Temporal Dynamics of Reactive Oxygen and Nitrogen Species and NF-κB Activation During Acute and Chronic T Cell-Driven Inflammation.

PURPOSE: Reactive oxygen and nitrogen species (ROS/RNS) production and the NF-κB activation are critically involved in inflammatory responses, but knowledge about the temporal dynamics during acute and chronic inflammation is limited. Here, we present a comparative longitudinal in vivo study of both parameters in an experimental model of acute and chronic T cell-driven delayed-type hypersensitivity reaction (DTHR) using noninvasive optical imaging. PROCEDURES: Trinitrochlorobenzene (TNCB)-sensitized NF-κB-luciferase-reporter and wild-type mice were TNCB challenged on the right ear to elicit acute DTHR and then repetitively challenged (up to five times) to induce chronic DTHR. Mice were treated with the ROS-scavenging and NF-κB inhibiting molecule N-acetylcysteine (NAC) or underwent sham treatment. ROS/RNS production was noninvasively analyzed in vivo using the ROS-/RNS-sensitive chemiluminescent probe L-012, and NF-κB activation was measured using NF-κB-luciferase-reporter mice. H&E staining, CD3 and myeloperoxidase (MPO) immunohistochemistry (IHC), and quantitative PCR (qPCR) analyses were employed to investigate immune cell infiltration and expression of NF-κB- and ROS-/RNS-driven genes. RESULTS: In acute DTHR, we found strongly elevated ROS/RNS production and NF-κB activation 12 h after the 1st TNCB ear challenge, peaking at 24 h after the challenge. In chronic DTHR, ROS production peaked as early as 4 h after the 5th TNCB challenge, whereas NF-κB activity peaked after 12 h. The increase in ROS/RNS production in acute DTHR was higher than the increase in NF-κB activity but the relationship was inverse in chronic DTHR. Treatment with the ROS scavenger NAC had differential effects on ROS/RNS production and NF-κB activation during acute and chronic DTHR. Ex vivo cross-validation by histopathology and qPCR analysis correlated closely with the in vivo imaging results. CONCLUSIONS: Noninvasive in vivo imaging is capable of assessing the temporal dynamics of ROS/RNS production and NF-κB activation during progression from acute to chronic DTHR and enables monitoring of anti-inflammatory treatment responses.

Weak Agonistic LPS Restores Intestinal Immune Homeostasis.

Generated by gram-negative bacteria, lipopolysaccharides (LPSs) are one of the most abundant and potent immunomodulatory substances present in the intestinal lumen. Interaction of agonistic LPS with the host myeloid-differentiation-2/Toll-like receptor 4 (MD-2/TLR4) receptor complex results in nuclear factor κB (NF-κB) activation, followed by the robust induction of pro-inflammatory immune responses. Here we have isolated LPS from a common gut commensal, Bacteroides vulgatus mpk (BVMPK), which provides only weak agonistic activity. This weak agonistic activity leads to the amelioration of inflammatory immune responses in a mouse model for experimental colitis, and it was in sharp contrast to strong agonists and antagonists. In this context, the administration of BVMPK LPS into mice with severe intestinal inflammation re-established intestinal immune homeostasis within only 2 weeks, resulting in the clearance of all symptoms of inflammation. These inflammation-reducing properties of weak agonistic LPS are grounded in the induction of a special type of endotoxin tolerance via the MD-2/TLR4 receptor complex axis in intestinal lamina propria CD11c+ cells. Thus, weak agonistic LPS represents a promising agent to treat diseases involving pathological overactivation of the intestinal immune system, e.g., in inflammatory bowel diseases.

Anti-inflammatory role of CD11b+Ly6G+ neutrophilic cells in allergic airway inflammation in mice.

Asthma is a chronic inflammatory disease driven by overactivation of T helper cell type 2 (Th2) responses. In the present study, we investigated the functional relevance of CD11b+Ly6G+ neutrophilic cells in allergic airway inflammation in vivo. Allergic airway inflammation in mice was induced by house dust mite (HDM) or ovalbumin (OVA) sensitization and challenge. CD11b+Ly6G+ neutrophilic cells and T cell phenotypes were quantified by flow cytometry. To assess the functional in vivo relevance, CD11b+Ly6G+ neutrophilic cells were adoptively transferred intravenously or intratracheally and consequences on airway inflammation were studied. Adoptively transferred CD11b+Ly6G+ neutrophilic cells attenuated Th2 and Th17 responses and airway inflammation in vivo. Collectively, our results demonstrate that CD11b+Ly6G+ neutrophilic cells suppress airway inflammation in allergic mice in vivo. Adoptive cellular transfer of suppressive neutrophilic cells may represent an attractive therapeutic strategy for allergic airway inflammation.

The emerging role of myeloid-derived suppressor cells in lung diseases.

Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterised by their potential to control T-cell responses and to dampen inflammation. While the role of MDSCs in cancer has been studied in depth, our understanding of their relevance for infectious and inflammatory disease conditions has just begun to evolve. Recent studies highlight an emerging and complex role for MDSCs in pulmonary diseases. In this review, we discuss the potential contribution of MDSCs as biomarkers and therapeutic targets in lung diseases, particularly lung cancer, tuberculosis, chronic obstructive pulmonary disease, asthma and cystic fibrosis.