Alterations in marginal zone macrophages and marginal zone B cells in old mice.

Marginal zones (MZs) are architecturally organized for clearance of and rapid response against blood-borne Ags entering the spleen. MZ macrophages (MZMs) and MZ B cells are particularly important in host defense against T-independent pathogens and may be crucial for the prevention of diseases, such as streptococcal pneumonia, that are devastating in older patients. Our objective was to determine whether there are changes in the cellular components of the MZ between old and young mice. Using immunocytochemistry and a blinded scoring system, we observed gross architectural changes in the MZs of old mice, including reduction in the abundance of MZMs surrounding the MZ sinus as well as disruptions in positioning of mucosal addressin cell adhesion molecule 1 (MAdCAM-1)(+) sinus lining cells and metallophilic macrophages. Loss of frequency of MZMs was corroborated by flow cytometry. A majority of old mice also showed reduced frequency of MZ B cells, which correlated with decreased abundance of MZM in individual old mice. The spleens of old mice showed less deposition of intravenously injected dextran particles within the MZ, likely because of the decreased frequency in MZMs, because SIGN-R1 expression was not reduced on MZM from old mice. The phagocytic ability of individual MZMs was examined using Staphylococcus aureus bioparticles, and no differences in phagocytosis were found between macrophages from young or old spleens. In summary, an anatomical breakdown of the MZ occurs in advanced age, and a reduction in frequency of MZM may affect the ability of the MZM compartment to clear blood-borne Ags and mount proper T-independent immune responses.

Intoxication by intraperitoneal injection or oral gavage equally potentiates postburn organ damage and inflammation.

The increasing prevalence of binge drinking and its association with trauma necessitate accurate animal models to examine the impact of intoxication on the response and outcome to injuries such as burn. While much research has focused on the effect of alcohol dose and duration on the subsequent inflammatory parameters following burn, little evidence exists on the effect of the route of alcohol administration. We examined the degree to which intoxication before burn injury causes systemic inflammation when ethanol is given by intraperitoneal (i.p.) injection or oral gavage. We found that intoxication potentiates postburn damage in the ileum, liver, and lungs of mice to an equivalent extent when either ethanol administration route is used. We also found a similar hematologic response and levels of circulating interleukin-6 (IL-6) when either ethanol paradigm achieved intoxication before burn. Furthermore, both i.p. and gavage resulted in similar blood alcohol concentrations at all time points tested. Overall, our data show an equal inflammatory response to burn injury when intoxication is achieved by either i.p. injection or oral gavage, suggesting that findings from studies using either ethanol paradigm are directly comparable.

Migration of immature and mature B cells in the aged microenvironment.

Studies in aged mice show that the architecture of B-cell areas appears disrupted and that newly made B cells fail to incorporate into the spleen. These observations may reflect altered migration of immature and mature B cells. Using adoptive transfer, we tested the effect of the aged microenvironment and the intrinsic ability of donor B cells from aged mice to migrate to spleens of intact hosts. Spleens of aged recipients were deficient in attracting young or old donor immature B cells. In contrast, immature and mature B cells maintained an intrinsic ability to migrate to young recipient spleens, except that as the aged immature B cells matured, fewer appeared to enter the recirculating pool. CXCL13 protein, which is necessary for the organization of B-cell compartments, was elevated with age and differences in CXCL13 distribution were apparent. In aged spleens, CXCL13 appeared less reticular, concentrated in patches throughout the follicles, and notably reduced in the MAdCAM-1(+) marginal reticular cells located at the follicular edge. Despite these differences, the migration of young donor follicular B cells into the spleens of old mice was not impacted; whereas, migration of young donor marginal zone B cells was reduced in aged recipients. Finally, the aged bone marrow microenvironment attracted more donor mature B cells than did the young marrow. Message for CXCL13 was not elevated in the marrow of aged mice. These results suggest that the aged splenic microenvironment affects the migration of immature B cells more than mature follicular B cells.

Alcohol potentiates postburn remote organ damage through shifts in fluid compartments mediated by bradykinin.

Of the 450,000 burn patients each year, 50% have a positive blood alcohol content, and this predisposes them to worsened clinical outcomes. Despite high prevalence and established consequences, the mechanisms responsible for alcohol-mediated complications of postburn remote organ damage are currently unknown. To this end, mice received a single dose of alcohol (1.12 g/kg) or water by oral gavage and were subjected to a 15% total body surface area burn. Animals with a burn alone lost ∼5% of their body weight in 24 h, whereas intoxicated and burned mice lost only 1% body weight (P < 0.05) despite a 17% increase in hematocrit (P < 0.05) and a 57% increase in serum creatinine (P < 0.05) over burn injury alone. This retention of water weight despite increased dehydration suggests that intoxication at the time of a burn causes a shift in fluid compartments that may exacerbate end-organ ischemia and damage as evidenced by a 3-fold increase in intestinal bacterial translocation (P < 0.05), a 30% increase (P < 0.05) in liver weight-to-body weight ratio, and an increase in alveolar wall thickness over a burn alone. Furthermore, administration of the bradykinin antagonist HOE140 30 min after intoxication and burn restored fluid balance and alleviated end-organ damage. These findings suggest that alcohol potentiates postburn remote organ damage through shifts in fluid compartments mediated by bradykinin.

Extracellular traps and macrophages: new roles for the versatile phagocyte.

MΦ are multipurpose phagocytes with a large repertoire of well-characterized abilities and functions, including regulation of inflammation, wound healing, maintenance of tissue homeostasis, as well as serving as an integral component of the innate-immune defense against microbial pathogens. Working along with neutrophils and dendritic cells, the other myeloid-derived professional phagocytes, MΦ are one of the key effector cells initiating and directing the host reaction to pathogenic organisms and resolving subsequent responses once the threat has been cleared. ETs are a relatively novel strategy of host defense involving expulsion of nuclear material and embedded proteins from immune cells to immobilize and kill bacteria, fungi, and viruses. As research on ETs expands, it has begun to encompass many immune cell types in unexpected ways, including various types of MΦ, which are not only capable of generating METs in response to various stimuli, but recent preclinical data suggest that they are an important agent in clearing ETs and limiting ET-mediated inflammation and tissue damage. This review aims to summarize historical and recent findings of biologic research regarding ET formation and function and discuss the role of MΦ in ET physiology and associated pathologies.

Alcohol and inflammatory responses: summary of the 2013 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

Loyola University Chicago, Health Sciences Campus in Maywood, Illinois hosted the 18th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting on November 22, 2013. This year's meeting emphasized alcohol's effect on inflammatory responses in diverse disease states and injury conditions. The meeting consisted of three plenary sessions demonstrating the adverse effects of alcohol, specifically, liver inflammation, adverse systemic effects, and alcohol's role in infection and immunology. Researchers also presented insight on modulation of microRNAs and stress proteins following alcohol consumption. Additionally, researchers revealed sex- and concentration-dependent differences in alcohol-mediated pathologies.

Alcohol and immunology: Summary of the 2012 Alcohol and Immunology Research Interest Group (AIRIG) meeting.

On October 27, 2012, the 17th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at the Grand Wailea Hotel in Maui, Hawaii as a satellite meeting to the 2012 Society of Leukocyte Biology conference. This year's meeting focused on the influence of alcohol on signal transduction pathways in various disease and injury models. Three plenary sessions were held where invited speakers shared their research on alcohol-mediated alterations of cell signaling components, immune cell subsets, and inflammation. These studies suggested alcohol has a negative effect on cell signaling machinery and immune cell homeostasis, resulting in disease, disease progression, and increased mortality. Researchers also identified tissue-specific alcohol-linked elevations in markers of inflammation, including cold-shock proteins and microRNAs. Additionally, one study revealed the effects of alcohol on immune cell subsets in a model of allergic asthma.

The effects of microenvironment and internal programming on plasma cell survival.

Two populations of plasma cells (PCs) are formed after immunization. A short-lived population in the spleen and lymph nodes provides rapid protection. A long-lived population, mainly in the bone marrow, provides lasting immunity. The mechanisms responsible for the differences in PCs life span remain largely unknown. The goal of the current study was to compare the intrinsic survival capacity of isolated short-lived (spleen) versus long-lived (bone marrow) PCs. We approached this question by using a previously established in vitro model that measures PC survival in a supportive stromal environment. Regardless of the tissue source or isolation time point after immunization, the two PC populations showed similar intrinsic ability to survive in vitro. To test differences in the stromal microenvironments, stromal cells from marrow, spleen or lymph nodes were evaluated for ability to support PCs survival. Survival of isolated PC was always greater when co-cultured with marrow stromal cells compared with those from spleen (or lymph node) despite the finding that IL-6, necessary for PC survival in culture, was secreted by all three stromal cell sources. Additionally, low expression of B-cell-activating factor belonging to the tumor necrosis factor-family was detected in all three stromal isolates. In contrast, marrow stromal cells were distinguished by cell-surface phenotype and CXC chemokine ligand (CXCL)12, IL-7 and stem cell factor expression. Although CXCL12 has been suggested as a possible survival factor for PC, addition or neutralization of CXCL12 had minimal effect on PC survival. We conclude the mechanisms regulating PC longevity appear extrinsically driven and marrow favored, but the factors that give marrow stromal cells a unique advantage remain unknown.