Search

International audience; Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.

Contains fulltext : 138552.pdf (Publisher’s version ) (Open Access) We have recently shown that BCG (Bacillus Calmette-Guerin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named 'trained immunity'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFalpha and IL-1beta to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months postvaccination, but these effects were less pronounced 1 year after vaccination. However, monocytes recovered 1 year after vaccination had an increased expression of pattern recognition receptors such as CD14, Toll-like receptor 4 (TLR4) and mannose receptor, and this correlated with an increase in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-gamma) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses. (c) 2013 S. Karger AG, Basel.

International audience; Inflammation-related dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is central to the course of systemic inflammatory response syndrome or sepsis. The underlying mechanisms, however, are not well understood. Initial activation of adrenocortical hormone production during early sepsis depends on the stimulation of hypothalamus and pituitary mediated by cytokines; in late sepsis, there is a shift from neuroendocrine to local immune-adrenal regulation of glucocorticoid production. Therefore, the modulation of the local immune-adrenal cross talk, and not of the neuroendocrine circuits involved in adrenocorticotropic hormone production, may be more promising in the prevention of the adrenal insufficiency associated with prolonged sepsis. In the present work, we investigated the function of the crucial Toll-like receptor (TLR) adaptor protein myeloid differentiation factor 88 (MyD88) in systemic and local activation of adrenal gland inflammation and glucocorticoid production mediated by lipopolysachharides (LPSs). To this end, we used mice with a conditional MyD88 allele. These mice either were interbred with Mx1 Cre mice, resulting in systemic MyD88 deletion, predominantly in the liver and hematopoietic system, or were crossed with Akr1b7 Cre transgenic mice, resulting thereby in deletion of MyD88, which was adrenocortical-specific. Although reduced adrenal inflammation and HPA-axis activation mediated by LPS were found in Mx1(Cre+)-MyD88(fl/fl) mice, adrenocortical-specific MyD88 deletion did not alter the adrenal inflammation or HPA-axis activity under systemic inflammatory response syndrome conditions. Thus, our data suggest an important role of immune cell rather than adrenocortical MyD88 for adrenal inflammation and HPA-axis activation mediated by LPS.

Bone resorption by osteoclasts and bone formation by osteoblasts are tightly coupled processes implicating factors in TNF, bone morphogenetic protein, and Wnt families. In osteoimmunology, macrophages were described as another critical cell population regulating bone formation by osteoblasts but the coupling factors were not identified. Using a high-throughput approach, we identified here Oncostatin M (OSM), a cytokine of the IL-6 family, as a major coupling factor produced by activated circulating CD14+ or bone marrow CD11b+ monocytes/macrophages that induce osteoblast differentiation and matrix mineralization from human mesenchymal stem cells while inhibiting adipogenesis. Upon activation of toll-like receptors (TLRs) by lipopolysaccharide or endogenous ligands, OSM was produced in classically activated inflammatory M1 and not M2 macrophages, through a cyclooxygenase-2 and prostaglandin-E2 regulatory loop. Stimulation of osteogenesis by activated monocytes/macrophages was prevented using neutralizing antibodies or siRNA to OSM, OSM receptor subunits gp130 and OSMR, or to the downstream transcription factor STAT3. The induced osteoblast differentiation program culminated with enhanced expression of CCAAT-enhancer-binding protein δ, Cbfa1, and alkaline phosphatase. Overexpression of OSM in the tibia of mice has led to new bone apposition with no sign of bone resorption. Two other cytokines have also a potent role in bone formation induced by monocytes/macrophages and activation of TLRs: IL-6 and leukemia inhibitory factor. We propose that during bone inflammation, infection, or injury, the IL-6 family signaling network activated by macrophages and TLR ligands stimulates bone formation that is largely uncoupled from bone resorption and is thus an important target for anabolic bone therapies. Disclosure of potential conflicts of interest is found at the end of this article.

The CDKN2A locus, which contains the tumor suppressor gene p16INK4a, is associated with an increased risk of age-related inflammatory diseases, such as cardiovascular disease and type 2 diabetes, in which macrophages play a crucial role. Monocytes can polarize toward classically (CAMφ) or alternatively (AAMφ) activated macrophages. However, the molecular mechanisms underlying the acquisition of these phenotypes are not well defined. Here, we show that p16INK4a deficiency (p16−/−) modulates the macrophage phenotype. Transcriptome analysis revealed that p16−/− BM-derived macrophages (BMDMs) exhibit a phenotype resembling IL-4–induced macrophage polarization. In line with this observation, p16−/− BMDMs displayed a decreased response to classically polarizing IFNγ and LPS and an increased sensitivity to alternative polarization by IL-4. Furthermore, mice transplanted with p16−/− BM displayed higher hepatic AAMφ marker expression levels on Schistosoma mansoni infection, an in vivo model of AAMφ phenotype skewing. Surprisingly, p16−/− BMDMs did not display increased IL-4–induced STAT6 signaling, but decreased IFNγ-induced STAT1 and lipopolysaccharide (LPS)–induced IKKα,β phosphorylation. This decrease correlated with decreased JAK2 phosphorylation and with higher levels of inhibitory acetylation of STAT1 and IKKα,β. These findings identify p16INK4a as a modulator of macrophage activation and polarization via the JAK2-STAT1 pathway with possible roles in inflammatory diseases.

International audience; The anti-inflammatory effects of CI-1044 and of the other selective PDE4 inhibitors rolipram and cilomilast were investigated in Brown-Norway (BN) rats, against lipopolysaccharide-induced tumor necrosis factor alpha (TNFalpha) production in whole blood and antigen-induced lung eosinophilia. In vitro, CI-1044 inhibited TNFalpha production with an IC(50) of 0.31 microm being equipotent to Cilomilast (IC(50) = 0.26 microm) and rolipram (IC(50) = 0.11 microm). Given orally, CI-1044 inhibited ex vivo TNFalpha production with an ED(50) value of 0.4 mg/kg after single administration, whereas rolipram (ED(50) = 1.4 mg/kg) and cilomilast (ED(50) = 1.6 mg/kg) were less potent. In the same ex vivo setting, but given repeatedly, CI-1044 led to an ED(50) of 0.5 mg/kg corresponding to a plasma concentration of 82.6 ng/mL (0.22 microm). In vivo, CI-1044 prevented TNFalpha release with an ED(50) of 1 mg/kg p.o. and inhibited ovalbumin-induced lung eosinophilia following single or repeated oral administration with an ED(50) of 3.25 and 4.8 mg/kg p.o., respectively, suggesting the absence of pharmacological tolerance. CI-1044 in this model was equipotent to rolipram (81% inhibition at 10 mg/kg) but better than cilomilast (25% inhibition at 10 mg/kg). Finally, CI-1044 (10 mg/kg) inhibited inflammatory cell recruitment with a long duration of action (up to 8 h) and was still active when given post-challenge. Our data show that CI-1044 is an orally active PDE4 inhibitor that may be used as an anti-inflammatory therapy in lung inflammatory diseases.

International audience; MicroRNAs (miRNAs) are small noncoding RNAs that regulate vast networks of genes that share miRNA target sequences. To examine the physiologic effects of an individual miRNA-mRNA interaction in vivo, we generated mice that carry a mutation in the putative microRNA-155 (miR-155) binding site in the 3'-untranslated region of activation-induced cytidine deaminase (AID), designated Aicda(155) mice. AID is required for immunoglobulin gene diversification in B lymphocytes, but it also promotes chromosomal translocations. Aicda(155) caused an increase in steady-state Aicda mRNA and protein amounts by increasing the half-life of the mRNA, resulting in a high degree of Myc-Igh translocations. A similar but more pronounced translocation phenotype was also found in miR-155-deficient mice. Our experiments indicate that miR-155 can act as a tumor suppressor by reducing potentially oncogenic translocations generated by AID.

International audience; Biogenesis of iron-sulfur (Fe-S) clusters in mammals involves a complex mitochondrial machinery that provides inorganic sulfide and iron for their assembly and insertion into apo-proteins. Mechanisms of Fe-S cluster assembly are just being unraveled, and regulation of the genes of this machinery remains unknown. In this study, we report that expression of two essential components of the Fe-S machinery, the cysteine desulfurase Nfs1 and its scaffold protein partner IscU, is down-regulated at both mRNA and protein levels when murine macrophages are physiologically stimulated with IFN-gamma and LPS. Regulation did not rely on cluster disassembly or NO production because exposure of cells to exogenous sources of NO did not alter Nfs1 expression, while it converted cytosolic Fe-S aconitase into its apo-form and because macrophages from NOS2 deficient mice displayed Nfs1 down-regulation. While IFN-gamma alone induced Nfs1 protein instability, LPS triggered a delayed decline of Nfs1, rather involving transcriptional events or mRNA instability. Also, the expression of IscU was down-regulated in IFN-gamma- and/or LPS-stimulated macrophages independently of NO, pointing to a general mechanism for marshalling the regulation of the Fe-S cluster assembly machinery in macrophages exposed to inflammatory stimuli.

International audience; Nod1 is an intracellular pattern recognition molecule activated following bacterial infection, which senses a specific muropeptide (l-Ala-d-Glu-meso-DAP (diaminopimelic acid); "Tri(DAP)") from peptidoglycan. Here we investigated the molecular basis of Tri(DAP) sensing by human (h) Nod1. Our results identified the domain responsible for Tri(DAP) detection in the center of the concave surface of hNod1 leucine-rich repeat domain. Amino acid residues critical for sensing define a contiguous surface patch that is largely conserved in Nod1 proteins from different species. Accordingly, the distinct specificities of human versus murine Nod1 toward muropeptide detection were also found to lie in this central cleft. Several splicing variants of Nod1 lacking repeats 7-9 have been characterized recently, the relative balance of which is thought to correlate with the onset of asthma or inflammatory bowel disease. We demonstrated that these isoforms failed to transduce NF-kappaB activation upon muropeptide stimulation. This study provided insights into the molecular mechanisms responsible for the detection of bacterial peptidoglycan by Nod1 and suggested that defects in Nod1-dependent peptidoglycan sensing may contribute to elicit certain inflammatory disorders.

Brucellosis is a worldwide human zoonosis caused by intracellular bacteria of the genus Brucella. Virulence factors play an important role in allowing Brucella infection and proliferation within macrophages. Brucella enters macrophages through lipid raft microdomains, avoids phagolysosome fusion, and inhibits TNF-alpha secretion and apoptosis. Furthermore, Brucella can perturb bactericidal activity in macrophages by influencing the host cell response to its advantage through its LPS or by activating the cAMP/PKA pathway. To date, small steps have been taken in defining and understanding the virulence factors of Brucella used in macrophage subversion, but further investigation is required to fully explain virulence and persistence.

Shigella , the leading cause of bacillary dysentery, uses a type III secretion system (TTSS) to inject proteins into human cells, leading to bacterial invasion and a vigorous inflammatory response. The bacterium is protected against the response by the O antigen of lipopolysaccharide (LPS) on its surface. We show that bacteriophage-encoded glucosylation of Shigella O antigen, the basis of different serotypes, shortens the LPS molecule by around half. This enhances TTSS function without compromising the protective properties of the LPS. Thus, LPS glucosylation promotes bacterial invasion and evasion of innate immunity, which may have contributed to the emergence of serotype diversity in Shigella .

International audience; NEMO (NF-κB essential modulator) plays a key role in the canonical NF-κB pathway as the scaffold/regulatory component of the IκB kinase (IKK) complex. The self-association of NEMO involves the C-terminal halves of the polypeptide chains containing two putative coiled-coil motifs (a CC2 and a LZ leucine zipper), a proline-rich region, and a ZF zinc finger motif. Using purified truncation mutants, we showed that the minimal oligomerization domain of NEMO is the CC2-LZ segment and that both CC2 and LZ subdomains are necessary to restore the LPS-dependent activation of the NF-κB pathway in a NEMO-deficient cell line. We confirmed the association of the oligomerization domain in a trimer and investigated the specific role of CC2 and LZ subdomains in the building of the oligomer. Whereas a recombinant CC2-LZ polypeptide self-associated into a trimer with an association constant close to that of the wild-type protein, the isolated CC2 and LZ peptides, respectively, formed trimers and dimers with weaker association constants. Upon mixing, isolated CC2 and LZ peptides associated to form a stable hetero-hexamer as shown by gel filtration and fluorescence anisotropy experiments. We propose a structural model for the organization of the oligomerization domain of activated NEMO in which three C-terminal domains associate into a pseudo-hexamer forming a six-helix bundle. This model is discussed in relation to the mechanism of activation of the IKK complex by upstream activators.

International audience; Pseudomonas fluorescens is a Gram-negative bacillus closely related to the pathogen P. aeruginosa known to provoke infectious disorders in the central nervous system (CNS). The endotoxin lipopolysaccharide (LPS) expressed by the bacteria is the first infectious factor that can interact with the plasma membrane of host cells. In the present study, LPS extracted from P. fluorescens MF37 was examined for its actions on delayed rectifier and A-type K(+) channels, two of the main types of voltage-activated K(+) channels involved in the action potential firing. Current recordings were performed in cultured rat cerebellar granule neurons at days 7 or 8, using the whole-cell patch-clamp technique. A 3-h incubation with LPS (200 ng/ml) markedly depressed both the delayed rectifier (I(KV)) and transient A-type (I(A)) K(+) currents evoked by depolarizations above 0 and -40 mV, respectively. The percent decrease of I(KV) and I(A) ( approximately 30%) did not vary with membrane potential, suggesting that inhibition of both types of K(+) channels by LPS was voltage-insensitive. The endotoxin did neither modify the steady-state voltage-dependent activation properties of I(KV) and I(A) nor the steady-state inactivation of I(A). The present results suggest that, by inhibiting I(KV) and I(A), LPS applied extracellulary increases the action potential firing in cerebellar granule neurons. It is concluded that P. fluorescens MF37 may provoke in the CNS disorders associated with sever alterations of membrane ionic channel functions.

International audience; The molecular bases of Mycobacterium tuberculosis pathogenicity remain unclear. We report here how M. tuberculosis mannosylated lipoarabinomannans contribute to the survival of bacilli in the human reservoir by (i) inhibiting IL-12 production by macrophages and dendritic cells and (ii) modulating M. tuberculosis-induced macrophage apoptosis.

International audience; This study examined the interaction of the poorly metastatic human melanoma cell line M4Be and the highly metastatic clone 4 derived from M4Be, with respect to fresh adherent leukocytes (AL) isolated from 17 different healthy blood donors. These AL contained 80% (73%-93%) monocytes, 15% (6%-20%) B lymphocytes and 5% (1%-8%) T lymphocytes. The survival of these tumor cells against the stress exerted by these AL was estimated with a clonogenic assay where isolated tumor cells were co-cultured for 14 days in contact with AL and lipopolysaccharide (LPS). For a given blood donor, AL either stimulates or inhibits the colony formation of the tumor cells (T) depending on the AL/T ratio, the AL activation status and the metastatic potential of tumor cells. At low AL/T ratios (< 10/1) in the presence of low (8 ng/ml) and trace (8 pg/ml) levels of LPS, hydrogen peroxide (H2O2) release is significantly reduced, and tumor cells significantly increase their colony formation; the feeder effect of AL is suggested to be due to low concentrations of soluble tumor necrosis factor-alpha (TNF-alpha). At high AL/T ratios (> 10/1), whatever the characteristics of the blood donor, clone 4 is significantly more sensitive than M4Be to AL activated with medium containing low (8 ng/ml) or high (1,000 ng/ml) levels of LPS; this killing effect is suggested to be due to TNF-alpha, both soluble and membrane-bound, but not to be due to release of H2O2. These data suggest that the regulatory role of AL, which remove the majority of human melanoma cells and stimulate the colony formation of a small fraction of them, is partly due to TNF-alpha.

Nod factor [NodRm-IV(Ac,S)], isolated from the bacterium Rhizobium meliloti, induces a well-known depolarization in Medicago sativa (cv Sitel) root hairs. Analysis of this membrane response using the discontinuous single-electrode voltage-clamp technique (dSEVC) shows that anion channel, K+ channel and H+-ATPase pump currents are involved in young growing root hairs. The early Nod-factor-induced depolarization is due to increase of the inward ion current and inhibition of the H+ pump. It involved an instantaneous inward anion current (IIAC) and/or a time-dependent inward K+ current (IRKC). These two ion currents are then down-regulated while the H+ pump is stimulated, allowing long-term rectification of the membrane potential (Em). Our results support the idea that the regulation of inward current plays a primary role in the Nod-factor-induced electrical response, the nature of the ions carried by these currents depending on the activated anion and/or K+ channels at the plasma membrane.

Lactoferrin is an iron-binding glycoprotein found in exocrine secretions of mammals and released from neutrophilic granules during inflammation. This review describes the biological roles of lactoferrin in host defence. Secreted lactoferrin exerts antimicrobial action either by chelation of iron or by destabilization of bacterial membranes. Furthermore, lactoferrin modulates the inflammatory process, mainly by preventing the release of cytokines from monocytes and by regulating the proliferation and differentiation of immune cells. Some of these activities are related to the ability of lactoferrin to bind lipopolysaccharides (LPS) with high affinity. Indeed, recentin vitrostudies indicate that lactoferrin is able to compete with the LPS-binding protein for LPS binding and therefore to prevent the transfer of LPS to CD14 present at the surface of monocytes. Moreover, the prophylactic properties of lactoferrin against septicemiain vivohave been demonstrated. Taken as a whole, these observations strongly suggest that lactoferrin is one of the key molecules which modulate the inflammatory response.

International audience; Mycobacteria are characterized by a complex cell wall, the lipid nature of which confers to the bacilli resistance to drying, acid or alkaline conditions, and to chemical disinfectants and therapeutic agents. Pathogenic species, such as Mycobacterium tuberculosis, M. leprae and M. ulcerans, have evolved various strategies to establish residence in their hosts and provoke long-term infections. There is mounting evidence that the unique lipids composing their envelopes, strategically located at the host-pathogen interface, contribute to their escape from immune surveillance. Here, the chemical structure, host cell receptors and biological actions of this emerging class of mycobacterial virulence factors are reviewed.

Recent studies on endotoxin/lipopolysaccharide (LPS)-induced acute inflammatory response in the lung are reviewed. The acute airway inflammatory response to inhaled endotoxin is mediated through Toll-like receptor 4 (TLR4) and CD14 signalling as mice deficient for TLR4 or CD14 are unresponsive to endotoxin. Acute bronchoconstriction, tumour necrosis factor (TNF), interleukin (IL)-12 and keratinocyte-derived chemokine (KC) production, protein leak and neutrophil recruitment in the lung are abrogated in mice deficient for the adaptor molecules myeloid differentiation factor 88 (MyD88) and Toll/Interleukin-1 receptor (TIR)-domain-containing adaptor protein (TIRAP), but independent of TIR-domain-containing adaptor-inducing interferon-beta (TRIF). In particular, LPS-induced TNF is required for bronchoconstriction, but dispensable for inflammatory cell recruitment. Lipopolysaccharide induces activation of the p38 mitogen-activated protein kinase (MAPK). Inhibition of pulmonary MAPK activity abrogates LPS-induced TNF production, bronchoconstriction, neutrophil recruitment into the lungs and broncho-alveolar space. In conclusion, TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin are dependent on TLR4/CD14/MD2 expression using the adapter proteins TIRAP and MyD88, while TRIF, IL-1R1 or IL-18R signalling pathways are dispensable. Further downstream in this axis of signalling, TNF blockade reduces only acute bronchoconstriction, while MAPK inhibition abrogates completely endotoxin-induced inflammation.

International audience; Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the most effective human pathogens and the molecular basis of its virulence remains poorly understood. Here, we review our current knowledge about the structure and biosynthesis of the mycobacterial cell-wall lipoglycans, lipoarabinomannans (LAM). LAM are ubiquitous of mycobacteria and appear as the most potent non-peptidic molecules to modulate the host immune response. Nevertheless, LAM structure differs according to the mycobacterial species and three types of LAM have been described: mannose-capped LAM (ManLAM), phospho-myo-inositol-capped LAM (PILAM) and non-capped LAM (AraLAM). The type of capping is a major structural feature determining the ability of LAM to modulate the immune response. ManLAM, found in slow-growing mycobacteria, such as M. tuberculosis, have been demonstrated to be powerful anti-inflammatory molecules and emerge as key virulence factors that may be relevant drug targets. LAM-like molecules are not only confined to mycobacteria but are also present in actinomycetes (including the genera Rhodococcus, Corynebacterium or Gordonia). This offers the possibility of comparative studies that should help in deciphering the structure-function relationships and biosynthesis of these complex molecules in the future.

The molecular mechanisms of de novo meristem formation, cell differentiation and the integration of the cell cycle machinery into appropriate stages of the developmental programmes are still largely unknown in plants. Legume root nodules, which house nitrogen-fixing rhizobia, are unique plant organs and their development may serve as a model for organogenetic processes in plants. Nodules form and are essential for the plant only under limitation of combined nitrogen in the soil. Moreover, their development is triggered by external mitogenic signals produced by their symbiotic partners, the rhizobia. These signals, the lipochitooligosaccharide Nod factors, act as host-specific morphogens and induce the re-entry of root cortical cells into mitotic cycles. Maintenance of cell division activity leads to the formation of a persistent nodule meristem from which cells exit continuously and enter the nodule differentiation programme, involving multiple cycles of endoreduplication and enlargement of nuclear and cell volumes. While the small diploid 2C cells remain uninfected, the large polyploid cells can be invaded and, after completing the differentiation programme, host the nitrogen-fixing bacteroids. This review summarizes the present knowledge on cell cycle reactivation and meristem formation in response to Nod factors and reports on a novel plant cell cycle regulator that can switch mitotic cycles to differentiation programmes.

BackgroundInflammation is a hallmark of acute lung injury and chronic airway diseases. In chronic airway diseases, it is associated with profound tissue remodeling. Peroxisome proliferator-activated receptor-α (PPARα) is a ligand-activated transcription factor, that belongs to the nuclear receptor family. Agonists for PPARα have been recently shown to reduce lipopolysaccharide (LPS)- and cytokine-induced secretion of matrix metalloproteinase-9 (MMP-9) in human monocytes and rat mesangial cells, suggesting that PPARα may play a beneficial role in inflammation and tissue remodeling.MethodsWe have investigated the role of PPARα in a mouse model of LPS-induced airway inflammation characterized by neutrophil and macrophage infiltration, by production of the chemoattractants, tumor necrosis factor-α (TNF-α), keratinocyte derived-chemokine (KC), macrophage inflammatory protein-2 (MIP-2) and monocyte chemoattractant protein-1 (MCP-1), and by increased MMP-2 and MMP-9 activity in bronchoalveolar lavage fluid (BALF). The role of PPARα in this model was studied using both PPARα-deficient mice and mice treated with the PPARα activator, fenofibrate.ResultsUpon intranasal exposure to LPS, PPARα-/-mice exhibited greater neutrophil and macrophage number in BALF, as well as increased levels of TNF-α, KC, MIP-2 and MCP-1, when compared to PPARα+/+mice. PPARα-/-mice also displayed enhanced MMP-9 activity. Conversely, fenofibrate (0.15 to 15 mg/day) dose-dependently reduced the increase in neutrophil and macrophage number induced by LPS in wild-type mice. In animals treated with 15 mg/day fenofibrate, this effect was associated with a reduction in TNF-α, KC, MIP-2 and MCP-1 levels, as well as in MMP-2 and MMP-9 activity. PPARα-/-mice treated with 15 mg/day fenofibrate failed to exhibit decreased airway inflammatory cell infiltrate, demonstrating that PPARα mediates the anti-inflammatory effect of fenofibrate.ConclusionUsing both genetic and pharmacological approaches, our data clearly show that PPARα downregulates cell infiltration, chemoattractant production and enhanced MMP activity triggered by LPS in mouse lung. This suggests that PPARα activation may have a beneficial effect in acute or chronic inflammatory airway disorders involving neutrophils and macrophages.