PMN are critical to innate immunity and are fundamental to antibacterial defense. To localize to sites of infection, PMN possess receptors that detect chemoattractant stimuli elicited at the site, such as chemokines, complement split products, or bioactive lipids. Signaling through these receptors stimulates chemotaxis toward the site of infection but also activates a number of biochemical processes, with the result that PMN kill invading bacteria. PMN possess two receptors, CXCR1 and CXCR2, for the N-terminal ELR motif-containing CXC chemokines, although only two chemokine members bind both receptors and the remainder binding only CXCR2. This peculiar pattern in receptor specificity has drawn considerable interest and investigation into whether signaling through each receptor might impart unique properties on the PMN. Indeed, at first glance, CXCR1 and CXCR2 appear to be functionally redundant; however, there are differences. Considering these proinflammatory activities of activating PMN through chemokine receptors, there has been great interest in the possibility that blocking CXCR1 and CXCR2 on PMN will provide a therapeutic benefit. The literature examining CXCR1 and CXCR2 in PMN function during human and modeled diseases will be reviewed, asking whether the functional differences can be perceived based on alterations in the role PMN play in these processes.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0208125

The functional significance behind expressing two IL-8 receptor types on PMN.

Gut-associated lymphoid tissue (GALT) is an early target for human immunodeficiency virus type 1 (HIV-1) infection and is a site for severe CD4(+) T-cell depletion. HIV-associated enteropathy is well-documented in chronic HIV-1 infection. However, the initial host responses to HIV infection in GALT and the early molecular correlates of HIV enteropathogenesis have not been characterized during primary HIV infection. In this study, we provide evidence of viral replication in GALT resident CD4(+) T cells and macrophages in primary-stage patients and identify early patterns of host mucosal responses and changes in the molecular microenvironment through gene expression profiling. High levels of viral replication in GALT and marked CD4(+) T-cell depletion correlated with decreased expression levels of genes regulating epithelial barrier maintenance and digestive/metabolic functions. These changes coincided with a marked increase in the transcription of immune activation-, inflammation-, and apoptosis-associated genes. Our findings indicate that HIV-induced pathogenesis in GALT emerges at both the molecular and cellular levels prior to seroconversion in primary HIV infection, potentially setting the stage for disease progression by impairing the ability to control viral replication and repair and regenerate intestinal mucosal tissues.

/pdf/rapid-onset-of-intestinal-epithelial-barrier-dysfunction-in-ed478kuavd.pdf

Rapid onset of intestinal epithelial barrier dysfunction in primary human immunodeficiency virus infection is driven by an imbalance between immune response and mucosal repair and regeneration.

The CCR6 chemokine receptor is expressed by most B cells and subsets of T cells and dendritic cells (DCs) found in the gut mucosal immune system. CCL20, the single chemokine ligand for CCR6, is selectively made by the follicle-associated epithelium (FAE) overlying Peyer's patches (PPs) and isolated lymphoid follicles (ILFs). CCL20 contributes to the recruitment of CCR6-expressing B cells to these structures. CCL20 expression by the intestinal epithelium is also highly inducible in response to inflammatory stimuli. Thus, CCL20 functions as both an inflammatory and homeostatic chemokine. Interactions between CCR6 and CCL20 play a role at several stages in the development of intestinal lymphoid structures. A subset of the c-kit(+) lymphoid precursors found in cryptopatches (CPs) expresses CCR6. Recruitment of B cells to CPs and the subsequent expansion and organization of these B cells allows differentiation of some of these structures into ILFs. In CCR6 knockout mice, PPs are smaller with fewer follicles and the development of ILFs is compromised. These defects in the development of mucosal inductive sites in CCR6-deficient mice are responsible for decreased IgA production to oral antigens. CCR6 can be included with CXCR5 and CCR7 in a list of chemokine receptors that participate in shaping the organized lymphoid structures that are part of the intestinal immune system.

CCR6 and CCL20: Partners in Intestinal Immunity and Lymphorganogenesis

Anti-inflammatory effects of dietary phenolic compounds in an in vitro model of inflamed human intestinal epithelium.

Targeting chemokine receptors in chronic inflammatory diseases: An extensive review

Summary


Background : Inflammatory bowel disease (IBD) is characterised by intense mucosal recruitment of activated leukocytes. Chemokines determine inflammatory leukocyte recruitment and retention.



Aim : To compare expression of the entire chemokine family within colonic mucosa from IBD patients and uninflamed controls.



Methods : A microarray of cDNAs, representing every member of this superfamily and their cognate receptors, was hybridised with probes derived from colonoscopic biopsies.



Results : A distinct subset of chemokines, consisting of CXCLs 1–3 and 8 and CCL20, was upregulated in active colonic IBD, compared with uninflamed areas or tissue from controls. Increased expression of their cognate receptors, CXCR1, CXCR2 and CCR6, was confirmed by quantitative PCR and immunohistochemistry. An identical chemokine response was induced in Caco-2 cells by stimulation with interleukin (IL)-1β, but not tumour necrosis factor-alpha (TNF-α). By contrast, IL-1β and TNF-α were synergistic in an HT29 cell line and primary keratinocytes.



Conclusions : IL-1β and TNF-α appear to be the pivotal mediators of a previously unidentified coordinated epithelial chemokine response that dominates the mucosal chemokine environment in inflamed IBD tissue.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2036.2004.02262.x

A. H. Bingham

Papers

A distinct subset of chemokines dominates the mucosal chemokine response in inflammatory bowel disease