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Intestinal macrophages arising from CCR2(+) monocytes control pathogen infection by activating innate lymphoid cells.

Seo SU, Kuffa P, Kitamoto S, Nagao-Kitamoto H, Rousseau J, Kim YG, Núñez G, Kamada N - Nat Commun (2015)

Bottom Line: Unlike resident intestinal MPs, de novo differentiated MPs are phenotypically pro-inflammatory and produce robust amounts of IL-1β (interleukin-1β) through the non-canonical caspase-11 inflammasome.Intestinal MPs from infected mice elicit the activation of RORγt(+) group 3 innate lymphoid cells (ILC3) in an IL-1β-dependent manner.Deletion of IL-1β in blood monocytes blunts the production of IL-22 by ILC3 and increases the susceptibility to infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 E Medical Center Dr Ann Arbor, Michigan 48109, USA.

ABSTRACT
Monocytes play a crucial role in antimicrobial host defence, but the mechanisms by which they protect the host during intestinal infection remains poorly understood. Here we show that depletion of CCR2(+) monocytes results in impaired clearance of the intestinal pathogen Citrobacter rodentium. After infection, the de novo recruited CCR2(+) monocytes give rise to CD11c(+)CD11b(+)F4/80(+)CD103(-) intestinal macrophages (MPs) within the lamina propria. Unlike resident intestinal MPs, de novo differentiated MPs are phenotypically pro-inflammatory and produce robust amounts of IL-1β (interleukin-1β) through the non-canonical caspase-11 inflammasome. Intestinal MPs from infected mice elicit the activation of RORγt(+) group 3 innate lymphoid cells (ILC3) in an IL-1β-dependent manner. Deletion of IL-1β in blood monocytes blunts the production of IL-22 by ILC3 and increases the susceptibility to infection. Collectively, these studies highlight a critical role of de novo differentiated monocyte-derived intestinal MPs in ILC3-mediated host defence against intestinal infection.

No MeSH data available.


Related in: MedlinePlus

Monocyte-derived intestinal macrophages are major producers of IL-1β and IL-23.(a) MP1 and DC1 subsets were isolated from uninfected (uninf) and C. rodentium-infected (inf) CD115GFP animals. Cytokine mRNA expression was analysed by qPCR. Data are given as mean±s.d. (n=5–7). *P<0.05; **P<0.01; ***P<0.001; NS, not significant by Dunn's test. (b) Purified MP1 and DC1 subsets (1 × 106 cells per ml) were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=4–6). (c) LPMCs were isolated from C. rodentium-infected CCR2WT and CCR2DTR mice. 2 × 106 cells per ml LPMCs were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=3, representative of three independent experiments). *** P<0.001; NS, not significant by Student's t-test.
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f3: Monocyte-derived intestinal macrophages are major producers of IL-1β and IL-23.(a) MP1 and DC1 subsets were isolated from uninfected (uninf) and C. rodentium-infected (inf) CD115GFP animals. Cytokine mRNA expression was analysed by qPCR. Data are given as mean±s.d. (n=5–7). *P<0.05; **P<0.01; ***P<0.001; NS, not significant by Dunn's test. (b) Purified MP1 and DC1 subsets (1 × 106 cells per ml) were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=4–6). (c) LPMCs were isolated from C. rodentium-infected CCR2WT and CCR2DTR mice. 2 × 106 cells per ml LPMCs were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=3, representative of three independent experiments). *** P<0.001; NS, not significant by Student's t-test.

Mentions: Since our data demonstrated that newly recruited monocytes give rise to the MP1 subset in situ during infection, we next assessed how the MP1 subset regulates host defence during infection. We first compared the cytokine profile of the MP1 subset and the ‘non-monocyte-derived' CD103+ DC1 subset which is known to play an important role in the induction of IL-22 in response to flagellin injection17. The MP1 and DC1 subsets were purified from the intestines of C. rodentium-infected and -uninfected mice to assess their cytokine profiles. As shown in Fig. 3a, the MP1 subset from infected mice expressed higher mRNA levels of pro-inflammatory cytokines, including IL-1β, IL-23p19 and IL-6, than MP1 cells from uninfected mice or the DC1 subset from uninfected or infected mice. Although most cytokines were found to be expressed at higher levels in MP1 compared with DC1 cells, IL-12/23p40 mRNA levels were higher in the DC1 subset (Fig. 3a). Consistently, MP1 cells from infected intestines produced higher amounts of IL-1β and IL-23 than MP1 cells from naive mice or the DC1 subset, while IL-12/23p40 production was much higher in the DC1 subset (Fig. 3b). To address whether the CCR2+ monocyte-derived MP1 subset is the major source of IL-1β and IL-23 during C. rodentium infection, CCR2WT and CCR2DTR/+ mice were infected with C. rodentium, and cytokine production by colonic LP cells was evaluated. The production of IL-1β and IL-23, but not IL-6, was almost abrogated in CCR2DTR/+ mice treated with DT (Fig. 3c), indicating that the CCR2+ monocyte-derived MP1 subset is the major producer of IL-1β and IL-23 during C. rodentium.


Intestinal macrophages arising from CCR2(+) monocytes control pathogen infection by activating innate lymphoid cells.

Seo SU, Kuffa P, Kitamoto S, Nagao-Kitamoto H, Rousseau J, Kim YG, Núñez G, Kamada N - Nat Commun (2015)

Monocyte-derived intestinal macrophages are major producers of IL-1β and IL-23.(a) MP1 and DC1 subsets were isolated from uninfected (uninf) and C. rodentium-infected (inf) CD115GFP animals. Cytokine mRNA expression was analysed by qPCR. Data are given as mean±s.d. (n=5–7). *P<0.05; **P<0.01; ***P<0.001; NS, not significant by Dunn's test. (b) Purified MP1 and DC1 subsets (1 × 106 cells per ml) were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=4–6). (c) LPMCs were isolated from C. rodentium-infected CCR2WT and CCR2DTR mice. 2 × 106 cells per ml LPMCs were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=3, representative of three independent experiments). *** P<0.001; NS, not significant by Student's t-test.
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Related In: Results  -  Collection

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f3: Monocyte-derived intestinal macrophages are major producers of IL-1β and IL-23.(a) MP1 and DC1 subsets were isolated from uninfected (uninf) and C. rodentium-infected (inf) CD115GFP animals. Cytokine mRNA expression was analysed by qPCR. Data are given as mean±s.d. (n=5–7). *P<0.05; **P<0.01; ***P<0.001; NS, not significant by Dunn's test. (b) Purified MP1 and DC1 subsets (1 × 106 cells per ml) were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=4–6). (c) LPMCs were isolated from C. rodentium-infected CCR2WT and CCR2DTR mice. 2 × 106 cells per ml LPMCs were cultured for 24 h without stimulation. Cytokines in the culture supernatant were analysed by ELISA. Data are given as mean±s.d. (n=3, representative of three independent experiments). *** P<0.001; NS, not significant by Student's t-test.
Mentions: Since our data demonstrated that newly recruited monocytes give rise to the MP1 subset in situ during infection, we next assessed how the MP1 subset regulates host defence during infection. We first compared the cytokine profile of the MP1 subset and the ‘non-monocyte-derived' CD103+ DC1 subset which is known to play an important role in the induction of IL-22 in response to flagellin injection17. The MP1 and DC1 subsets were purified from the intestines of C. rodentium-infected and -uninfected mice to assess their cytokine profiles. As shown in Fig. 3a, the MP1 subset from infected mice expressed higher mRNA levels of pro-inflammatory cytokines, including IL-1β, IL-23p19 and IL-6, than MP1 cells from uninfected mice or the DC1 subset from uninfected or infected mice. Although most cytokines were found to be expressed at higher levels in MP1 compared with DC1 cells, IL-12/23p40 mRNA levels were higher in the DC1 subset (Fig. 3a). Consistently, MP1 cells from infected intestines produced higher amounts of IL-1β and IL-23 than MP1 cells from naive mice or the DC1 subset, while IL-12/23p40 production was much higher in the DC1 subset (Fig. 3b). To address whether the CCR2+ monocyte-derived MP1 subset is the major source of IL-1β and IL-23 during C. rodentium infection, CCR2WT and CCR2DTR/+ mice were infected with C. rodentium, and cytokine production by colonic LP cells was evaluated. The production of IL-1β and IL-23, but not IL-6, was almost abrogated in CCR2DTR/+ mice treated with DT (Fig. 3c), indicating that the CCR2+ monocyte-derived MP1 subset is the major producer of IL-1β and IL-23 during C. rodentium.

Bottom Line: Unlike resident intestinal MPs, de novo differentiated MPs are phenotypically pro-inflammatory and produce robust amounts of IL-1β (interleukin-1β) through the non-canonical caspase-11 inflammasome.Intestinal MPs from infected mice elicit the activation of RORγt(+) group 3 innate lymphoid cells (ILC3) in an IL-1β-dependent manner.Deletion of IL-1β in blood monocytes blunts the production of IL-22 by ILC3 and increases the susceptibility to infection.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, 1500 E Medical Center Dr Ann Arbor, Michigan 48109, USA.

ABSTRACT
Monocytes play a crucial role in antimicrobial host defence, but the mechanisms by which they protect the host during intestinal infection remains poorly understood. Here we show that depletion of CCR2(+) monocytes results in impaired clearance of the intestinal pathogen Citrobacter rodentium. After infection, the de novo recruited CCR2(+) monocytes give rise to CD11c(+)CD11b(+)F4/80(+)CD103(-) intestinal macrophages (MPs) within the lamina propria. Unlike resident intestinal MPs, de novo differentiated MPs are phenotypically pro-inflammatory and produce robust amounts of IL-1β (interleukin-1β) through the non-canonical caspase-11 inflammasome. Intestinal MPs from infected mice elicit the activation of RORγt(+) group 3 innate lymphoid cells (ILC3) in an IL-1β-dependent manner. Deletion of IL-1β in blood monocytes blunts the production of IL-22 by ILC3 and increases the susceptibility to infection. Collectively, these studies highlight a critical role of de novo differentiated monocyte-derived intestinal MPs in ILC3-mediated host defence against intestinal infection.

No MeSH data available.


Related in: MedlinePlus