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Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes.

Asano K, Takahashi N, Ushiki M, Monya M, Aihara F, Kuboki E, Moriyama S, Iida M, Kitamura H, Qiu CH, Watanabe T, Tanaka M - Nat Commun (2015)

Bottom Line: Selective depletion of CD169(+) macrophages or administration of neutralizing anti-CCL8 antibody ameliorates the symptoms of experimentally induced colitis in mice.Collectively, we identify an LP-resident macrophage subset that links mucosal damage and inflammatory monocyte recruitment.Our results suggest that CD169(+) macrophage-derived CCL8 serves as an emergency alert for the collapse of barrier defence, and is a promising target for the suppression of mucosal injury.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Immune regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan [2] Japan Science and Technology Agency, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.

ABSTRACT
Lamina propria (LP) macrophages are constantly exposed to commensal bacteria, and are refractory to those antigens in an interleukin (IL)-10-dependent fashion. However, the mechanisms that discriminate hazardous invasion by bacteria from peaceful co-existence with them remain elusive. Here we show that CD169(+) macrophages reside not at the villus tip, but at the bottom-end of the LP microenvironment. Following mucosal injury, the CD169(+) macrophages recruit inflammatory monocytes by secreting CCL8. Selective depletion of CD169(+) macrophages or administration of neutralizing anti-CCL8 antibody ameliorates the symptoms of experimentally induced colitis in mice. Collectively, we identify an LP-resident macrophage subset that links mucosal damage and inflammatory monocyte recruitment. Our results suggest that CD169(+) macrophage-derived CCL8 serves as an emergency alert for the collapse of barrier defence, and is a promising target for the suppression of mucosal injury.

No MeSH data available.


Related in: MedlinePlus

Amelioration of DSS-induced colitis by anti-CCL8-neutralizing antibody.(a) WT mice were administered with 3% DSS in drinking water for 7 days. One hundred micrograms of anti-CCL8 antibody (clone 17D6, white squares) or isotype IgG (black squares) was injected intravenously into the mice on days 3 and 4. Body weight change relative to the initial value was plotted up to 14 days after the DSS administration. Values are averages and s.e.m. of four to six mice per group. Representative data of four independent experiments are shown. *P<0.05, two-way analysis of variance with multiple comparison. (b) Macroscopic observation of the colon 7 days after the administration of DSS from WT mice injected with isotype IgG (top two colons) or anti-CCL8 antibody (bottom two colons). (c) Average lengths and s.d. of four colons are shown. *P<0.05, Student's t-test. (d) Haematoxylin and eosin staining of colon section from WT mice that received DSS for 5 days. The mice were treated with isotype IgG (left) or anti-CCL8 antibody (right). Representative images of four mice per group are shown. Scale bar, 200 μm. Original magnification, × 20. (e) IL-17 and IL-22 mRNA expression levels in colon tissue of WT mice on day 7, which were treated with isotype IgG (black bar) or anti-CCL8 antibody (white bar) were determined by qRT–PCR. Expression levels are shown as fold induction relative to the expression level in WT naive colon. Average values and s.e.m. of four colons are shown. P<0.05. NS, not significant, Student's t-test. Representative data of three independent experiments are shown.
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f7: Amelioration of DSS-induced colitis by anti-CCL8-neutralizing antibody.(a) WT mice were administered with 3% DSS in drinking water for 7 days. One hundred micrograms of anti-CCL8 antibody (clone 17D6, white squares) or isotype IgG (black squares) was injected intravenously into the mice on days 3 and 4. Body weight change relative to the initial value was plotted up to 14 days after the DSS administration. Values are averages and s.e.m. of four to six mice per group. Representative data of four independent experiments are shown. *P<0.05, two-way analysis of variance with multiple comparison. (b) Macroscopic observation of the colon 7 days after the administration of DSS from WT mice injected with isotype IgG (top two colons) or anti-CCL8 antibody (bottom two colons). (c) Average lengths and s.d. of four colons are shown. *P<0.05, Student's t-test. (d) Haematoxylin and eosin staining of colon section from WT mice that received DSS for 5 days. The mice were treated with isotype IgG (left) or anti-CCL8 antibody (right). Representative images of four mice per group are shown. Scale bar, 200 μm. Original magnification, × 20. (e) IL-17 and IL-22 mRNA expression levels in colon tissue of WT mice on day 7, which were treated with isotype IgG (black bar) or anti-CCL8 antibody (white bar) were determined by qRT–PCR. Expression levels are shown as fold induction relative to the expression level in WT naive colon. Average values and s.e.m. of four colons are shown. P<0.05. NS, not significant, Student's t-test. Representative data of three independent experiments are shown.

Mentions: The identification of CCL8 as a cytokine produced exclusively by CD169+ macrophages under the inflammatory condition prompted us to neutralize this molecule in vivo in colitis mice. To this end, we generated anti-CCL8 antibody by immunizing Wistar rats with CCL8 peptide. To suppress the activity of CCL8, we intravenously injected one of these antibodies (clone 17D6) into WT mice on days 3 and 4 after the administration of DSS. WT mice injected with isotype immunoglobulin (Ig)G exhibited weight loss that bottomed 8 to 9 days after the administration of DSS (Fig. 7a). In contrast, anti-CCL8 antibody ameliorated the clinical symptoms of DSS-induced colitis (Fig. 7a). Macroscopically, anti-CCL8 antibody suppressed colorectal bleeding and shortening of the colon (Fig. 7b,c). Pathological examination revealed de-epithelialized mucosa with distorted crypts in the isotype IgG-injected mice, in contrast to the significantly reduced tissue damage in the anti-CCL8 antibody-injected mice (Fig. 7d). qRT–PCR revealed decreased IL-17 mRNA levels in mice treated with anti-CCL8 antibody (Fig. 7e). These results highlight the clinical importance of CD169+ macrophage-derived CCL8 in the progression of mucosal inflammation subsequent to epithelial injury.


Intestinal CD169(+) macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes.

Asano K, Takahashi N, Ushiki M, Monya M, Aihara F, Kuboki E, Moriyama S, Iida M, Kitamura H, Qiu CH, Watanabe T, Tanaka M - Nat Commun (2015)

Amelioration of DSS-induced colitis by anti-CCL8-neutralizing antibody.(a) WT mice were administered with 3% DSS in drinking water for 7 days. One hundred micrograms of anti-CCL8 antibody (clone 17D6, white squares) or isotype IgG (black squares) was injected intravenously into the mice on days 3 and 4. Body weight change relative to the initial value was plotted up to 14 days after the DSS administration. Values are averages and s.e.m. of four to six mice per group. Representative data of four independent experiments are shown. *P<0.05, two-way analysis of variance with multiple comparison. (b) Macroscopic observation of the colon 7 days after the administration of DSS from WT mice injected with isotype IgG (top two colons) or anti-CCL8 antibody (bottom two colons). (c) Average lengths and s.d. of four colons are shown. *P<0.05, Student's t-test. (d) Haematoxylin and eosin staining of colon section from WT mice that received DSS for 5 days. The mice were treated with isotype IgG (left) or anti-CCL8 antibody (right). Representative images of four mice per group are shown. Scale bar, 200 μm. Original magnification, × 20. (e) IL-17 and IL-22 mRNA expression levels in colon tissue of WT mice on day 7, which were treated with isotype IgG (black bar) or anti-CCL8 antibody (white bar) were determined by qRT–PCR. Expression levels are shown as fold induction relative to the expression level in WT naive colon. Average values and s.e.m. of four colons are shown. P<0.05. NS, not significant, Student's t-test. Representative data of three independent experiments are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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f7: Amelioration of DSS-induced colitis by anti-CCL8-neutralizing antibody.(a) WT mice were administered with 3% DSS in drinking water for 7 days. One hundred micrograms of anti-CCL8 antibody (clone 17D6, white squares) or isotype IgG (black squares) was injected intravenously into the mice on days 3 and 4. Body weight change relative to the initial value was plotted up to 14 days after the DSS administration. Values are averages and s.e.m. of four to six mice per group. Representative data of four independent experiments are shown. *P<0.05, two-way analysis of variance with multiple comparison. (b) Macroscopic observation of the colon 7 days after the administration of DSS from WT mice injected with isotype IgG (top two colons) or anti-CCL8 antibody (bottom two colons). (c) Average lengths and s.d. of four colons are shown. *P<0.05, Student's t-test. (d) Haematoxylin and eosin staining of colon section from WT mice that received DSS for 5 days. The mice were treated with isotype IgG (left) or anti-CCL8 antibody (right). Representative images of four mice per group are shown. Scale bar, 200 μm. Original magnification, × 20. (e) IL-17 and IL-22 mRNA expression levels in colon tissue of WT mice on day 7, which were treated with isotype IgG (black bar) or anti-CCL8 antibody (white bar) were determined by qRT–PCR. Expression levels are shown as fold induction relative to the expression level in WT naive colon. Average values and s.e.m. of four colons are shown. P<0.05. NS, not significant, Student's t-test. Representative data of three independent experiments are shown.
Mentions: The identification of CCL8 as a cytokine produced exclusively by CD169+ macrophages under the inflammatory condition prompted us to neutralize this molecule in vivo in colitis mice. To this end, we generated anti-CCL8 antibody by immunizing Wistar rats with CCL8 peptide. To suppress the activity of CCL8, we intravenously injected one of these antibodies (clone 17D6) into WT mice on days 3 and 4 after the administration of DSS. WT mice injected with isotype immunoglobulin (Ig)G exhibited weight loss that bottomed 8 to 9 days after the administration of DSS (Fig. 7a). In contrast, anti-CCL8 antibody ameliorated the clinical symptoms of DSS-induced colitis (Fig. 7a). Macroscopically, anti-CCL8 antibody suppressed colorectal bleeding and shortening of the colon (Fig. 7b,c). Pathological examination revealed de-epithelialized mucosa with distorted crypts in the isotype IgG-injected mice, in contrast to the significantly reduced tissue damage in the anti-CCL8 antibody-injected mice (Fig. 7d). qRT–PCR revealed decreased IL-17 mRNA levels in mice treated with anti-CCL8 antibody (Fig. 7e). These results highlight the clinical importance of CD169+ macrophage-derived CCL8 in the progression of mucosal inflammation subsequent to epithelial injury.

Bottom Line: Selective depletion of CD169(+) macrophages or administration of neutralizing anti-CCL8 antibody ameliorates the symptoms of experimentally induced colitis in mice.Collectively, we identify an LP-resident macrophage subset that links mucosal damage and inflammatory monocyte recruitment.Our results suggest that CD169(+) macrophage-derived CCL8 serves as an emergency alert for the collapse of barrier defence, and is a promising target for the suppression of mucosal injury.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratory of Immune regulation, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan [2] Japan Science and Technology Agency, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.

ABSTRACT
Lamina propria (LP) macrophages are constantly exposed to commensal bacteria, and are refractory to those antigens in an interleukin (IL)-10-dependent fashion. However, the mechanisms that discriminate hazardous invasion by bacteria from peaceful co-existence with them remain elusive. Here we show that CD169(+) macrophages reside not at the villus tip, but at the bottom-end of the LP microenvironment. Following mucosal injury, the CD169(+) macrophages recruit inflammatory monocytes by secreting CCL8. Selective depletion of CD169(+) macrophages or administration of neutralizing anti-CCL8 antibody ameliorates the symptoms of experimentally induced colitis in mice. Collectively, we identify an LP-resident macrophage subset that links mucosal damage and inflammatory monocyte recruitment. Our results suggest that CD169(+) macrophage-derived CCL8 serves as an emergency alert for the collapse of barrier defence, and is a promising target for the suppression of mucosal injury.

No MeSH data available.


Related in: MedlinePlus