Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility

doi:10.1016/j.cell.2014.04.050

. 2014 Jul 17;158(2):300-313.

doi: 10.1016/j.cell.2014.04.050.

Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility

Paul Andrew Muller¹, Balázs Koscsó², Gaurav Manohar Rajani², Korey Stevanovic³, Marie-Luise Berres⁴, Daigo Hashimoto⁴, Arthur Mortha⁴, Marylene Leboeuf⁴, Xiu-Min Li⁵, Daniel Mucida⁶, E Richard Stanley⁷, Stephanie Dahan⁸, Kara Gross Margolis³, Michael David Gershon⁹, Miriam Merad¹⁰, Milena Bogunovic¹¹

Affiliations

¹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
² Department of Microbiology and Immunology, Penn State University College of Medicine and Milton Hershey Medical Center, Hershey, PA 17033, USA.
³ Department of Pediatrics, Morgan Stanley Children's Hospital, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
⁴ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
⁵ Division of Allergy and Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
⁶ Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
⁷ Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁸ The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
⁹ Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
¹⁰ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA. Electronic address: miriam.merad@mssm.edu.
¹¹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Department of Microbiology and Immunology, Penn State University College of Medicine and Milton Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: mbogunovich@hmc.psu.edu.

PMID: 25036630
PMCID: PMC4149228
DOI: 10.1016/j.cell.2014.04.050

Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility

Paul Andrew Muller et al. Cell. 2014.

. 2014 Jul 17;158(2):300-313.

doi: 10.1016/j.cell.2014.04.050.

Authors

Affiliations

¹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
² Department of Microbiology and Immunology, Penn State University College of Medicine and Milton Hershey Medical Center, Hershey, PA 17033, USA.
³ Department of Pediatrics, Morgan Stanley Children's Hospital, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
⁴ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
⁵ Division of Allergy and Immunology, Department of Pediatrics, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
⁶ Laboratory of Mucosal Immunology, The Rockefeller University, New York, NY 10065, USA.
⁷ Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
⁸ The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA.
⁹ Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
¹⁰ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA. Electronic address: miriam.merad@mssm.edu.
¹¹ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; The Immunology Institute, Icahn School of Medicine at Mount Sinai Hospital, New York, NY 10029, USA; Department of Microbiology and Immunology, Penn State University College of Medicine and Milton Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: mbogunovich@hmc.psu.edu.

PMID: 25036630
PMCID: PMC4149228
DOI: 10.1016/j.cell.2014.04.050

Erratum in

Cell. 2014 Aug 28;158(5):1210. Dosage error in article text

Abstract

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

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Figures

**Figure 1. MHCII⁺CX₃CR1⁺ MMs require CSF1R signaling for their development**
(A–B) Distribution of CX₃CR1⁺ MMs shown in cross-section (A) or muscularis sheet (B) of large bowel (LB) from *Cx₃cr1*-GFP^+/– mice. Scale bar – 100 nm. (C) Phenotype of MMs in small bowel (SB) muscularis from *Cx₃cr1*-GFP^+/– mice by FACS analysis (gated on DAPI^– cells). (D) *Flt3* and *Csf1r* gene expression in sorted MMs measured by whole mouse genome microarray and presented as relative units (RU). (E) FACS plots of whole bowel suspensions from WT or *Cscf1r*^–/– mice show % of CD11c^loMHCII^hi MMs (oval gate, solid line) and CD11c^hiMHCII^hi LP phagocytes (oval gate, dashed line). Gated on CD45⁺CD11c^lo/hiCD11b^lo/hi cells as demonstrated in Figure S1. (F) Absolute numbers of MMs in total gut of WT and *Csf1r*^–/– mice quantified by FACS. (G) Relative reduction of MMs and CD103⁺CD11b⁺ and CD103^–CD11b⁺ LP phagocytes in *Csf1r*^–/– mice as compared to WT littermates (quantified by FACS). (H) % of WT CD45.1⁺ and *Csf1r*^–/– CD45.2⁺ cells among CD45⁺ LP CD103⁺CD11b⁺ and LP CD103^–CD11b⁺ phagocytes and MMs (Muscularis) in SB from 10% WT + 90% *Csf1r*^–/– mixed BM chimeras.

**Figure 2. Model of MM depletion**
(A–B) FACS plots of separated SB muscularis (A) and whole SB (B) single cell suspensions from WT mice 2 days after i.p. injection of isotype IgG or αCSF1R mAb show % of CD11c^loMHCII^hi MMs (oval gate, solid line) and CD11c^hiMHCII^hi LP phagocytes (oval gate, dashed line). A – gated on total viable cells. B – gated on CD45⁺CD11c^lo/hiCD11b^lo/hi cells using the gating strategy as in Figure S1. (C) Absolute numbers of LP CD103⁺CD11b⁺ and LP CD103^–CD11b⁺ phagocyte and MMs (Muscularis) in SB of WT mice 2 days after i.p. injection with isotype IgG or αCSF1R mAb quantified by FACS. (D) Relative reduction of LP phagocyte and MM numbers quantified by FACS in WT mice treated with αCSF1R mAb (Day 2) as compared to isotype IgG treated mice. (E–F) Distribution of MHCII⁺ macrophages (E) and CD3⁺ T cells (F) in LB muscularis from WT mice 2 days after i.p. injection of isotype IgG or αCSF1R mAb analyzed by immunofluorescence (IF). Scale bars – 100 nm.

**Figure 3. Depletion of MMs results in intestinal dysmotility**
(A) Illustration of *ex vivo* method to measure stretch-induced peristaltic contractions of colonic rings using a myograph. (B) Five hour recording of stretch-induced contractions of colonic rings during repeated application of 0.25 mm long stretching up to 5.00 mm total stretch length. 3 mm colonic rings were obtained from WT mice 2 days after i.p. injection of isotype IgG or αCSF1R mAb. (C) Number of peaks (left) or Root Mean Square (RMS) normalized to baseline in % (right) during 10 min recordings of colonic contraction at stretch distance 2.75 mm. (D) RMS normalized to baseline (%) during 10 min recordings of colonic contractions at each stretching step from 1.5 to 3.5 mm. (E) Colonic transit time measured by bead expulsion assay in WT mice 1, 3 and 5 days after i.p. injection of isotype IgG or αCSF1R mAb.

**Figure 4. MMs regulate intestinal peristalsis by secreting BMP2**
(A–B) *Bmp2* gene expression levels in MMs (Muscularis) compared to LP CD103^–CD11b⁺ phagocytes (A) and LP CD103⁺CD11b⁺ and LP CD103^–CD11b⁺ phagocytes (B) measured by whole mouse genome microarray. (C) *Bmp2-7* gene expression levels in MMs measured by whole mouse genome microarray. (D) *Bmp2* relative gene expression levels measured by qPCR in intact SB muscularis (whole tissue) or in SSC^loCD45⁺CD11b^– lymphocytes and macrophages sorted from separated SB muscularis. FI – fold increase as compared to “whole tissue”. (E) IF analysis of LB muscularis from WT mice stained with anti-BMP2 and anti-MHCII mAbs and counterstained with DAPI. Scale bar – 100 nm. (F) RMS of colonic contraction recordings normalized to baseline (%) at stretch intervals 1.5–3.5 mm. 3 mm colonic rings were obtained from WT mice treated with BMP receptor inhibitor dorsomorphin or control vehicle. (G) WT mice were injected i.p. with isotype IgG (top) or αCSF1R mAb (bottom) and analyzed 2 days later. Panels show *ex vivo* recordings of stretch-induced contractions of colonic rings from these mice before and after adding 1, 5 and 10 ng of human recombinant BMP2 or control vehicle (performed at 2.75 mm “optimal” stretch distance). (H) RMS of 10 min recordings described in F (bottom panel, αCSF1R mAb treated mice) before and after adding 5 ng of BMP2. (I) RMS normalized to baseline (%) of recordings described in F (bottom panel, αCSF1R mAb treated mice) after adding BMP2 (1, 5, 10 ng) or control vehicle. Baseline here is the recording at the same stretch distance (2.75 mm) prior to adding BMP2 or control vehicle. (J) Colonic transit time measured by bead expulsion assay in WT mice prior receiving αCSF1R mAb (day −1) and on days 3 and 4 after receiving αCSF1R mAb; 18 and 3 hours prior the last assessment (day 4) mice received 1 µg of BMP2 i.p.

**Figure 5. MMs activate BMP2 receptor on enteric neurons**
(A) Distribution of CX₃CR1⁺ MMs in colon (left) and ileum (middle and right) muscularis from *Cx₃cr1*-GFP^+/– mice stained with anti- βIII Tubulin Ab and analyzed by IF. Scale bars – 500 nm (left), 100 nm (middle) and 10 nm (right). (B) IF analysis of LB muscularis from WT mice stained with anti-BMPRII and anti-βIII Tubulin Abs and counterstained with DAPI. Scale bars – 500 nm. (C) IF analysis of LB muscularis from WT mice 2 days after i.p. injection of isotype IgG (top), αCSF1R mAb (middle and bottom) stained with anti-pSMAD1/5/8 and anti-BMPRII Abs and counterstained with DAPI. The bottom panel shows pSMAD1/5/8 distribution in the muscularis from αCSF1R mAb injected mouse that was incubated with BMP2 as described in D. Scale bars – 100 nm. (D) Quantitative summary of the distribution of pSMAD1/5/8⁺BMPRII⁺ neurons in the muscularis from WT mice 2 days after i.p. injection of isotype IgG or αCSF1R mAb. In all cases, the muscularis was incubated for 30 min at 37°C in complete medium in the presence or absence of BMP2 (10 ng/ml) as indicated. Each data point represents % of pSMAD1/5/8⁺ neurons among total BMPRII⁺ neurons in each visual field; each column summarizes the results from three animals.

**Figure 6. Enteric neurons produce CSF1 required for MM development**
(A) *Csf1* gene expression levels measured by qPCR in intact muscularis (whole tissue), macrophages sorted from SB muscularis and cultured primary enteric neurons (FI compared to the “whole tissue”). (B) *Il-34* and *Csf1* relative gene expression levels (FI) measured by qPCR in cultured enteric neurons as compared to *Il-34*. (C) IF analysis of LB muscularis from WT mice stained with anti-BMPRII and anti-CSF1 Abs. Scale bar – 100 nm. (D) FACS plots of whole bowel single cell suspensions from WT mice and their *Csf1^op/op* littermates show % of CD11c^loMHCII^hi MMs (oval gate, solid line) and CD11c^hiMHCII^hi LP phagocytes (oval gate, dashed line). Gated on CD45⁺CD11c^lo/hiCD11b^lo/hi cells (E) Absolute MM numbers in the bowel of WT mice and *Csf1^op/op* mice quantified by FACS. (F) IF analysis of LB (cecum) muscularis from WT mice and their *Csf1^op/op* littermates stained with anti- βIII Tubulin and anti-MHCII Abs. Scale bars – 500 nm. (G) Quantitative summary of the distribution of pSMAD1/5/8⁺BMPRII⁺ neurons in the LB muscularis from WT and *Csf1^op/op* mice. Each data point represents % of pSMAD1/5/8⁺ neurons among total BMPRII⁺ neurons in each visual field; each column summarizes the results from three animals. (H) IF analysis of LB (colon) muscularis from WT and *Csf1^op/op* littermates stained with anti-BMPRII Ab. Scale bars – 500 nm. (I) Quantitative summary of the distribution of BMPRII⁺ neurons in the colon of WT and *Csf1^op/op* mice. Each data point represents the counts of BMPRII⁺ neurons in each visual field; each column summarizes the results from two animals.

**Figure 7. Luminal microbiota regulates intestinal motility and MM-neuronal crosstalk**
(A–D) WT mice received antibiotics with drinking water for 4 weeks and control age matched mice received only water. (A) Total GI transit time that represents the time required to expel feces containing carmine red dye measured in antibiotic-treated and control mice. (B) RMS of colonic contraction recordings normalized to baseline (%) at stretch intervals 1.5–3.5 mm. 3 mm colonic rings were obtained from antibiotic-treated and control mice. (C) *Bmp2* relative gene expression levels measured by qPCR in macrophages sorted from separated SB muscularis of antibiotic-treated and control mice. FI – fold increase as compared to *Bmp2* levels in the intact muscularis. Each data point represents qPCR results obtained from analyzing 50,000 cells after a single sort from 5 mice. Cell sorting from each group was performed in pairs, on the same day and under identical conditions. (D) Quantitative summary of the distribution of pSMAD1/5/8⁺BMPRII⁺ neurons in the muscularis from antibiotic-treated and control mice. Each data point represents % of pSMAD1/5/8⁺ neurons among total BMPRII⁺ neurons in each visual field; each column summarizes the results from three animals. (E) *Csf1* relative gene expression levels in cultured primary enteric neurons measured by qPCR. Differentiated neurons were cultured with or without 10 ng/ml of LPS for 18 hrs prior to analyses. FI – fold increase as compared to *Csf1* levels in the intact muscularis. Each data point represents qPCR results obtained from an independent neuronal culture. FI – fold increase as compared to *Csf1* levels in the intact muscularis. (F) *Csf1* relative gene expression levels quantified by qPCR in LB muscularis from WT mice were treated with antibiotics for 4 weeks (left), from WT mice treated with antibiotics and 50 µg/ml LPS in drinking water for 4 weeks (middle) and from WT mice 3 weeks after they received fecal transfer (FT) following a 4-week course of antibiotics (right). The data are compared to age matched control mice received only water. FI – fold increase as compared to average *Csf1* levels in the control group received water. (G) Absolute numbers of MMs quantified by FACS in LB from WT mice received antibiotics (left), antibiotics with LPS (middle) and FT following antibiotic treatment (right) as in F. The data are compared to age matched control mice received only water. (H) Total GI transit time in WT mice received antibiotics and 50 µg/ml LPS with drinking water for 4 weeks and age matched mice that received only antibiotics for 4 weeks. (I) Total GI transit time in WT mice 3 weeks after they received FT following a 4-week course of antibiotics and control mice received water.

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Comment in

Macrophages have a grip on the gut.
Locati M. Locati M. Immunity. 2014 Jul 17;41(1):11-3. doi: 10.1016/j.immuni.2014.07.002. Immunity. 2014. PMID: 25035949
GI motility: microbiota and macrophages join forces.
Robinette ML, Colonna M. Robinette ML, et al. Cell. 2014 Jul 17;158(2):239-240. doi: 10.1016/j.cell.2014.06.040. Cell. 2014. PMID: 25036623

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References

1. Aberle H, Haghighi AP, Fetter RD, McCabe BD, Magalhaes TR, Goodman CS. wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron. 2002;33:545–558. - PubMed
1. Abrams GD, Bishop JE. Effect of the normal microbial flora on gastrointestinal motility. Proc Soc Exp Biol Med. 1967;126:301–304. - PubMed
1. Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP, Chandler RL, de Caestecker MP. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. American journal of physiology Regulatory, integrative and comparative physiology. 2010;298:R833–R842. - PMC - PubMed
1. Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S. Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology. 2012;143:1006–1016. e1004. - PMC - PubMed
1. Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 2009;58:1300–1311. - PubMed

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[1] Aberle H, Haghighi AP, Fetter RD, McCabe BD, Magalhaes TR, Goodman CS. wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron. 2002;33:545–558. - PubMed

[2] Aberle H, Haghighi AP, Fetter RD, McCabe BD, Magalhaes TR, Goodman CS. wishful thinking encodes a BMP type II receptor that regulates synaptic growth in Drosophila. Neuron. 2002;33:545–558. - PubMed

[3] Abrams GD, Bishop JE. Effect of the normal microbial flora on gastrointestinal motility. Proc Soc Exp Biol Med. 1967;126:301–304. - PubMed

[4] Abrams GD, Bishop JE. Effect of the normal microbial flora on gastrointestinal motility. Proc Soc Exp Biol Med. 1967;126:301–304. - PubMed

[5] Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP, Chandler RL, de Caestecker MP. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. American journal of physiology Regulatory, integrative and comparative physiology. 2010;298:R833–R842. - PMC - PubMed

[6] Anderson L, Lowery JW, Frank DB, Novitskaya T, Jones M, Mortlock DP, Chandler RL, de Caestecker MP. Bmp2 and Bmp4 exert opposing effects in hypoxic pulmonary hypertension. American journal of physiology Regulatory, integrative and comparative physiology. 2010;298:R833–R842. - PMC - PubMed

[7] Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S. Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology. 2012;143:1006–1016. e1004. - PMC - PubMed

[8] Anitha M, Vijay-Kumar M, Sitaraman SV, Gewirtz AT, Srinivasan S. Gut microbial products regulate murine gastrointestinal motility via Toll-like receptor 4 signaling. Gastroenterology. 2012;143:1006–1016. e1004. - PMC - PubMed

[9] Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 2009;58:1300–1311. - PubMed

[10] Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut. 2009;58:1300–1311. - PubMed

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Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility

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Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility

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