Intestinal CX ₃ C chemokine receptor 1 ^high (CX ₃ CR1 ^high ) myeloid cells prevent T-cell-dependent colitis

Abstract

Adequate activation of CD4 + T lymphocytes is essential for host defense against invading pathogens; however, exaggerated activity of effector CD4 + T cells induces tissue damage, leading to inflammatory disorders such as inflammatory bowel diseases. Several unique subsets of intestinal innate immune cells have been identified. However, the direct involvement of innate immune cell subsets in the suppression of T-cell-dependent intestinal inflammation is poorly understood. Here, we report that intestinal CX 3 C chemokine receptor 1 high (CX 3 CR1 high ) CD11b + CD11c + cells are responsible for prevention of intestinal inflammation through inhibition of T-cell responses. These cells inhibit CD4 + T-cell proliferation in a cell contact-dependent manner and prevent T-cell-dependent colitis. The suppressive activity is abrogated in the absence of the IL-10/Stat3 pathway. These cells inhibit T-cell proliferation by two steps. Initially, CX 3 CR1 high CD11b + CD11c + cells preferentially interact with T cells through highly expressed intercellular adhesion molecule-1/vascular cell adhesion molecule-1; then, they fail to activate T cells because of defective expression of CD80/CD86. The IL-10/Stat3 pathway mediates the reduction of CD80/CD86 expression. Transfer of wild-type CX 3 CR1 high CD11b + CD11c + cells prevents development of colitis in myeloid-specific Stat3-deficient mice. Thus, these cells are regulatory myeloid cells that are responsible for maintaining intestinal homeostasis. mucosal immunology | innate immunity

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

“…Although our findings indicate that LCN2 preferentially affects the function of AMs, it is tempting to speculate that other antiinflammatory macrophage subsets might also respond to IL-10/ LCN2 induction. Potential candidates include intestinal myeloid regulatory cells (Mregs), given the importance of IL-10 in intestinal homeostasis (32), and also tumor-associated macrophages, since LCN2 was found to be significantly elevated in the plasma of tumor-bearing mice (33). In fact, while this manuscript was in preparation, Jung et al reported that IL-10 induced LCN2 in human macrophages (34).…”

Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells

“…Specific experimental support for SIK inhibition as a potential IBD treatment comes from our observation that the IL-10-potentiating activity of HG-9-91-01 is maintained in murine CD11c + CX 3 CR1 hi cells, a highly abundant subset of myeloid cells that play a key role in maintaining gut immune homeostasis (13,14). The anti-inflammatory activity of CD11c + CX 3 CR1 hi myeloid cells in the CD45RB hi T-cell transfer colitis model requires intact IL-10/STAT3 signaling (15), which suggests that SIK inhibition will enhance the T-cell suppressive activity of these cells and, in turn, suppress pathogenic auto-inflammation characteristic of IBD.…”

“…The anti-inflammatory function of CD11c + CX 3 CR1 hi myeloid cells is highlighted in adoptive transfer experiments where coadministration of these cells suppresses colitis induced by CD45RB hi CD4 + T cells in lymphopenic hosts (15). Given the central role of myeloid cells in shaping gut immunity, using small molecules to enhance IL-10 production by DCs-MΦs represents a potentially promising approach to increase levels of IL-10 specifically in this tissue microenvironment.…”

Regulatory T Cells and Immune Tolerance in the Intestine

“…Myeloid-specific ablation of STAT3 leads to spontaneous colitis driven by dysregulated CD4 þ T-cell responses. In this setting, defective IL-10R signaling in colonic macrophages results in elevated levels of costimulatory molecules CD80/86 and hyperactivation of colitogenic CD4 þ T cells (Takeda et al 1999;Kayama et al 2012 (Rubtsov et al 2010;Chaudhry et al 2011). Whether the loss of Foxp3 expression in lymphopenia-driven colitis represents a failure to maintain the Treg program or is a specific consequence of the cell transfer system requires further study, especially given the interest in Treg cell therapy in the clinical setting.…”