Pulmonary tissue damage resulting from influenza virus infection is caused by both the cytolytic activity of the virus and the host immune response. Immune-mediated injury results from T cell-mediated destruction of virus-infected cells and by release of cytokines and chemokines that attract polymorphonuclear leukocytes (PML) and macrophages to the infected site. The cytokines/chemokines potentiate dendritic cell (DC) activation and T cell expansion, which further enhances local damage. Here we report that immune modulation by local administration to the respiratory tract of sphingosine analog AAL-R significantly dampens the release of cytokines and chemokines while maintaining protective neutralizing antibody and cytotoxic T cell responses. As a result there was a marked reduction of infiltrating PML and macrophages into the lung and resultant pulmonary tissue injury. DC maturation was suppressed, which limited proliferation of specific antiviral T cells in the lung and draining lymph nodes. Further, AAL-R was effective in controlling CD8 ⁺ T cell accumulation in the lungs even when given 4 days after initiation of influenza virus infection. These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus.

The etiology of bioaerosol-related pulmonary diseases remains poorly understood. Recently, archaea emerged as prominent airborne components of agricultural environments, but the consequences of airway exposure to archaea remain unknown. Since subcomponents of archaea can be immunogenic, we used a murine model to study the pulmonary immune responses to two archaeal species found in agricultural facilities: Methanobrevibacter smithii (MBS) and Methanosphaera stadtmanae (MSS). Mice were administered intranasally with 6.25, 25 or 100 µg of MBS or MSS, once daily, 3 days a week, for 3 weeks. MSS induced more severe histopathological alterations than MBS with perivascular accumulation of granulocytes, pronounced thickening of the alveolar septa, alveolar macrophages accumulation and increased perivascular mononucleated cell accumulation. Analyses of bronchoalveolar lavage fluids revealed up to 3 times greater leukocyte accumulation with MSS compared to MBS. Instillation of 100 µg of MBS or MSS caused predominant accumulation of monocyte/macrophages (4.5×10⁵ and 4.8×10⁵ cells/ml respectively) followed by CD4⁺ T cells (1.38×10⁵ and 1.94×10⁵ cells/ml respectively), B cells (0.73×10⁵ and 1.28×10⁵ cells/ml respectively), and CD8⁺ T cells (0.20×10⁵ and 0.31×10⁵ cells/ml respectively) in the airways. Both archaeal species induced similar titers of antigen-specific IgGs in plasma. MSS but not MBS caused an accumulation of eosinophils and neutrophils in the lungs, which surprisingly, correlated inversely with the size of the inoculum. Stronger immunogenicity of MSS was confirmed by a 3 fold higher accumulation of myeloid dendritic cells in the airways, compared to MBS. Thus, the dose and species of archaea determine the magnitude and nature of the pulmonary immune response. This is the first report of an immunomodulatory role of archaeal species found in bioaerosols.

Sequential accumulation of M1 and M2 macrophages is critical for skeletal muscle recovery after an acute injury. While M1 accumulation is believed to rely on monocyte infiltration, the mechanisms of M2 accumulation remain controversial, but could involve an infiltrating precursor. Yet, strong depletion of monocytes only partially impairs skeletal muscle healing, supporting the existence of alternative mechanisms to palliate the loss of infiltrating macrophage progenitors. The aims of this study are thus to investigate if proliferation occurs in macrophage subsets within injured skeletal muscles; and to determine if monocyte depletion leads to increased proliferation of macrophages after injury.

The endocannabinoids 2-arachidonoyl-glycerol and N-arachidonoyl-ethanolamine mediate an array of pro- and anti-inflammatory effects. These effects are related, in part, to their metabolism by eicosanoid biosynthetic enzymes. For example, N-arachidonoyl-ethanolamine and 2-arachidonoyl-glycerol can be metabolized by cyclooxygenase-2 into PG-ethanolamide (PG-EA) and PG-glycerol (PG-G), respectively. Although PGE₂ is a recognized suppressor of neutrophil functions, the impact of cyclooxygenase-derived endocannabinoids such as PGE₂-EA or PGE₂-G on neutrophils is unknown. This study’s aim was to define the effects of these mediators on neutrophil functions and the underlying cellular mechanisms involved. We show that PGE₂-G, but not PGE₂-EA, inhibits leukotriene B₄ biosynthesis, superoxide production, migration, and antimicrobial peptide release. The effects of PGE₂-G were prevented by EP₁/EP₂ receptor antagonist AH-6809 but not the EP₄ antagonist ONO-AE2-227. The effects of PGE₂-G required its hydrolysis into PGE₂, were not observed with the non-hydrolyzable PGE₂-serinol amide, and were completely prevented by methyl-arachidonoyl-fluorophosphate and palmostatin B, and partially prevented by JZL184 and WWL113. Although we could detect six of the documented PG-G hydrolases in neutrophils by quantitative PCR, only ABHD12 and ABHD16A were detected by immunoblot. Our pharmacological data, combined with our protein expression data, did not allow us to pinpoint one PGE₂-G lipase, and rather support the involvement of an uncharacterized lipase and/or of multiple hydrolases. In conclusion, we show that PGE₂-G inhibits human neutrophil functions through its hydrolysis into PGE₂, and by activating the EP₂ receptor. This also indicates that neutrophils could regulate inflammation by altering the balance between PG-G and PG levels in vivo.

Anne-Marie Lemay, Olivier Courtemanche, Timothy A. Couttas, Giuleta Jamsari, Andréanne Gagné, Yohan Bossé, Philippe Joubert, Anthony S. Don, David Marsolais