Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes

Nevius, Erin; Srivastava, Pramod K.; Basu, Sreyashi

doi:10.1038/mi.2011.50

Cited by 55 publications

(44 citation statements)

References 45 publications

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“…We observed (Fig. 3H) that orally gavaged AEA provided significant protection from T1D in a mouse model, as seen by us previously in CP-fed mice (25).…”

Section: Cd11csupporting

confidence: 66%

See 1 more Smart Citation

Endocannabinoid system acts as a regulator of immune homeostasis in the gut

Acharya

Penukonda

Shcheglova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

137

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Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1 hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1−/− or CB2 −/− mice have fewer CX3CR1 hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4 + cells, the Tr1 cells, in an IL-27-dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4 + T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.T he endocannabinoid system (ECS) is highly conserved in evolution dating back to at least 600 million years (1). It consists of (i) lipid endocannabinoids; (ii) their receptors such as the G protein-coupled receptors, cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), and a ligand-gated cation channel vanilloid receptor 1 (i.e., TRPV1); and (iii) the enzymes such as fatty acid amide hydrolyase (FAAH) that regulate the levels of endocannabinoids in vivo (2). The ECS impacts several aspects of mammalian physiology, particularly in the gut. Endogenous cannabinoids such as anandamide (AEA) belong to the N-acylethanolamine family and are synthesized from membrane glycerophospholipids (3, 4). AEA is an intestinal endocannabinoid, which engages its cognate receptors on the enteric nervous system and contributes to control of appetite and energy balance (5). Here, we have unraveled a role of the ECS in regulating immune homeostasis in the gutpancreas axis.The intestinal immune system is continuously exposed to a variety of antigens. An effective immune response must be launched against pathogenic insults; however, it must maintain tolerance to the vast amount of antigens such as those in commensal flora, endogenous metabolites, and food components. Mononuclear phagocytes (MNPs) such as CX3CR1 hi macrophage (Mϕ) and CD103 + dendritic cells (DCs), which are present abundantly in the small intestina...

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“…We observed (Fig. 3H) that orally gavaged AEA provided significant protection from T1D in a mouse model, as seen by us previously in CP-fed mice (25).…”

Section: Cd11csupporting

confidence: 66%

“…Engagement of ECS also leads to a significant increase in the frequency of the regulatory Tr1 cells in the siLP and PLN, although it does not, as reported earlier, increase the number and/ or function of Foxp3 + Tregs (25). Induction of Tr1 cells in vivo occurs through the established IL-27-IL-27R axis (28,29).…”

Section: Discussionmentioning

confidence: 81%

Endocannabinoid system acts as a regulator of immune homeostasis in the gut

Acharya

Penukonda

Shcheglova

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

137

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“…CD11b + F4/80 + macrophages in LN can play a key role in T cell proliferation (32). We further observed that adoptively transferred DO11.10 CD4 + T cells can localize adjacent to F4/80-expressing cells in both CD18 +/− and CD18 −/− PLN (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

T Cell–Extrinsic CD18 Attenuates Antigen-Dependent CD4+ T Cell Activation In Vivo

Lahiri

Sarin

et al. 2015

The Journal of Immunology

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The β2 integrins (CD11/CD18) are heterodimeric leukocyte adhesion molecules expressed on hematopoietic cells. The role of T cell-intrinsic CD18 in trafficking of naïve T cells to secondary lymphoid organs, and in antigen-dependent T cell activation in vitro and in vivo has been well-defined. However, the T cell-extrinsic role for CD18, including on antigen presenting cells (APC), in contributing to T cell activation in vivo is less well understood. We examined the role for T cell-extrinsic CD18 in the activation of WT CD4+ T cells in vivo through the adoptive transfer of DO11.10 Ag-specific CD4+ T cells into CD18−/− mice. We found that T cell-extrinsic CD18 was required for attenuating OVA-induced T cell proliferation in peripheral lymph nodes (PLN). The increased proliferation of WT DO11.10 CD4+ T cells in CD18−/− PLN was associated with a higher percentage of APC, and these APC demonstrated an increased activation profile and increased Ag-uptake, in particular in F4/80+ APC. Depletion of F4/80+ cells both reduced and equalized antigen-dependent T cell proliferation in CD18−/− relative to littermate control PLN, demonstrating that these cells play a critical role in the enhanced T cell proliferation in CD18−/− mice. Consistently, CD11b blockade, which is expressed on F4/80+ macrophages, enhanced the proliferation of DO11.10+ T cells in CD18+/− PLN. Thus, in contrast to the T cell-intrinsic essential role for CD18 in T cell activation, T cell-extrinsic expression of CD18 attenuates antigen-dependent CD4+ T cell activation in PLN in vivo.

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“…The effects of CAP have been investigated in diabetes as a dietary supplement (Nevius et al 2012), by topical application (Webster et al 2011) and by subcutaneous (van de Wall et al 2005) and intraperitoneal (Guillot et al 1996, Zhang and Ritter 2012) injection. Guillot et al (1996) reported that intraperitoneal administration of CAP in neonatal STZ-diabetic rats improved glucose tolerance without changing insulin secretion and Webster et al (2011) reported that topical application of CAP may be benefi cial for diabetic nephropathy.…”

Section: Immunohistochemistry Examinationmentioning

confidence: 99%

Distribution of glutathione peroxidase 1 in liver tissues of healthy and diabetic rats treated with capsaisin

Deprem

et al. 2014

Biotechnic & Histochemistry

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We investigated the immunohistochemical localization of glutathione peroxidase 1 (GPx 1) and the structural changes that occur in the livers of healthy and diabetic rats that were treated with capsaisin (CAP). Fifty female rats were divided into five groups: group 1, sham; group 2, untreated control; group 3, CAP-treated; group 4, streptozotocin (STZ) diabetic; group 5, STZ diabetic + CAP-treated. STZ was administered to groups 4 and 5; after verifying diabetes, CAP was administered daily for 2 weeks to groups 3 and 5. Diffuse, microvesicular and some macrovesicular fatty degeneration were observed in the cytoplasms of hepatocytes in the livers of the diabetic group. In the CAP-treated diabetic group, fat degeneration in the livers decreased slightly by day 7. Irregularity of the external contours of nuclei of the hepatocytes, swelling of the nuclei, and slight anisocytosis and anisokaryosis were observed in the hepatocytes of the diabetic group. In the CAP-treated diabetic groups, the severity of anisocytosis and anisokaryosis decreased slightly by day 7. In all groups, GPx 1 showed similar immunolocalization, but in the diabetic and diabetic + CAP groups, GPx 1 immunoreactivity was less than in the other groups. GPx 1 immunoreactivity in the CAP-treated diabetic group was weaker than in the diabetic group. In all groups, GPx 1 immunoreactivity was diffusely cytoplasmic in some of the hepatocytes, and diffusely cytoplasmic and diffusely nuclear in other hepatocytes. Also, GPx 1 immunoreactivity in the liver was more intense in the hepatocytes around Kiernan's space. We found that CAP caused a decrease in GPx 1.

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Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes

Cited by 55 publications

References 45 publications

Endocannabinoid system acts as a regulator of immune homeostasis in the gut

Endocannabinoid system acts as a regulator of immune homeostasis in the gut

T Cell–Extrinsic CD18 Attenuates Antigen-Dependent CD4+ T Cell Activation In Vivo

Distribution of glutathione peroxidase 1 in liver tissues of healthy and diabetic rats treated with capsaisin

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