Cell death induced by NLRP3-palmitate axis impairs pulmonary damage tolerance and aggravates immunopathology during obesity-tuberculosis comorbidity.

A low-grade and persistent inflammation, which is the hallmark of obesity, requires the participation of NLRP3 and cell death. During Mycobacterium tuberculosis infection, NLRP3 signaling is important for bacterial killing by macrophages in vitro but was shown to be dispensable for host protection in vivo. We hypothesized that during obesity-tuberculosis (TB) comorbidity, NLRP3 signaling might play a detrimental role by inducing excessive inflammation. We employed a model of high-fat-diet-induced obesity, followed by M. tuberculosis infection in C57BL/6 mice. Obese mice presented increased susceptibility to infection and pulmonary immunopathology compared to lean mice. Using treatment with NLRP3 antagonist and Nlrp3-/- mice, we showed that NLRP3 signaling promoted cell death, with no effect in bacterial loads. The levels of palmitate were higher in the lungs of obese infected mice compared to lean counterparts, and we observed that this lipid increased M. tuberculosis-induced macrophage death in vitro, which was dependent on NLRP3 and caspase-1. At the chronic phase, although lungs of obese Nlrp3-/- mice showed an indication of granuloma formation compared to obese wild-type mice, there was no difference in the bacterial load. Our findings indicate that NLRP3 may be a potential target for host-directed therapy to reduce initial and severe inflammation-mediated disease and to treat comorbidity-associated TB. © 2022 The Pathological Society of Great Britain and Ireland.

Macrophage-Derived MicroRNA-21 Drives Overwhelming Glycolytic and Inflammatory Response during Sepsis via Repression of the PGE2/IL-10 Axis.

Myeloid cells are critical for systemic inflammation, microbial control, and organ damage during sepsis. MicroRNAs are small noncoding RNAs that can dictate the outcome of sepsis. The role of myeloid-based expression of microRNA-21 (miR-21) in sepsis is inconclusive. In this study, we show that sepsis enhanced miR-21 expression in both peritoneal macrophages and neutrophils from septic C57BL/6J mice, and the deletion of miR-21 locus in myeloid cells (miR-21Δmyel mice) enhanced animal survival, decreased bacterial growth, decreased systemic inflammation, and decreased organ damage. Resistance to sepsis was associated with a reduction of aerobic glycolysis and increased levels of the anti-inflammatory mediators PGE2 and IL-10 in miR-21Δmyel in vivo and in vitro. Using blocking Abs and pharmacological tools, we discovered that increased survival and decreased systemic inflammation in septic miR-21Δmyel mice is dependent on PGE2/IL-10-mediated inhibition of glycolysis. Together, these findings demonstrate that expression of miR-21 in myeloid cells orchestrates the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm during sepsis.

Leukotriene B4 licenses inflammasome activation to enhance skin host defense.

The initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1ß and IL-18 in addition to inducing a type of inflammatory cell death termed "pyroptosis." Leukotriene B4 (LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, increases cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4 directly activates the inflammasome remains to be determined. Our data show that endogenously produced LTB4 is required for the expression of pro-IL-1ß and enhances inflammasome assembly in vivo and in vitro. Furthermore, LTB4-mediated Bruton's tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1ß-enhanced skin host defense. Together, these data unveil a new role for LTB4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4 can be used as an adjuvant to boost inflammasome-dependent host defense.

Lactone Derivatives Produced by a Phaeoacremonium sp., an Endophytic Fungus from Senna spectabilis.

Three new isoaigialones, A, B, and C (1-3), along with aigialone (4), were isolated from the crude EtOAc extract of a Phaeoacremonium sp., an endophytic fungus obtained from the leaves of Senna spectabilis. The structures of these compounds were elucidated based on the analysis of spectroscopic data. Compounds 2 and 4 were active against the phytopathogenic fungi Cladosporium cladosporioides and C. sphaerospermum. This is the first report of metabolites produced by an Phaeoacremonium sp., associated with S. spectabilis.

Protective Effect of Galectin-1 during Histoplasma capsulatum Infection Is Associated with Prostaglandin E2 and Nitric Oxide Modulation.

Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1-/- mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1-/- mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1-/- mice exhibited elevated levels of prostaglandin E2 (PGE2, a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 (Ptgs2) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum, in vitro, suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE2 as an important lipid mediator in the pathogenesis of histoplasmosis.

Potent anti-inflammatory activity of pyrenocine A isolated from the marine-derived fungus Penicillium paxilli Ma(G)K.

Very little is known about the immunomodulatory potential of secondary metabolites isolated from marine microorganisms. In the present study, we characterized pyrenocine A, which is produced by the marine-derived fungus Penicillium paxilli Ma(G)K and possesses anti-inflammatory activity. Pyrenocine A was able to suppress, both pretreatment and posttreatment, the LPS-induced activation of macrophages via the inhibition of nitrite production and the synthesis of inflammatory cytokines and PGE2. Pyrenocine A also exhibited anti-inflammatory effects on the expression of receptors directly related to cell migration (Mac-1) as well as costimulatory molecules involved in lymphocyte activation (B7.1). Nitrite production was inhibited by pyrenocine A in macrophages stimulated with CpG but not Poly I:C, suggesting that pyrenocine A acts through the MyD88-dependent intracellular signaling pathway. Moreover, pyrenocine A is also able to inhibit the expression of genes related to NF κ B-mediated signal transduction on macrophages stimulated by LPS. Our results indicate that pyrenocine A has promissory anti-inflammatory properties and additional experiments are necessary to confirm this finding in vivo model.

The class A scavenger receptor, macrophage receptor with collagenous structure, is the major phagocytic receptor for Clostridium sordellii expressed by human decidual macrophages.

Clostridium sordellii is an emerging pathogen associated with highly lethal female reproductive tract infections following childbirth, abortion, or cervical instrumentation. Gaps in our understanding of the pathogenesis of C. sordellii infections present major challenges to the development of better preventive and therapeutic strategies against this problem. We sought to determine the mechanisms whereby uterine decidual macrophages phagocytose this bacterium and tested the hypothesis that human decidual macrophages use class A scavenger receptors to internalize unopsonized C. sordellii. In vitro phagocytosis assays with human decidual macrophages incubated with pharmacological inhibitors of class A scavenger receptors (fucoidan, polyinosinic acid, and dextran sulfate) revealed a role for these receptors in C. sordellii phagocytosis. Soluble macrophage receptor with collagenous structure (MARCO) receptor prevented C. sordellii internalization, suggesting that MARCO is an important class A scavenger receptor in decidual macrophage phagocytosis of this microbe. Peritoneal macrophages from MARCO-deficient mice, but not wild-type or scavenger receptor AI/II-deficient mice, showed impaired C. sordellii phagocytosis. MARCO-null mice were more susceptible to death from C. sordellii uterine infection than wild-type mice and exhibited impaired clearance of this bacterium from the infected uterus. Thus, MARCO is an important phagocytic receptor used by human and mouse macrophages to clear C. sordellii from the infected uterus.

Crosstalk between prostaglandin E2 and leukotriene B4 regulates phagocytosis in alveolar macrophages via combinatorial effects on cyclic AMP.

Eicosanoid lipid mediators, including prostaglandin E(2) (PGE(2)) and leukotrienes (LTs) B(4) and D(4), are produced in abundance in the infected lung. We have previously demonstrated that individually, PGE(2) suppresses while both classes of LTs augment alveolar macrophage (AM) innate immune functions. In this study, we sought to more appropriately model the milieu at a site of infection by studying the in vitro effects of these lipid mediators on Fc gammaR-mediated phagocytosis when they are present in combination. Consistent with their individual actions, both LTB(4) and LTD(4) opposed the suppressive effect of PGE(2) on phagocytosis, but only LTB(4) did so by mitigating the stimulatory effect of PGE(2) on intracellular cAMP production. Unexpectedly, we observed that IgG-opsonized targets themselves elicited a dose-dependent reduction in intracellular cAMP in AMs, but this was not observed in peritoneal macrophages or elicited peritoneal neutrophils; this effect in AMs was completely abolished by treatment with the LT synthesis inhibitor AA861, the BLT receptor 1 antagonist CP 105,696, and the G alpha i inhibitor pertussis toxin. Of two downstream cAMP effectors, protein kinase A and exchange protein activated by cAMP, the ability of PGE(2) to activate the latter but not the former was abrogated by both LTs B(4) and D(4). Taken together, our results indicate that both classes of LTs oppose the immune suppressive actions of PGE(2), with the stimulatory actions of LTB(4) reflecting combinatorial modulation of intracellular cAMP and those of LTD(4) being cAMP independent.

Leukotrienes are potent adjuvant during fungal infection: effects on memory T cells.

Leukotrienes (LTs) are potent lipid mediators involved in the control of host defense. LTB(4) induces leukocyte accumulation, enhances phagocytosis and bacterial clearance, and increases NO synthesis. LTB(4) is also important in early effector T cell recruitment that is mediated by LTB(4) receptor 1, the high-affinity receptor for LTB(4). The aims of this study were to evaluate whether LTs are involved in the secondary immune response to vaccination in a murine model of Histoplasma capsulatum infection. Our results demonstrate that protection of wild-type mice immunized with cell-free Ags from H. capsulatum against histoplasmosis was associated with increased LTB(4) and IFN-gamma production as well as recruitment of memory T cells into the lungs. In contrast, cell-free Ag-immunized mice lacking 5-lipoxygenase(-/-), a critical enzyme involved in LT synthesis, displayed a marked decrease on recruitment of memory T cells to the lungs associated with increased synthesis of TGF-beta as well as IL-10. Strikingly, these effects were associated with increased mortality to 5-lipoxygenase(-/-)-infected mice. These data establish an important immunomodulatory role of LTs, in both the primary and secondary immune responses to histoplasmosis.

Diterpenoids with inhibitory activity of nitrite production from Croton floribundus.

ETHNOPHARMACOLOGICAL RELEVANCE: Croton floribundus Spreng. (Euphorbiaceae), popularly known as Capixinguí, stands out due to its widespread use in traditional medicine to treat wounds, syphilis, hemorrhoids, eye diseases and as a purgative. AIM OF THE STUDY: To characterize clerodanes diterpenes from C. floribundus and to evaluate the effects of the fraction and diterpenes (1-5) on inhibition of nitrite production. MATERIALS AND METHODS: The hydroethanolic root extract of C. floribundus was fractionated on a solid phase extraction column to obtain the fraction named Fr80%. From this, five compounds were obtained and characterized. The absolute configuration of compound 1 was determined by a combination of electronic and vibrational circular dichroism spectroscopies. Additionally, compounds 1-5 were evaluated for their inhibitory effects on nitrite production induced by lipopolysaccharide (LPS) in RAW 264 macrophage cell. RESULTS: Five clerodane diterpenoids were characterized, and the absolute stereochemistry of 1 was established as 3R,4R,5R,8R,9R,10S,12S. The IC50 values obtained through inhibition of nitrite production were 28.52 ±â€¯2.21 µM (1), 40.26 ±â€¯2.79 µM (2), 25.47 ±â€¯2.16 µM (3), 35.78 ±â€¯2.93 µM (4) and 40.58 ±â€¯4.78 µM (5). In the tested concentrations, the samples presented low toxicity in macrophages. CONCLUSIONS: Four new diterpenes were characterized from C. floribundus, these being croflorins A-D (1-4) and a known halimane (5). These compounds exhibited inhibitory effect on nitrite production.

Near-infrared photodynamic inactivation of S. pneumoniae and its interaction with RAW 264.7 macrophages.

Pneumonia is the main cause of children mortality worldwide, and its major treatment obstacle stems from the microorganisms increasing development of resistance to several antibiotics. Photodynamic therapy has been presenting, for the last decades, promising results for some subtypes of cancer and infections. In this work we aimed to develop a safe and efficient in vitro protocol for photodynamic inactivation of Streptococcus pneumoniae, one of the most commonly found bacteria in pneumonia cases, using two near-infrared light sources and indocyanine green, a FDA approved dye. Photodynamic inactivation experiments with bacteria alone allowed to determine the best parameters for microbial inactivation. Cytotoxicity assays with RAW 264.7 macrophages evaluated the safety of the PDI. To determine if the photodynamic inactivation had a positive or negative effect on the natural killing action of macrophages, we selected and tested fewer indocyanine green concentrations and 10 J/cm2 on macrophage-S. pneumoniae co-cultures. We concluded that ICG has potential as a photosensitizer for near-infrared photodynamic inactivation of S. pneumoniae, producing minimum negative impact on RAW 264.7 macrophages and having a positive interaction with the immune cell's microbicidal action.

Gr-1+ cells play an essential role in an experimental model of disseminated histoplasmosis.

Recent studies have shown the participation of Gr-1(+) cells in many types of infections; however, the role played by these cells in the immune response to fungal pathogens is controversial. In this study we determined whether Gr-1(+) cells are involved in the protective immune response in systemic Histoplasma capsulatum infection. Depletion of Gr-1(+) cells using the monoclonal antibody (MAb) RB6-8C5 increased histoplasmosis severity and inhibited the subsequent development of a protective immune response. In addition to the increased fungal burden in lungs and spleens, the Th1 response was found to be unbalanced in these mice and the suppression of the cellular immune response seemed to be associated with increased nitric oxide production. Taken together, these results indicate that Gr-1(+) cell depletion at the beginning of infection allows yeast multiplication and increases mice mortality. This study improves the understanding of the role of Gr-1(+) cells on the protective immunity in histoplasmosis.

Inhibition of leukotriene biosynthesis abrogates the host control of Mycobacterium tuberculosis.

Leukotrienes produced from arachidonic acid by the action of 5-lipoxygenase (5-LO) are classical mediators of inflammatory responses. Recently, it has been demonstrated that leukotrienes also play an important role in host defense against microorganisms. In vitro studies have shown that leukotrienes augmented the anti-mycobacterial activity of neutrophils. In this study, we examined the role of leukotrienes in regulating host response and cytokine generation in a murine model of tuberculosis. Administration of the 5-LO pathway inhibitor MK 886, which reduced lung levels of both the leukotriene B(4) and the anti-inflammatory substance lipoxin A(4) by approximately 50%, increased 60-day mortality from 14% to approximately 57% in Mycobacterium tuberculosis-infected mice, and increased lung bacterial burden by approximately 15-fold. Although MK 886-treated animals exhibited no reduction in pulmonary leukocyte accumulation, they did manifest reduced levels of nitric oxide generation and of the protective type 1 cytokines interleukin-12 and gamma interferon. Together our results demonstrate that 5-LO pathway product(s) - presumably leukotrienes - positively regulate protective Th1 responses against mycobacterial infection in vivo. Moreover, the immunosuppressive phenotype in infected mice observed with MK 886 is most consistent with inhibition of an activator (LTB(4)) rather than a suppressor (LXA(4)) of antimicrobial defense, suggesting the major effect of leukotrienes.

In vitro and in vivo activities of leukotriene B4-loaded biodegradable microspheres.

Leukotriene B(4) (LTB(4)) is a potent inflammatory mediator and stimulates the immune response. In addition, LTB(4) promotes leukocyte functions such as phagocytosis, chemotaxis and chemokinesis of polymorphonuclear leukocytes, as well as modulates cytokine release. However, some physicochemical characteristics of leukotrienes, such as poor solubility in water and chemical instability, make them difficult to administer in vivo. The aim of this study was to develop LTB(4)-loaded microspheres (MS) that prolong and sustain the in vivo release of this mediator. An oil-in-water emulsion solvent extraction-evaporation method was chosen to prepare the lipid-loaded MS. We determined their diameters, evaluated the in vitro release of LTB(4), using enzyme immunoassay and evaluated in vitro MS uptake by peritoneal macrophages. To assess the preservation of neutrophil chemoattractant activity, LTB(4)-loaded MS were tested in vitro (in a modified Boyden microchamber) and in vivo, after intratracheal administration.

Efferocytosis-induced prostaglandin E2 production impairs alveolar macrophage effector functions during Streptococcus pneumoniae infection.

Alveolar macrophages (AMs) are multitasking cells that maintain lung homeostasis by clearing apoptotic cells (efferocytosis) and performing antimicrobial effector functions. Different PRRs have been described to be involved in the binding and capture of non-opsonized Streptococcus pneumoniae, such as TLR-2, mannose receptor (MR) and scavenger receptors (SRs). However, the mechanism by which the ingestion of apoptotic cells negatively influences the clearance of non-opsonized S. pneumoniae remains to be determined. In this study, we evaluated whether the prostaglandin E2 (PGE2) produced during efferocytosis by AMs inhibits the ingestion and killing of non-opsonized S. pneumoniae. Resident AMs were pre-treated with an E prostanoid (EP) receptor antagonist, inhibitors of cyclooxygenase and protein kinase A (PKA), incubated with apoptotic Jurkat T cells, and then challenged with S. pneumoniae. Efferocytosis slightly decreased the phagocytosis of S. pneumoniae but greatly inhibited bacterial killing by AMs in a manner dependent on PGE2 production, activation of the EP2-EP4/cAMP/PKA pathway and inhibition of H2O2 production. Our data suggest that the PGE2 produced by AMs during efferocytosis inhibits H2O2 production and impairs the efficient clearance non-opsonized S. pneumoniae by EP2-EP4/cAMP/PKA pathway.

Inhibition of 5-Lipoxygenase (5-Lo) Attenuates Inflammation and Bone Resorption in Lipopolysaccharide (Lps)-Induced Periodontal Disease.

BACKGROUND: Arachidonate-5-lipoxygenase (5-LO) activity and increased leukotriene B4 (LTB4) production have been implicated in various inflammatory conditions. Increased production of leukotrienes has been associated with periodontal diseases; however their relative contribution to the tissue destruction is unknown. We used an orally-active specific 5-LO inhibitor to assess its role in inflammation and bone resorption in a murine model of lipopolysaccharide (LPS)-induced periodontal disease. METHODS: Periodontal disease was induced in Balb/c mice by direct injections of LPS into the palatal gingival tissues adjacent to the upper first molars 3 times/week for four weeks. Animals were treated with the biochemical inhibitor (2 mg/Kg/day) or the same volume of the vehicle by oral gavage. µCT analysis was used to assess bone resorption. EIA determined leukotriene B4, and ELISAs quantified TNF, IL-12 and IL-10 in the gingival tissues. Histological sections were used for the morphometric analysis (number neutrophils and mononuclear cells). Osteoclasts were counted in TRAP-stained sections. RESULTS: Administration of 5-LO inhibitor effectively reduced the production of LTB4 (23.7% decrease) and significantly reduced TNF and IL-12 levels in the gingival tissues. Moreover, reduction of LTB4 levels in the gingival tissues was associated with a significant decrease in bone resorption and a marked reduction in the number of osteoclasts and inflammatory cells. CONCLUSION: 5-LO activity plays a relevant role in inflammation and bone resorption associated with the LPS model of experimental periodontal disease.

Inhibition of 5-lipoxygenase attenuates inflammation and BONE resorption in lipopolysaccharide-induced periodontal disease.

BACKGROUND: Arachidonate-5-lipoxygenase (5-LO) activity and increased leukotriene B4 (LTB4) production have been implicated in various inflammatory conditions. Increased production of leukotrienes has been associated with periodontal diseases; however, their relative contribution to tissue destruction is unknown. In this study, an orally active specific 5-LO inhibitor is used to assess its role in inflammation and bone resorption in a murine model of lipopolysaccharide (LPS)-induced periodontal disease. METHODS: Periodontal disease was induced in Balb/c mice by direct injections of LPS into the palatal gingival tissues adjacent to the maxillary first molars three times per week for 4 weeks. Animals were treated with biochemical inhibitor (2 mg/kg/daily) or the same volume of the vehicle by oral gavage. Microcomputed tomography analysis was used to assess bone resorption. Enzyme immunoassay determined LTB4, and enzyme-linked immunosorbent assays quantified tumor necrosis factor (TNF), interleukin (IL)-12, and IL-10 in gingival tissues. Histologic sections were used for the morphometric analysis (number of neutrophils and mononuclear cells). Osteoclasts were counted in tartrate-resistant acid phosphatase-stained sections. RESULTS: Administration of 5-LO inhibitor effectively reduced production of LTB4 (23.7% decrease) and significantly reduced TNF and IL-12 levels in gingival tissues. Moreover, reduction of LTB4 levels in gingival tissues was associated with a significant decrease in bone resorption and a marked reduction in number of osteoclasts and inflammatory cells. CONCLUSION: 5-LO activity plays a relevant role in inflammation and bone resorption associated with the LPS model of experimental periodontal disease.

Pneumonia treatment by photodynamic therapy with extracorporeal illumination - an experimental model.

Infectious pneumonia is a major cause of morbidity/mortality, mainly because of the increasing rate of microorganisms resistant to antibiotics. Photodynamic Therapy (PDT) is emerging as a promising approach, as effects are based on oxidative stress, preventing microorganism resistance. In two previous studies, the in vitro inactivation of Streptococcus pneumoniae using indocyanine green (ICG) and infrared light source was a success killing 5 log10 colony-forming units (CFU/mL) with only 10 µmol/L ICG. In this work, a proof-of-principle protocol was designed to treat lung infections by PDT using extracorporeal illumination with a 780 nm laser device and also ICG as photosensitizer. Hairless mice were infected with S. pneumoniae and PDT was performed two days after infection. For control groups, CFU recovery ranged between 103-104/mouse. For PDT group, however, no bacteria were recovered in 80% of the animals. Based on this result, animal survival was evaluated separately over 50 days. No deaths occurred in PDT group, whereas 60% of the control group died. Our results indicate that extracorporeal PDT has the potential for pneumonia treatment, and pulmonary decontamination with PDT may be used as a single therapy or as an antibiotics adjuvant.

Modulation of eosinophil generation and migration by Mangifera indica L. extract (Vimang).

The effects of Vimang, an aqueous extract of the stem bark of Mangifera indica L. (Anacardiaceae), on cell migration in an experimental model of asthma was investigated. In vivo treatment of Toxocara canis-infected BALB/c mice for 18 days with 50 mg/kg Vimang reduced eosinophil migration into the bronchoalveolar space and peritoneal cavity. Also, eosinophil generation in bone marrow and blood eosinophilia were inhibited in infected mice treated with Vimang. This reduction was associated with inhibition of IL-5 production in serum and eotaxin in lung homogenates. In all these cases the effects of Vimang were more selective than those observed with dexamethasone. Moreover, Vimang treatment is not toxic for the animals, as demonstrated by the normal body weight increase during infection. These data confirm the potent anti-inflammatory effect of Vimang and support its potential use as an alternative therapeutic drug to the treatment of eosinophilic disorders including those caused by nematodes and allergic diseases.

Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice.

People with diabetes are more prone to Staphylococcus aureus skin infection than healthy individuals. Control of S. aureus infection depends on dendritic cell (DC)-induced T-helper 17 (Th17)-mediated neutrophil recruitment and bacterial clearance. DC ingestion of infected apoptotic cells (IACs) drive prostaglandin E2 (PGE2) secretion to generate Th17 cells. We speculated that hyperglycemia inhibits skin DC migration to the lymph nodes and impairs the Th17 differentiation that accounts for poor skin host defense in diabetic mice. Diabetic mice showed increased skin lesion size and bacterial load and decreased PGE2 secretion and Th17 cells compared with nondiabetic mice after methicillin-resistant S. aureus (MRSA) infection. Bone marrow-derived DCs (BMDCs) cultured in high glucose (25 mmol/L) exhibited decreased Ptges mRNA expression, PGE2 production, lower CCR7-dependent DC migration, and diminished maturation after recognition of MRSA-IACs than BMDCs cultured in low glucose (5 mmol/L). Similar events were observed in DCs from diabetic mice infected with MRSA. Topical treatment of diabetic mice with the PGE analog misoprostol improved host defense against MRSA skin infection by restoring DC migration to draining lymph nodes, Th17 differentiation, and increased antimicrobial peptide expression. These findings identify a novel mechanism involved in poor skin host defense in diabetes and propose a targeted strategy to restore skin host defense in diabetes.