest that L. mexicana fails to promote the recruitment of monocytes, reducing the number of cells available for subsequent differentiation into mo-DCs capable of controlling parasite numbers.


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)

Fewer CD11bhi Ly6C+ cells in the ear following L. mexicana infection compared to L. major.Ears from naïve, as well as L. major or L. mexicana infected C57BL/6 mice were processed to single cell suspensions. (A) Percentage of CD11bhi cells present in the ear of naïve or infected mice on day 3 and 14. Cells are previously gated on total, single live cells. Histograms of monocytes (B) or mo-DCs (C) in the ear of naïve (grey shaded histogram) or infected mice (black line) on day 3 and 14 and absolute number of monocytes (B) or mo-DCs (C) from naïve, day 3 and day 14 infected mice. Monocytes are pre-gated on CD11bhi CD11c− cells and mo-DCs are previously gated on CD11bhi CD11c+ cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly lower (p<0.05) compared to L. major infected mice in Fig. 1A or p<0.05 between indicated groups in Fig. 1B and C.
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getmorefigures.php?uid=PMC3475671&req=5

pntd-0001858-g001: Fewer CD11bhi Ly6C+ cells in the ear following L. mexicana infection compared to L. major.Ears from naïve, as well as L. major or L. mexicana infected C57BL/6 mice were processed to single cell suspensions. (A) Percentage of CD11bhi cells present in the ear of naïve or infected mice on day 3 and 14. Cells are previously gated on total, single live cells. Histograms of monocytes (B) or mo-DCs (C) in the ear of naïve (grey shaded histogram) or infected mice (black line) on day 3 and 14 and absolute number of monocytes (B) or mo-DCs (C) from naïve, day 3 and day 14 infected mice. Monocytes are pre-gated on CD11bhi CD11c− cells and mo-DCs are previously gated on CD11bhi CD11c+ cells. The results expressed are the mean percentage (± SD for FACS plots) or the mean number of cells (± SE for bar graphs) of 3 mice per group. The results are representative of two experiments. * significantly lower (p<0.05) compared to L. major infected mice in Fig. 1A or p<0.05 between indicated groups in Fig. 1B and C.
Mentions: The development of a protective response following L. major infection is associated with the recruitment of monocytes into the lesion, which are believed to differentiate into mo-DCs (defined as CD11bhi, CD11c+, Ly6C+) to prime a strong Th1 response [24]. Since L. mexicana infection promotes chronic, non-healing lesions and a minimal Th1 response, we hypothesized that fewer monocytes would be recruited to lesions following infection with L. mexicana compared to L. major. To test this, we infected C57BL/6 mice with either L. major or L. mexicana parasites and assessed the cellular composition of the lesions at 3 and 14 days post-infection. Expression of CD11b, a subunit of αMβ2 (also known as Mac-1 and CR3), was used to detect infiltrating leukocyte populations, including monocytes, macrophages, and granulocytes [28]. At 3 days post-infection, there was a significant increase in the percentage of CD11bhi cells in dermal lesions from L. major infected mice compared to normal skin (Fig. 1A). In contrast, no increase in CD11bhi cells was observed in lesions from L. mexicana infected mice. Moreover, the difference in percentage of CD11bhi cells between L. major and L. mexicana lesions was still evident two weeks after infection (Fig. 1A). In contrast, neutrophil (CD11bhi Ly6G+) frequency increased equally in lesions of both L. major and L. mexicana infected mice by day 14 as compared to normal skin (data not shown). Consistent with the observed alterations in CD11bhi cells, there was an increase in inflammatory monocytes (CD11bhi CD11c− Ly6C+) in the lesions from 3-day and 14-day L. major infected mice as compared with normal skin (Fig. 1B) while no such increase was observed following L. mexicana infection (Fig. 1B). By day 14, mo-DCs (CD11bhi CD11c+ Ly6C+) were evident in lesions of both L. major and L. mexicana infected mice, however, mo-DCs were preferentially represented in L. major lesions (Fig. 1C). Taken together, these results suggest that L. mexicana fails to promote the recruitment of monocytes, reducing the number of cells available for subsequent differentiation into mo-DCs capable of controlling parasite numbers.

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