Dataset Information

The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis.

ABSTRACT: Monocytes/macrophages have been found to be an important component of colitis. However, the key chemokine that initiates the CCR2⁺ monocytes migration from circulation to colitis tissue remains to be undiscovered. PC3-secreted microprotein (PSMP) is a novel chemokine whose receptor is CCR2. The physiological and pathological functions of PSMP have not yet been reported. In this study, PSMP was found to be expressed in colitis and colonic tumor tissues from patients and significantly up-regulated in mouse DSS-induced colitis tissues. PSMP overexpression in the colon aggravated the DSS-induced colitis and the anti-PSMP neutralizing antibody mollified the colitis by reducing macrophage infiltration and inhibiting the expression of IL-6, TNF-? and CCL2. Furthermore, we demonstrated that lipopolysaccharide and muramyl dipeptide induced PSMP expression in the colonic epithelial cells. PSMP was up-regulated in the initial stage prior to IL-6, TNF-? and CCL2 up-regulated expression in DSS colitis and promoted the M1 macrophages to produce CCL2. PSMP chemo-attracted Ly6C^hi monocytes in a CCR2 dependent manner via in situ chemotaxis and adoptive transfer assays. Our data identify PSMP as a key molecule in ulcerative colitis, which provides a novel mechanism of monocyte/macrophage migration that affects gut innate immunity and makes PSMP a potential target for controlling colitis.

SUBMITTER: Pei X

PROVIDER: S-EPMC5506041 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis.

Pei Xiaolei X Zheng Danfeng D She Shaoping S Ma Jing J Guo Changyuan C Mo Xiaoning X Zhang Yingmei Y Song Quansheng Q Zhang Yu Y Ma Dalong D Wang Ying Y

Scientific reports 20170711 1

Monocytes/macrophages have been found to be an important component of colitis. However, the key chemokine that initiates the CCR2<sup>+</sup> monocytes migration from circulation to colitis tissue remains to be undiscovered. PC3-secreted microprotein (PSMP) is a novel chemokine whose receptor is CCR2. The physiological and pathological functions of PSMP have not yet been reported. In this study, PSMP was found to be expressed in colitis and colonic tumor tissues from patients and significantly u ...[more]

PMID: 28698550

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Project description:AimTo investigate efficacy and safety for granulocyte, monocyte apheresis in a population of pediatric patients with ulcerative colitis.MethodsThe ADAPT study was a prospective, open-label, multicenter study in pediatric patients with moderate, active ulcerative colitis with pediatric ulcerative colitis activity index (PUCAI) of 35-64. Patients received one weekly apheresis with Adacolumn(®) granulocyte, monocyte/macrophage adsorptive (GMA) apheresis over 5 consecutive weeks, optionally followed by up to 3 additional apheresis treatments over 3 consecutive weeks. The primary endpoint was the change in mean PUCAI between baseline and week 12; the secondary endpoint was improvement in PUCAI categorized as (Significant Improvement, PUCAI decrease of ≥ 35), Moderate Improvement (PUCAI decrease of 20 < 35), Small Improvement (PUCAI decrease of 10 < 20) or No change (PUCAI decrease of < 10).ResultsTwenty-five patients (mean age 13.5 years; mean weight 47.7 kg) were enrolled. In the intention-to-treat set (ITT), the mean value for PUCAI improvement was 22.3 [95%CI: 12.9-31.6; n = 21]. In the per-protocol (PP) set, the mean improvement was 36.3 [95%CI: 31.4-41.1; n = 8]. Significant Improvement was recorded for 9 out of 20 patients (45%); 5 out of 20 patients (25%) had Moderate Improvement and one patient (5%) had No Change in PUCAI score at week 12. In the PP set, six out of eight patients (75%) showed Significant Improvement; and in two out of eight patients (25%) Moderate Improvement was recorded. The endoscopic activity index (EAI) decreased by 3 points on average. Seven (7) out of 21 (33%) patients in ITT and 4 out of 8 (50%) patients in PP have used steroids during the clinical investigation. The mean steroid dosage for these patients in the ITT set decreased from a mean 12.4 mg to 10 mg daily on average from Baseline to week 12.ConclusionAdacolumn(®) GMA apheresis treatment was effective in pediatric patients with moderate active Ulcerative Colitis. No new safety signals were reported. The present data contribute to considering GMA apheresis as a therapeutic option in pediatric patients having failed first line therapy.

Project description:Although post-cholecystectomy (PC) patients usually have gastrointestinal complications and a higher risk of colorectal cancer, previous studies undetected a heightened risk of inflammatory bowel disease. Thus, we tried to investigate cholecystectomy's impact and pathophysiological mechanism on murine colitis models and clarify the association among fecal bile acids (BAs), mucosal bacterial microbiota, and immune cells in the PC patients. One month or three months after cholecystectomy, mice have induced colitis and tested BAs and fecal microbiota analysis. Next, mice were treated with various cholecystectomy-accumulated bile acids in drinking water for three months before inducing colitis. All 14 paired PC patients and healthy subjects were enrolled for BAs and mucosal microbiota analysis. Cholecystectomy ameliorated DSS-induced murine colitis, accelerated mucosal repair, and induced a significant shifting of fecal microbiota and BAs profiles under colitis status, which featured a higher relative abundance of species involved in BAs metabolism and increased secondary BAs concentrations. Cholecystectomy-associated secondary BAs (LCA, DCA, and HDCA) also ameliorated DSS-induced colitis and accelerated mucosal repair in mice. Cholecystectomy and specific secondary BAs treatments inhibited monocytes/macrophages recruitment in colitis mice. In vitro, cholecystectomy-associated secondary BAs also downregulated monocytes chemokines in the THP-1 derived macrophages through activation of the LXRα-linked signaling pathway. The alterations of mucosal microbiota and fecal BAs profiles were found in the PC patients, characterized as increased species with potential immuno-modulating effects and secondary BAs, which were negatively associated with peripheral monocytes levels. Cholecystectomy-induced secondary bile acids accumulation ameliorated colitis through inhibiting monocyte/macrophage recruitment, which might be mediated by the LXRα-related signaling pathway. Cholecystectomy, after 3 months follow-up, has an immune-regulatory role in murine colitis, preliminarily explaining that no increased risk of IBD had been reported in the PC patients, which still warrants further studies.

Project description:BackgroundChronic alcohol consumption is associated with neuroinflammation, neuronal damage, and behavioral alterations including addiction. Alcohol-induced neuroinflammation is characterized by increased expression of proinflammatory cytokines (including TNFα, IL-1β, and CCL2) and microglial activation. We hypothesized chronic alcohol consumption results in peripheral immune cell infiltration to the CNS. Since chemotaxis through the CCL2-CCR2 signaling axis is critical for macrophage recruitment peripherally and centrally, we further hypothesized that blockade of CCL2 signaling using the dual CCR2/5 inhibitor cenicriviroc (CVC) would prevent alcohol-induced CNS infiltration of peripheral macrophages and alter the neuroinflammatory state in the brain after chronic alcohol consumption.MethodsC57BL/6J female mice were fed an isocaloric or 5% (v/v) ethanol Lieber DeCarli diet for 6 weeks. Some mice received daily injections of CVC. Microglia and infiltrating macrophages were characterized and quantified by flow cytometry and visualized using CX3CR1eGFP/+ CCR2RFP/+ reporter mice. The effect of ethanol and CVC treatment on the expression of inflammatory genes was evaluated in various regions of the brain, using a Nanostring nCounter inflammation panel. Microglia activation was analyzed by immunofluorescence. CVC-treated and untreated mice were presented with the two-bottle choice test.ResultsChronic alcohol consumption induced microglia activation and peripheral macrophage infiltration in the CNS, particularly in the hippocampus. Treatment with CVC abrogated ethanol-induced recruitment of peripheral macrophages and partially reversed microglia activation. Furthermore, the expression of proinflammatory markers was upregulated by chronic alcohol consumption in various regions of the brain, including the cortex, hippocampus, and cerebellum. Inhibition of CCR2/5 decreased alcohol-mediated expression of inflammatory markers. Finally, microglia function was impaired by chronic alcohol consumption and restored by CVC treatment. CVC treatment did not change the ethanol consumption or preference of mice in the two-bottle choice test.ConclusionsTogether, our data establish that chronic alcohol consumption promotes the recruitment of peripheral macrophages into the CNS and microglia alterations through the CCR2/5 axis. Therefore, further exploration of the CCR2/5 axis as a modulator of neuroinflammation may offer a potential therapeutic approach for the treatment of alcohol-associated neuroinflammation.

Dataset Information

The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis.

Publications

The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis.

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