17 research outputs found
Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis
Abstract included in the text
Mucosal associated invariant T cells are altered in patients with Hidradenitis Suppurativa and contribute to the inflammatory milieu
Mucosal Associated Invariant T cells are a population of “innate” T cells, which express
the invariant T cell receptor (TCR) a chain Va7.2-Ja33 and are capable of robust rapid
cytokine secretion, producing a milieu of cytokines including IFN-g and IL-17. MAIT
cells have been reported in multiple human tissues including the gut, periphery and
skin. On-going research has highlighted their involvement in numerous inflammatory
diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis
Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in
painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been
implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is
currently unknown. In this study we show for the first time, that MAIT cells are altered
in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17
cytokine bias. We show that CCL20 expression is elevated in lesions of patients with
H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT
cells can accumulate in the lesionsfrom patients with H.S. when compared to adjacent
skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation
of dermal fibroblasts, promoting the expression of chemotactic signals including
CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt
robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively
our data detailsIL-17 producing MAIT cells as a novel player in the pathogenesis of H.S
and highlights the potential of RORyt inhibition as a novel therapeutic strategy
Cellular Plasticity of Defa4Cre-Expressing Paneth Cells in Response to Notch Activation and Intestinal InjurySummary
Background & Aims: Loss of leucine-rich repeat-containing G-protein–coupled receptor 5–positive crypt base columnar cells provides permissive conditions for different facultative stem cell populations to dedifferentiate and repopulate the stem cell compartment. In this study, we used a defensin α4-Cre recombinase (Defa4Cre) line to define the potential of Paneth cells to dedifferentiate and contribute to intestinal stem cell (ISC) maintenance during normal homeostasis and after intestinal injury. Methods: Small intestine and enteroids from Defa4Cre;Rosa26 tandem dimer Tomato (tdTomato), a red fluoresent protein, (or Rosa26 Enhanced Yellow Fluorescent Protein (EYFP)) reporter, Notch gain-of-function (Defa4Cre;Rosa26 Notch Intracellular Domain (NICD)-ires-nuclear Green Fluorescent Protein (nGFP) and Defa4Cre;Rosa26reverse tetracycline transactivator–ires Enhanced Green Fluorescent Protein (EGFP);TetONICD), A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) loss-of-function (Defa4Cre;ADAM10flox/flox), and Adenomatous polyposis coli (APC) inactivation (Defa4Cre;APCflox/flox) mice were analyzed. Doxorubicin treatment was used as an acute intestinal injury model. Lineage tracing, proliferation, and differentiation were assessed in vitro and in vivo. Results: Defa4Cre-expressing cells are fated to become mature Paneth cells and do not contribute to ISC maintenance during normal homeostasis in vivo. However, spontaneous lineage tracing was observed in enteroids, and fluorescent-activated cell sorter–sorted Defa4Cre-marked cells showed clonogenic enteroid growth. Notch activation in Defa4Cre-expressing cells caused dedifferentiation to multipotent ISCs in vivo and was required for adenoma formation. ADAM10 deletion had no significant effect on crypt homeostasis. However, after acute doxorubicin-induced injury, Defa4Cre-expressing cells contributed to regeneration in an ADAM10–Notch–dependent manner. Conclusions: Our studies have shown that Defa4Cre-expressing Paneth cells possess cellular plasticity, can dedifferentiate into multipotent stem cells upon Notch activation, and can contribute to intestinal regeneration in an acute injury model. Keywords: Defensin, Paneth Cell, Intestinal Stem Cells, Regeneration, Enteroid, Notch, Chemotherap
The chemokine receptor CCR9 is required for the T cellmediated regulation of chronic ileitis in mice
Background & Aims—A balance between effector and regulatory (Treg) T-cell responses is
required to maintain intestinal homeostasis. To regulate immunity, T cells migrate to the intestine
using a combination of adhesion molecules and chemokine receptors. However, it is not known
whether the migration pathways of effector cells and Tregs are distinct or shared. We sought to
determine whether interaction between the chemokine CCR9 and its receptor, CCL25, allows
effectors or Tregs to localize to chronically inflamed small intestine.
Methods—Using a mouse model that develops Crohn's-like ileitis (TNFΔARE mice) we
examined the role of CCL25–CCR9 interactions for effector and Treg traffic using flow
cytometry, quantitative reverse transcription PCR, immunohistochemistry, immunoneutralization,
and proliferation analyses.
Results—In TNFΔARE mice, expression of CCL25 and the frequency of CCR9-expressing
lymphocytes increased during late-stage disease. In the absence of CCR9, TNFΔARE mice
developed exacerbated disease, compared with their CCR9-sufficient counterparts, which
coincided with a deficiency of CD4+/CD25+/FoxP3+ and CD8+/CD103+ Tregs within the
intestinal lamina propria and mesenteric lymph nodes. Furthermore, the CD8+/CCR9+ subset
decreased the proliferation of CD4+ T cells in vitro. Administration of a monoclonal antibody
against CCR9 to TNFΔARE mice exacerbated ileitis in vivo, confirming the regulatory role of
CD8+/CCR9+ cells.
Conclusions—Signaling of the chemokine CCL25 through its receptor CCR9 induces Tregs to
migrate to the intestine. These findings raise concerns about the development of reagents to
disrupt this pathway for the treatment of patients with Crohn's disease