IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration.

Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2-/- mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation.

Expression of high-mobility group box 1 and of receptor for advanced glycation end products in chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is characterized by airway inflammation and remodeling. High-mobility group box 1 (HMGB1), a nuclear protein that is released during inflammation and repair, interacts with proinflammatory cytokines and with the receptor for advanced glycation end products (RAGE), which is highly expressed in the lung. OBJECTIVES: To determine whether HMGB1 is augmented in COPD and is associated with IL-1beta and RAGE. METHODS: HMGB1 was assessed in the bronchoalveolar lavage (BAL) of 20 never-smokers, 20 smokers, and 30 smokers with COPD and it was correlated with inflammatory and clinical parameters. In parallel, HMGB1 and RAGE immunolocalization was determined in bronchial and lung tissues. Last, binding of HMGB1 to IL-1beta in human macrophages and in BAL fluid was examined. MEASUREMENTS AND MAIN RESULTS: BAL levels of HMGB1 were higher in smokers with COPD than in smokers and never-smokers (P < 0.0001 for both comparisons), and similar differences were observed in epithelial cells and alveolar macrophages. BAL HMGB1 correlated positively with IL-1beta (r(s) = 0.438; P = 0.0006) and negatively with FEV(1) (r(s) = -0.570; P < 0.0001) and transfer factor of the lung for carbon monoxide (r(s) = -0.382; P = 0.0026). HMGB1-IL-1beta complexes were found in BAL supernatant and alveolar macrophages from smokers and patients with COPD, as well as in the human macrophage cell line, THP-1, where they enhanced the synthesis of tumor-necrosis factor-alpha. RAGE was overexpressed in the airway epithelium and smooth muscle of patients with COPD and it colocalized with HMGB1. CONCLUSIONS: Elevated HMGB1 expression in COPD airways may sustain inflammation and remodeling through its interaction with IL-1beta and RAGE.

A role for Bid in eosinophil apoptosis and in allergic airway reaction.

Bid, a proapoptotic member of Bcl-2 family, is involved in Fas receptor signaling. Fas activation promotes human eosinophil cell death and is believed to accelerate the resolution of pulmonary Th2-driven allergic reaction in mice. We hypothesized that Bid would regulate eosinophil apoptosis and Ag-induced airway inflammation, particularly eosinophilia. C57BL/6 Bid(-/-) and wild-type mice were immunized and repeatedly challenged with OVA, and bronchoalveolar lavage (BAL) fluid, lung, and spleen were collected 4-240 h after the final challenge. Cultured BAL eosinophils from Bid-deficient mice showed resistance to Fas-mediated apoptotic DNA fragmentation, phosphatidylserine exposure, mitochondria depolarization, and caspase-3 activity. In addition, OVA-challenged Bid(-/-) mice had higher BAL eosinophilia and a lower proportion of BAL apoptotic eosinophils than Bid(+/+) mice. This was accompanied by augmented BAL levels of the eosinophilotactic cytokine, IL-5, and of the eosinophil-associated mediators, TGF-beta1 and fibronectin. Finally, cultured OVA-stimulated lung mononuclear cells and splenocytes from Bid-deficient mice showed increased release of the Th2-type cytokines, IL-4 and IL-5, but no change in cell number. We conclude that Bid modulates BAL eosinophilia by regulating both eosinophil apoptosis and Th2-type cytokine production.

Liposomal retinoic acids modulate asthma manifestations in mice.

Signaling of all-trans retinoic acid (ATRA) through nuclear retinoid acid (RA) receptors regulates several biological functions in airway epithelial cells, eosinophils, and immune cells, yet its impact on different in vivo aspects of pulmonary allergic reaction remains elusive. We compared the effect of a treatment with liposomally encapsulated ATRA (Lipo-ATRA) in a mouse model of ovalbumin (OVA)-induced T helper (Th) 2-type responses and airway remodeling. Daily intraperitoneal injections of 10 mg/kg Lipo-ATRA, at the time of each of the 2 systemic sensitizing injections, increased OVA-induced Immunoglobulin E synthesis, bronchoalveolar lavage (BAL) eosinophilia, and accumulation of IL-5, transforming-growth factor beta1, fibronectin, eotaxin/chemokine (C-C motif) ligand 11 (eotaxin/CCL11) and regulated upon activation, normal T expressed and secreted chemokine (C-C motif) ligand 5. In contrast, Lipo-ATRA, administered during each of the 4 intranasal OVA challenges, did not affect these variables. Regardless of the treatment regimen, Lipo-ATRA augmented mucin levels in BAL fluid and reduced lung total collagen content. In vitro incubation of mouse splenocytes or purified spleen cluster of differentiation (CD) 4-positive T lymphocytes, with ATRA, increased, respectively, OVA- and anti-CD 3 antibody-induced IL-4 and IL-5 production and inhibited IFNgamma release. These findings demonstrate that, when given during systemic sensitization, Lipo-ATRA exacerbates allergic immune and inflammatory responses, most likely by promoting Th2 development.

T cell-derived TNF down-regulates acute airway response to endotoxin.

Acute and chronic airway inflammations caused by environmental agents including endotoxin represent an increasing health problem. Local TNF production may contribute to lung dysfunction and inflammation, although pulmonary neutrophil recruitment occurs in the absence of TNF. First, we demonstrate that membrane-bound TNF is sufficient to mediate the inflammatory responses to lipopolysaccharide (LPS). Secondly, using cell type-specific TNF-deficient mice we show that TNF derived from either macrophage/neutrophil (M/N) or T lymphocytes have differential effects on LPS-induced respiratory dysfunction (enhanced respiratory pause, Penh) and pulmonary neutrophil recruitment. While Penh, vascular leak, neutrophil recruitment, TNF, and thymus- and activation-regulated chemokine/CCL17 (TARC) expression in the lung were reduced in M/N-deficient mice, T cell-specific TNF-deficient mice displayed augmented Penh, vascular leak, neutrophil influx, increased CD11c+ cells and expression of TNF, TARC and murine CXC chemokines KC/CXCL1 in the lung. In conclusion, inactivation of TNF in either M/N or T cells has differential effects on LPS-induced lung disease, suggesting that selective deletion of TNF in T cells may aggravate airway pathology.