CD312, the human adhesion-GPCR EMR2, is differentially expressed during differentiation, maturation, and activation of myeloid cells

EMR2/CD312 is a member of the adhesion-GPCR family that contains extracellular EGF-like domains. Previously it has been shown to interact with chondroitin sulphate glycosaminoglycans in an isoform-specific manner. Although EMR2 expression has been found to be restricted to human myeloid cells, its expression profile has not yet been systemically characterized. In this report, we show that EMR2 receptor expression is up-regulated during differentiation and maturation of macrophages, and is conversely down-regulated during dendritic cell maturation. We also demonstrate that EMR2 receptor alternative splicing and glycosylation is regulated during myeloid differentiation. In monocytes and macrophages, EMR2 can be specifically up-regulated by LPS and IL-10 via an IL-10-mediated pathway. In inflamed tissues, EMR2 is detected in subpopulations of myeloid cells including macrophages and neutrophils. The results presented here further support the idea that EMR2 plays a role in the migration and adhesion of myeloid cells during cell differentiation, maturation, and activation.     

G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9

Certain chemokines possess anti-angiogenic and antibacterial activity, in addition to their ability to recruit leukocytes. Herein, we demonstrate that CXCL9/MIG induces the expression, by a monocytic cell line and peripheral blood mononuclear cells, of a variety of chemokines including CXCL8/IL-8, CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1 in a pertussis toxin insensitive manner. Similarly, another cationic chemokine CCL20/MIP-3α, but not the non-cationic chemokines CCL2 or CCL3, stimulated monocytic cells to produce substantial amounts of CXCL8 and CCL3. Microarray experiments demonstrated that CXCL9, but not CCL2, induced the expression of hundreds of genes, many of which have known or proposed immunomodulatory functions. Induction of CXCL8 required the p38 and ERK1/2 mitogen-activated protein kinases but not NFκB, JAK-STAT or JNK signaling pathways. These results collectively demonstrate that CXCL9 has immunomodulatory functions that are not mediated through a G-protein coupled receptor and may possess additional roles in host defenses against infection.     

TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity

Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C⁺ monocytes from old (18–22 mo) mice and CD14⁺CD16⁺ intermediate/inflammatory monocytes from older adults also contributed to this “age-associated inflammation” as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C⁺ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C⁺ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C⁺ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity.     

Culture and molecular-based profiles show shifts in bacterial communities of the upper respiratory tract that occur with age

The upper respiratory tract (URT) is a crucial site for host defense, as it is home to bacterial communities that both modulate host immune defense and serve as a reservoir of potential pathogens. Young children are at high risk of respiratory illness, yet the composition of their URT microbiota is not well understood. Microbial profiling of the respiratory tract has traditionally focused on culturing common respiratory pathogens, whereas recent culture-independent microbiome profiling can only report the relative abundance of bacterial populations. In the current study, we used both molecular profiling of the bacterial 16S rRNA gene and laboratory culture to examine the bacterial diversity from the oropharynx and nasopharynx of 51 healthy children with a median age of 1.1 years (range 1–4.5 years) along with 19 accompanying parents. The resulting profiles suggest that in young children the nasopharyngeal microbiota, much like the gastrointestinal tract microbiome, changes from an immature state, where it is colonized by a few dominant taxa, to a more diverse state as it matures to resemble the adult microbiota. Importantly, this difference in bacterial diversity between adults and children accompanies a change in bacterial load of three orders of magnitude. This indicates that the bacterial communities in the nasopharynx of young children have a fundamentally different structure from those in adults and suggests that maturation of this community occurs sometime during the first few years of life, a period that includes ages at which children are at the highest risk for respiratory disease.     

Evidence for host-associated races in a gall-forming midge: trade-offs in potential fecundity

Abstract. 1. The gall midge, Asphondylia borrichiae , attacks the terminals of three plants in the aster family: Borrichia frutescens , Iva frutescens , and I. imbricata .
2. In the field, Borrichia suffers the highest rate of galling and I. imbricata the lowest. Common garden experiments also revealed highly significant differences in the attack rates of the three host species by Asphondylia . However, these differences depended on the source of the attacking midge population.
3. Midges collected from Borrichia and I. frutescens attacked the host in which they developed almost exclusively, whereas those from I. imbricata attacked both Iva spp.
4. Each Asphondylia larva develops in its own chamber within a gall. Borrichia galls were 2.5–3.5-fold less crowded than those from I. imbricata and I. frutescens , respectively. Consequently, midges that developed in Borrichia were significantly larger and eclosed with 30–40% more eggs than those that developed in I. imbricata and I. frutescens , respectively.
5. Although performance of Asphondylia larvae was lowest on the two Iva spp., especially I. frutescens , these hosts may provide an escape from natural enemies as a trade-off for reduced offspring performance.
6. Differences in host-plant species phenology may reduce gene flow among host-associated populations of Asphondylia , thereby favouring the formation of races at the level of plant genus.