M. Breitenbach, R. Crameri, and S. B. Lehrer. Fungal Allergy and Pathogenicity .

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43274/1/11046_2004_Article_5122151.pd

T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7-/- mice

Abstract Background C-C chemokine receptor (CCR)7 is a regulator of dendritic cell and T cell migration, and its role in tissue wound healing has been investigated in various disease models. We have previously demonstrated that CCR7 and its ligand, chemokine (C-C motif) ligand (CCL)21, modulates wound repair in pulmonary fibrosis (PF) but the mechanism of this is unknown. The objective of this study was to investigate whether the absence of CCR7 protects against bleomycin (BLM)-induced PF. CCR7-/- mice failed to mount a fibrotic pulmonary response as assessed by histologic collagen staining and quantification by hydroxyproline. We hypothesized that the prominent characteristics of CCR7-/- mice, including elevated levels of cytokine and chemokine mediators and the presence of bronchus-associated lymphoid tissue (BALT) might be relevant to the protective phenotype. Results Pulmonary fibrosis was induced in CCR7+/+ and CCR7-/- mice via a single intratracheal injection of BLM. We found that the lung cytokine/chemokine milieu associated with the absence of CCR7 correlated with an increase in BALT, and might be attributable to regulatory T cell (Treg) homeostasis and trafficking within the lungs and lymph nodes. In response to BLM challenge, CCR7-/- mice exhibited an early, steady increase in lung CD4+ T cells and increased CD4+ CD25+ FoxP3+ Tregs in the lungs 21 days after challenge. These findings are consistent with increased lung expression of interleukin-2 and indoleamine 2,3-dioxygenase in CCR7-/- mice, which promote Treg expansion. Conclusions Our study demonstrates that the protective phenotype associated with BLM-treated CCR7-/- mice correlates with the presence of BALT and the anchoring of Tregs in the lungs of CCR7-/- mice. These data provide novel evidence to support the further investigation of CCR7-mediated Treg trafficking in the modulation of BLM-induced PF.http://deepblue.lib.umich.edu/bitstream/2027.42/112768/1/13069_2010_Article_33.pd

IL-18 modulates chronic fungal asthma in a murine model; putative involvement of Toll-like receptor-2

Fungus-induced asthmatic disease is characterized by persistent airway hyperreactivity and remodeling.¶ Objective and design: To determine the role of IL-18 in the allergic airway response to Aspergillus fumigatus conidia in a murine model of A. fumigatus -induced asthma.¶ Methods: A. fumigatus -sensitized mice were depleted of IL-18 using a polyclonal anti-IL-18 antibody for 3 days after a conidia challenge.¶ Results: Airway hyperresponsiveness and eosinophil numbers were significantly elevated 3-30 days after conidia challenge compared to the normal serum-treated group. Histological evidence showed retention of A. fumigatus conidia, airway remodeling, subepithelial fibrosis, and increased collagen deposition in the lungs of IL-18-depleted mice at day 30 after the conidia challenge. Prolonged retention of conidia in IL-18 depleted A. fumigatus -sensitized mice was associated with decreased Toll-like receptor-2 (TLR-2) expression compared with the control group.¶ Conclusions: IL-18 modulates the innate immune response against A. fumigatus conidia and prevents the development of severe fungus-induced asthmatic disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41823/1/11-50-11-552_10500552.pd

Acute inhibition of nitric oxide exacerbates airway hyperresponsiveness, eosinophilia and C-C chemokine generation in a murine model of fungal asthma

Objective and Design: This study examined he role of nitric oxide in changes in airway physiology and inflammation in a murine model of fungal allergy induced by Aspergillus fumigatus (A. fumigatus) by treatment of A. fumigatus-sensitized mice with NG-nitro-L-arginine methyl ester (L-NAME) or D-NAME (8 mg/kg; i.p.).¶ Materials and Methods: Female CBA/J mice received A. fumigatus antigen dissolved in incomplete Freund's adjuvant (10 mg/100 ml i.p. and s.c.) followed 2 weeks later by A. fumigatus antigens (20 mg; i.n.) and a subsequent i.t. challenge 4 days later. Airway physiology and inflammation were examined (24 to 72 h) following i.t. challenge.¶ Results: L-NAME-treated mice had lower lung nitrite levels 24 h after A. fumigatus challenge, but higher airway hyperresponsiveness and inflammation compared to D-NAME controls. Airway inflammation in the L-NAME treatment group (72 h) was characterized by a greater bronchoalveolar lavage (BAL), peribronchial eosinophilia and augmented levels of CC chemokines compared to controls.¶ Conclusions: These findings suggest that nitric oxide is an important modulator of airway hyperresponsiveness, inflammation and C-C chemokine generation during allergic airway responses to A. fumigatus.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41821/1/11-49-6-297_00490297.pd

The chemokine receptor CCR6 is an important component of the innate immune response

In our initial studies we found that naÏve CCR6-deficient (CCR6 –/– ) C57BL/6 mice possessed significantly lower number of both F4/80 + macrophages and dendritic cells (DC), but higher number of B cells in the peritoneal cavity, as compared to naÏve wild type (WT) controls. Furthermore, peritoneal macrophages isolated from CCR6 –/– mice expressed significantly lower levels of inflammatory cytokines and nitric oxide following lipopolysaccharide (LPS)stimulation, as compared to WT macrophages. In a severe experimental peritonitis model induced by cecal ligation and puncture (CLP), CCR6 –/– mice were protected when compared with WT controls. At 24 h following the induction of peritonitis, CCR6 –/– mice exhibited significantly lower levels of inflammatory cytokines/chemokines in both the peritoneal cavity and blood. Interestingly, DC recruitment into the peritoneal cavity was impaired in CCR6 –/– mice during the evolution of CLP-induced peritonitis. Peritoneal macrophages isolated from surviving CCR6 –/– mice 3 days after CLP-induced peritonitis exhibited an enhanced LPS response compared with similarly treated WT peritoneal macrophages. These data illustrate that CCR6 deficiency alters the innate response via attenuating the hyperactive local and systemic inflammatory response during CLP-induced peritonitis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56112/1/2487_ftp.pd

A systemic granulomatous response to Schistosoma mansoni eggs alters responsiveness of bone marrow‐derived macrophages to Toll‐like receptor agonists

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141008/1/jlb0314.pd

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

Macrophage/fibroblast coculture induces macrophage inflammatory protein‐1a production mediated by intercellular adhesion molecule‐1 and oxygen radicals

This study examined the cell‐to‐cell interaction between fibroblasts and macrophages as a possible contributor to the chronic inflammatory state. In a coculture system, consisting of macrophages layered over confluent fibroblasts, there was a significant increase in macrophage inflammatory protein 1α (MIP‐1α) compared with control cultures. ICAM‐1 adhesion was identified as an important stimulus of MIP‐1α production by using ICAM‐1‐specific monoclonal antibodies. Furthermore, fibroblasts from ICAM‐1 knockout mice induced significantly less MIP‐1α production from peritoneal macrophages when compared to control fibroblasts. In addition, it appeared that oxygen radicals functioned as activating molecules during cellular interaction and production of MIP‐1α, as the addition of the antioxidant N‐acetylcysteine (NAC) prevented MIP‐1α secretion. Thus, the ICAM‐1 and oxygen radical‐mediated induction of MIP‐1α associated with a macrophage/fibroblast coculture system provides one possible mechanism by which immune/inflammatory cell interactions may augment chemokine production and exacerbate chronic inflammatory diseases. J. Leukoc. Biol. 64: 636–641; 1998.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141120/1/jlb0636.pd