Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages

Abstract Background Interleukin-33 is a member of the IL-1 cytokine family whose functions are mediated and modulated by the ST2 receptor. IL-33-ST2 expression and interactions have been explored in mouse macrophages but little is known about the effect of IL-33 on human macrophages. The expression of ST2 transcript and protein levels, and IL-33-mediated effects on M1 (i.e. classical activation) and M2 (i.e. alternative activation) chemokine marker expression in human bone marrow-derived macrophages were examined. Results Human macrophages constitutively expressed the membrane-associated (i.e. ST2L) and the soluble (i.e. sST2) ST2 receptors. M2 (IL-4 + IL-13) skewing stimuli markedly increased the expression of ST2L, but neither polarizing cytokine treatment promoted the release of sST2 from these cells. When added to naïve macrophages alone, IL-33 directly enhanced the expression of CCL3. In combination with LPS, IL-33 blocked the expression of the M2 chemokine marker CCL18, but did not alter CCL3 expression in these naive cells. The addition of IL-33 to M1 macrophages markedly increased the expression of CCL18 above that detected in untreated M1 macrophages. Similarly, alternatively activated human macrophages treated with IL-33 exhibited enhanced expression of CCL18 and the M2 marker mannose receptor above that detected in M2 macrophages alone. Conclusions Together, these data suggest that primary responses to IL-33 in bone marrow derived human macrophages favors M1 chemokine generation while its addition to polarized human macrophages promotes or amplifies M2 chemokine expression.http://deepblue.lib.umich.edu/bitstream/2027.42/78250/1/1471-2172-11-52.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78250/2/1471-2172-11-52.pdfPeer Reviewe

The Role of CC Chemokine Receptor 7 During Pulmonary Invasive Aspergillosis.

Invasive aspergillosis (IA) is a serious, life-threatening disease caused by the mold Aspergillus fumigatus (A. fumigatus). IA primarily affects immunocompromised individuals, and is especially common among hematopoietic stem cell transplantation (HSCT) patients. Immune strategies directed at promoting antifungal responses following HSCT hold promise. In particular, alteration of chemokines and their receptors have been shown to markedly modulate the immune response against A. fumigatus. Examples include chemokine receptor 1 (CCR1), CCR2, CCR4, CCR6, CXCR2, and their associated chemokine ligands. However, more recently it was shown that Aspergillus infection upregulates CC chemokine receptor 7 (CCR7) expression on dendritic cells, a major effector cell mediating antifungal immune responses in the lung. CCR7 via activation by chemokine ligand 19 (CCL19) and chemokine ligand 21 (CCL21) is a key trafficking receptor found on naïve lymphocytes and mature dendritic cells. In addition, CCR7 gene transcripts are found in hematopoietic stem cells and myeloid progenitor cells. Given the role of CCR7 for immune cell trafficking, we hypothesized that CCR7 would be an important chemokine receptor during IA. To test our hypothesis, we utilized two distinct murine models of immunosuppression. In our first model, we describe a potentially deleterious role for CCR7 during primary immune responses directed against A. fumigatus following antibody-induced neutropenia. CCR7-deficient chimeric mice displayed significantly reduced mortality, which correlated with rapid fungal clearance and increased effector responses by myeloid dendritic cells compared to wild-type chimeras. In our second model, we demonstrate a novel inhibitory role for CCR7 on hematopoietic stem cell and myeloid progenitor cell proliferation following HSCT. Mice reconstituted with CCR7-deficient hematopoietic stem cells and myeloid progenitors had greater numbers of immune cells in the lung 14 days after transplantation, compared with mice receiving wild-type hematopoietic stem cells and myeloid progenitors, and this resulted in accelerated fungal clearance in A. fumigatus challenged mice. Collectively, our results demonstrate a detrimental role for CCR7 during primary immune responses against A. fumigatus and following HSCT, and suggest CCR7 as a new target for the treatment and prevention of IA.Ph.D.ImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/63754/1/ajhart_1.pd

Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-b superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.Stem Cell and Regenerative Biolog