Targeted acidosis mediated delivery of antigenic MHC-binding peptides.

Cytotoxic T lymphocytes are the primary effector immune cells responsible for protection against cancer, as they target peptide neoantigens presented through the major histocompatibility complex (MHC) on cancer cells, leading to cell death. Targeting peptide-MHC (pMHC) complex offers a promising strategy for immunotherapy due to their specificity and effectiveness against cancer. In this work, we exploit the acidic tumor micro-environment to selectively deliver antigenic peptides to cancer using pH(low) insertion peptides (pHLIP). We demonstrated the delivery of MHC binding peptides directly to the cytoplasm of melanoma cells resulted in the presentation of antigenic peptides on MHC, and activation of T cells. This work highlights the potential of pHLIP as a vehicle for the targeted delivery of antigenic peptides and its presentation via MHC-bound complexes on cancer cell surface for activation of T cells with implications for enhancing anti-cancer immunotherapy.

Motility and Mechanical Properties of Dendritic Cells Deteriorated by Extracellular Acidosis.

Dendritic cells (DCs) are the most powerful antigen-presenting cells known to date and play an important role in initiating and amplifying both innate and adaptive immune responses. Extracellular acidosis is an important hallmark of a variety of inflammatory processes and solid tumors. However, few studies have focused on the effect of extracellular acidosis on DCs and their functions. Cellular mechanical properties reflect the relationship between cell structure and function, including cytoskeleton (especially F-actin organization), membrane negative charges, membrane fluidity, and osmotic fragility. The study investigated the effects of extracellular acidosis on the DCs functions from the perspective of cellular migration and mechanical properties. The results showed that migration ability, F-actin contents, and membrane negative charges of DCs were reduced by extracellular acidosis no matter whether LPS stimulated its maturation or not. And these functions could not return to normal after removing acidic microenvironment, which revealed that the function impairment induced by extracellular acidosis might be irreversible. In addition, the proliferation capacity of stimulated allogeneic T cells was impaired by extracellular acidosis. Our results suggest extracellular acidosis may play an immunosuppressive role in DCs-mediated immune process.

In utero inflammatory challenge induces an early activation of the hepatic innate immune response in late gestation fetal sheep.

Chorioamnionitis is associated with inflammatory end-organ damage in the fetus. Tissues in direct contact with amniotic fluid drive a pro-inflammatory response and contribute to this injury. However, due to a lack of direct contact with the amniotic fluid, the liver contribution to this response has not been fully characterized. Given its role as an immunologic organ, we hypothesized that the fetal liver would demonstrate an early innate immune response to an in utero inflammatory challenge. Fetal sheep (131 ± 1 d gestation) demonstrated metabolic acidosis and high cortisol and norepinephrine values within 5 h of exposure to intra-amniotic LPS. Likewise, expression of pro-inflammatory cytokines increased significantly at 1 and 5 h of exposure. This was associated with NF-κB activation, by inhibitory protein IκBα degradation, and nuclear translocation of NF-κB subunits (p65/p50). Corroborating these findings, LPS exposure significantly increased pro-inflammatory innate immune gene expression in fetal sheep hepatic macrophages in vitro. Thus, an in utero inflammatory challenge induces an early hepatic innate immune response with systemic metabolic and stress responses. Within the fetal liver, hepatic macrophages respond robustly to LPS exposure. Our results demonstrate that the fetal hepatic innate immune response must be considered when developing therapeutic approaches to attenuate end-organ injury associated with in utero inflammation.

Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.

Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units. Using unbiased approaches, we sought to define acid-adaptive pathways elicited by PMN TEM. Given the significant amount of adenosine (Ado) generated during PMN TEM, we profiled the influence of Ado on IECs gene expression by microarray and identified the induction of SLC26A3, the major apical Cl-/HCO3- exchanger in IECs. Utilizing loss- and gain-of-function approaches, as well as murine and human colonoids, we demonstrate that Ado-induced SLC26A3 promotes an adaptive IECs phenotype that buffers local pH during active inflammation. Extending these studies, chronic murine colitis models were used to demonstrate that SLC26A3 expression rebounds during chronic DSS-induced inflammation. In conclusion, Ado signaling during PMN TEM induces an adaptive tissue response to inflammatory acidification through the induction of SLC26A3 expression, thereby promoting pH homeostasis.

Potential for a localized immune response by the ruminal epithelium in nonpregnant heifers following a short-term subacute ruminal acidosis challenge.

The aim of this study was to investigate whether the ruminal epithelium activates a local inflammatory response following a short-term subacute ruminal acidosis (SARA) challenge. Seven ruminally cannulated, nonpregnant, nonlactating beef heifers, fed a baseline total mixed ration (TMR) with 50:50 forage-to-concentrate ratio, were used in a crossover design with 2 periods and 2 treatments: SARA and control (CON). Induction of SARA included feed restriction (25% of dry matter intake [DMI] for 24 h) followed by a grain overload (30% of baseline DMI) and provision of the full TMR; whereas, the CON group received the TMR ad libitum. Ruminal pH was recorded using indwelling probes, and ruminal lipopolysaccharide (LPS) concentration was measured daily following the challenge until d 6. Biopsies of ruminal papillae from the ventral sac were collected on d 2 and 6 after the grain overload. Transcript abundance of genes associated with acute inflammation was measured by quantitative real-time PCR, normalized to the geometric mean of 3 stable housekeeping genes. Target genes included toll-like receptor-2 (TLR2), TLR4, TLR9, tumor necrosis factor-α (TNFA), prostaglandin endoperoxide synthase-1 (PTGS1), PTGS2 transforming growth factor ß-1 (TGFB1), and 4 intermediate enzymes of leukotriene synthesis (ALOX5, ALOX5AP, LTA4H, and LTC4S). Protein localization and expression of TLR4 were quantified by image analysis of fluorescence intensity. Statistical analysis was performed using as a crossover design with fixed effects of treatment, day, and the treatment × day interaction with the random effect of day within period. Ruminal pH was below 5.6 for 4.5 h/d and below 5.8 for 6.9 h/d in the SARA group compared with 22 and 72 min/d, respectively, for CON. Ruminal LPS concentration peaked on d 2 in SARA heifers at 51,481 endotoxin units (EU)/mL compared with 13,331 EU/mL in CON. Following grain overload, small but statistically significant decreases in the transcriptional abundance of TLR2, TLR4, TNF, PTGS2, ALOX5, and ALOX5AP were seen in SARA versus CON heifers. A functionally relevant decrease in TLR4 expression in SARA heifers compared with CON was confirmed by a decrease in fluorescence intensity of the corresponding protein following immunohistofluorescent staining of papillae. The study results indicate a suppression of the inflammatory response in the ruminal epithelium and suggest that the response is tightly regulated, allowing for tissue recovery and return to homeostasis following SARA.

Carbonic Anhydrase Inhibition Ameliorates Inflammation and Experimental Pulmonary Hypertension.

Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. Carbonic anhydrase inhibition induces mild metabolic acidosis and exerts protective effects in hypoxic pulmonary hypertension. Carbonic anhydrases and metabolic acidosis are further known to modulate immune cell activation. To evaluate if carbonic anhydrase inhibition modulates macrophage activation, inflammation, and VSMC phenotypic switching in severe experimental pulmonary hypertension, pulmonary hypertension was assessed in Sugen 5416/hypoxia (SU/Hx) rats after treatment with acetazolamide or ammonium chloride (NH4Cl). We evaluated pulmonary and systemic inflammation and characterized the effect of carbonic anhydrase inhibition and metabolic acidosis in alveolar macrophages and bone marrow-derived macrophages (BMDMs). We further evaluated the treatment effects on VSMC phenotypic switching in pulmonary arteries and pulmonary artery smooth muscle cells (PASMCs) and corroborated some of our findings in lungs and pulmonary arteries of patients with PAH. Both patients with idiopathic PAH and SU/Hx rats had increased expression of lung inflammatory markers and signs of PASMC dedifferentiation in pulmonary arteries. Acetazolamide and NH4Cl ameliorated SU/Hx-induced pulmonary hypertension and blunted pulmonary and systemic inflammation. Expression of carbonic anhydrase isoform 2 was increased in alveolar macrophages from SU/Hx animals, classically (M1) and alternatively (M2) activated BMDMs, and lungs of patients with PAH. Carbonic anhydrase inhibition and acidosis had distinct effects on M1 and M2 markers in BMDMs. Inflammatory cytokines drove PASMC dedifferentiation, and this was inhibited by acetazolamide and acidosis. The protective antiinflammatory effect of acetazolamide in pulmonary hypertension is mediated by a dual mechanism of macrophage carbonic anhydrase inhibition and systemic metabolic acidosis.

Acidosis and cancer: from mechanism to neutralization.

The extracellular pH of solid tumors is unequivocally acidic due to a combination of high rates of lactic acid production (a consequence of fermentative glycolytic metabolism) and poor perfusion. This has been documented by us and others in a wide variety of solid tumor models, primarily using magnetic resonance spectroscopic imaging (MRSI). This acidity contributes to tumor progression by inducing genome instability, promoting local invasion and metastases, inhibiting anti-tumor immunity, and conferring resistance to chemo- and radio-therapies. Systemic buffer therapies can neutralize tumor acidity and has been shown to inhibit local invasion and metastasis and improve immune surveillance in a variety of cancer model systems. This review will revisit the causes and consequences of acidosis by summarizing strategies used by cancer cells to adapt to acidosis, and how this acidity associated with carcinogenesis, metastasis, and immune function. Finally, this review will discuss how neutralization of acidity can be used to inhibit carcinogenesis and metastasis and improve anti-cancer immunotherapy.

Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages.

Many tumors evolve sophisticated strategies to evade the immune system, and these represent major obstacles for efficient antitumor immune responses. Here we explored a molecular mechanism of metabolic communication deployed by highly glycolytic tumors for immunoevasion. In contrast to colon adenocarcinomas, melanomas showed comparatively high glycolytic activity, which resulted in high acidification of the tumor microenvironment. This tumor acidosis induced Gprotein-coupled receptor-dependent expression of the transcriptional repressor ICER in tumor-associated macrophages that led to their functional polarization toward a non-inflammatory phenotype and promoted tumor growth. Collectively, our findings identify a molecular mechanism of metabolic communication between non-lymphoid tissue and the immune system that was exploited by high-glycolytic-rate tumors for evasion of the immune system.

Inflammatory mechanism of Rumenitis in dairy cows with subacute ruminal acidosis.

BACKGROUND: Subacute ruminal acidosis (SARA) is a metabolic disease in high-producing dairy cattle, and is accompanied by rumenitis. However, the mechanism of rumenitis remains unclear. Therefore, the aim of this study was to investigate the molecular mechanism of rumenitis in dairy cows with SARA. RESULTS: The results showed that SARA cows displayed high concentrations of ruminal volatile fatty acids, lactic acid and lipopolysaccharide (LPS). Furthermore, the blood concentrations of LPS and acute phase proteins haptoglobin, serum amyloid-A, and LPS binding protein were significantly higher in SARA cows than in control cows. Importantly, the phosphorylation levels of nuclear factor-kappaB (NF-κB) p65, inhibitor of NF-κB (IκB), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase 1/2 (ERK1/2) were significantly higher in the rumen epithelium of SARA cows than those of control cows. The ruminal mRNA and protein levels of NF-κB- and mitogen-activated protein kinase (MAPK)s -regulated inflammatory cytokines, tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 1ß (IL-1ß), were markedly higher in SARA cows than in control cows. Similarly, serum concentrations of TNF-α and IL-6 were also significantly higher in SARA cows. CONCLUSIONS: These results indicate that SARA results in high concentration of ruminal LPS, which over activates the NF-κB and MAPKs inflammatory pathways and then significantly increases the expression and synthesis of pro-inflammation cytokines in the rumen epithelium, thereby partly inducing rumenitis.

Hypoxia and acidosis: immune suppressors and therapeutic targets.

Due to imbalances between vascularity and cellular growth patterns, the tumour microenvironment harbours multiple metabolic stressors including hypoxia and acidosis, which have significant influences on remodelling both tumour and peritumoral tissues. These stressors are also immunosuppressive and can contribute to escape from immune surveillance. Understanding these effects and characterizing the pathways involved can identify new targets for therapy and may redefine our understanding of traditional anti-tumour therapies. In this review, the effects of hypoxia and acidosis on tumour immunity will be summarized, and how modulating these parameters and their sequelae can be a useful tool for future therapeutic interventions is discussed.

Unravelling the Interplay between Extracellular Acidosis and Immune Cells.

The development of an acidic tissue environment is a hallmark of a variety of inflammatory processes and solid tumors. However, little attention has been paid so far to analyze the influence exerted by extracellular pH on the immune response. Tissue acidosis (pH 6.0 to 7.0) is usually associated with the course of infectious processes in peripheral tissues. Moreover, it represents a prominent feature of solid tumors. In fact, values of pH ranging from 5.7 to 7.0 are usually found in a number of solid tumors such as breast cancer, brain tumors, sarcomas, malignant melanoma, squamous cell carcinomas, and adenocarcinomas. Both the innate and adaptive arms of the immune response appear to be finely regulated by extracellular acidosis in the range of pH values found at inflammatory sites and tumors. Low pH has been shown to delay neutrophil apoptosis, promoting their differentiation into a proangiogenic profile. Acting on monocytes and macrophages, it induces the activation of the inflammasome and the production of IL-1ß, while the exposure of conventional dendritic cells to low pH promotes the acquisition of a mature phenotype. Overall, these observations suggest that high concentrations of protons could be recognized by innate immune cells as a danger-associated molecular pattern (DAMP). On the other hand, by acting on T lymphocytes, low pH has been shown to suppress the cytotoxic response mediated by CD8+ T cells as well as the production of IFN-γ by TH1 cells. Interestingly, modulation of tumor microenvironment acidity has been shown to be able not only to reverse anergy in human and mouse tumor-infiltrating T lymphocytes but also to improve the antitumor immune response induced by checkpoint inhibitors. Here, we provide an integrated view of the influence exerted by low pH on immune cells and discuss its implications in the immune response against infectious agents and tumor cells.

Histamine Induces Bovine Rumen Epithelial Cell Inflammatory Response via NF-κB Pathway.

BACKGROUND/AIMS: Subacute ruminal acidosis (SARA) is a common disease in high-producing lactating cows. Rumenitis is the initial insult of SARA and is associated with the high concentrations of histamine produced in the rumen of dairy cows during SARA. However, the exact mechanism remains unclear. The objective of the current study is to investigate whether histamine induces inflammation of rumen epithelial cells and the underlying mechanism of this process. METHODS: Bovine rumen epithelial cells were cultured and treated with different concentrations of histamine and pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) cultured in different pH medium (pH 7.2 or 5.5). qRT-PCR, Western-blotting, ELISA and immunocytofluorescence were used to evaluate whether histamine activated the NF-κB pathway and inflammatory cytokines. RESULTS: The results showed that histamine significantly increased the activity of IKK ß and the phosphorylation levels of IκB α, as well as upregulated the mRNA and protein expression levels of NF-κB p65 in the rumen epithelial cells cultured in neutral (pH=7.2) and acidic (pH=5.5) medium. Furthermore, histamine treatment also significantly increased the transcriptional activity of NF-κB p65. High expression and transcriptional activity of NF-κB p65 significantly increased the mRNA expressions and concentrations of inflammatory cytokines, tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1ß), thereby inducing the inflammatory response in bovine rumen epithelial cells. However, inhibition of NF-κB p65 by PDTC significantly decreased the expressions and concentrations of the inflammatory cytokines induced by histamine in the rumen epithelial cells cultured in the neutral and acidic medium. CONCLUSION: The present data indicate that histamine induces the inflammatory response of bovine rumen epithelial cells through the NF-κB pathway.

The acidic microenvironment as a possible niche of dormant tumor cells.

Although surgical excision, chemo-, and radio-therapy are clearly advanced, tumors may relapse due to cells of the so-called "minimal residual disease". Indeed, small clusters of tumor cells persist in host tissues after treatment of the primary tumor elaborating strategies to survive and escape from immunological attacks before their relapse: this variable period of remission is known as "cancer dormancy". Therefore, it is crucial to understand and consider the major concepts addressing dormancy, to identify new targets and disclose potential clinical strategies. Here, we have particularly focused the relationships between tumor microenvironment and cancer dormancy, looking at a re-appreciated aspect of this compartment that is the low extracellular pH. Accumulating evidences indicate that acidity of tumor microenvironment is associated with a poor prognosis of tumor-bearing patients, stimulates a chemo- and radio-therapy resistant phenotype, and suppresses the tumoricidal activity of cytotoxic lymphocytes and natural killer cells, and all these aspects are useful for dormancy. Therefore, this review discusses the possibility that acidity of tumor microenvironment may provide a new, not previously suggested, adequate milieu for "dormancy" of tumor cells.

Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-γ and induces NK cell-dependent lymphoma control without other immunotherapies.

Like other immune cells, natural killer (NK) cells show impaired effector functions in the microenvironment of tumors, but little is known on the underlying mechanisms. Since lactate acidosis, a hallmark of malignant tissue, was shown to contribute to suppression of effective antitumor immune responses, we investigated the impact of tissue pH and lactate concentration on NK-cell functions in an aggressive model of endogenously arising B-cell lymphoma. The progressive loss of IFN-γ production by NK cells observed during development of this disease could be ascribed to decreased pH values and lactate accumulation in the microenvironment of growing tumors. Interestingly, IFN-γ expression by lymphoma-derived NK cells could be restored by transfer of these cells into a normal micromilieu. Likewise, systemic alkalization by oral delivery of bicarbonate to lymphoma-developing mice was capable of enhancing IFN-γ expression in NK cells and increasing the NK-cell numbers in the lymphoid organs where tumors were growing. By contrast, NK-cell cytotoxicity was dampened in vivo by tumor-dependent mechanisms that seemed to be different from lactate acidosis and could not be restored in a normal milieu. Most importantly, alkalization and the concomitant IFN-γ upregulation in NK cells were sufficient to significantly delay tumor growth without any other immunotherapy. This effect was strictly dependent on NK cells.

Small-Volume Adenosine, Lidocaine, and Mg2+ 4-Hour Infusion Leads to 88% Survival after 6 Days of Experimental Sepsis in the Rat without Antibiotics.

Innovative host-directed drug therapies are urgently required to treat sepsis. We tested the effect of a small-volume 0.9% NaCl adenosine, lidocaine, and Mg2+ (ALM) bolus and a 4-h intravenous infusion on survivability in the rat model of polymicrobial sepsis over 6 days. ALM treatment led to a significant increase in survivability (88%) compared to that of controls (25%). Four controls died on day 2 to 3, and two died on day 5. Early death was associated with elevated plasma and lung inflammatory markers (interleukin-6 [IL-6], IL-1ß, C-reactive protein), reduced white blood cell (WBC) count, hypoxemia, hypercapnia, acidosis, hyperkalemia, and elevated lactate, whereas late death was associated with a massive cytokine storm, a neutrophil-dominated WBC rebound/overshoot, increased lung oxidant injury, edema, and persistent ischemia. On day 6, seven of eight ALM survivors had inflammatory and immunological profiles not significantly different from those of sham-treated animals. We conclude in the rat model of experimental sepsis that small-volume ALM treatment led to higher survivability at 6 days (88%) than that of controls (25%). Early death in controls (day 2 to 3) was associated with significantly elevated plasma levels of IL-1ß, IL-6, and C-reactive protein, severe plasma lymphocyte deficiency, reduced neutrophils, and acute lung injury. Late death (day 5) was associated with a massive neutrophil inflammatory storm, increased lung injury, and persistent ischemia. Possible mechanisms of ALM protection are discussed.

Acidosis differently modulates the inflammatory program in monocytes and macrophages.

Inflammation, ischemia or the microenvironment of solid tumors is often accompanied by a reduction of extracellular pH (acidosis) that stresses the cells and acts on cellular signaling and transcription. The effect of acidosis on the expression of various inflammatory markers, on functional parameters (migration, phagocytic activity) and on signaling pathways involved was studied in monocytic cells and macrophages. In monocytic cell lines acidosis led to a reduction in expression of most of the inflammatory mediators, namely IL-1ß, IL-6, TNF-α, MCP-1, COX-2 and osteopontin. In primary human monocytes MCP-1 and TNF-α were reduced but COX-2 and IL-6 were increased. In RAW264.7 macrophage cell line IL-1ß, COX-2 and iNOS expression was increased, whereas MCP-1 was reduced similar to the effect in monocytic cells. For primary human monocyte-derived macrophages the regulation of inflammatory markers by acidosis depended on activation state, except for the acidosis-induced downregulation of MCP-1 and TNF-α. Acidosis affected functional immune cell behavior when looking at phagocytic activity which was increased in a time-dependent manner, but cellular motility was not changed. Neither ERK1/2 nor CREB signaling was stimulated by the reduction of extracellular pH. However, p38 was activated by acidosis in RAW264.7 cells and this activation was critical for the induction of IL-1ß, COX-2 and iNOS expression. In conclusion, acidosis may impede the recruitment of immune cells, but fosters inflammation when macrophages are present by increasing the level of COX-2 and iNOS and by functionally forcing up the phagocytic activity.

Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes.

The major effector cells for cellular adaptive immunity are CD8(+) cytotoxic T lymphocytes (CTLs), which can recognize and kill virus-infected cells and tumor cells. Although CTLs exhibit strong cytolytic activity against target cells in vitro, a number of studies have demonstrated that their function is often impaired within tumors. Nevertheless, CTLs can regain their cytotoxic ability after escaping from the tumor environment, suggesting that the milieu created by tumors may affect the function of CTLs. As for the tumor environment, the patho-physiological situation present in vivo has been shown to differ from in vitro experimental conditions. In particular, low pH and hypoxia are the most important microenvironmental factors within growing tumors. In the present study, to determine the effect of these factors on CTL function in vivo, we examined the cytolytic activity of CTLs against their targets using murine CTL lines and the induction of these cells from memory cells under low pH or hypoxic conditions using antigen-primed spleen cells. The results indicated that both cytotoxic activity and the induction of functional CTLs were markedly inhibited under low pH. In contrast, in hypoxic conditions, although cytotoxic activity was almost unchanged, the induction of CTLs in vitro showed a slight enhancement, which was completely abrogated in low pH conditions. Therefore, antigen-specific CTL functions may be more vulnerable to low pH than to the oxygen concentration in vivo. The findings shown here provide new therapeutic approaches for controlling tumor growth by retaining CTL cytotoxicity through the maintenance of higher pH conditions.

Extracellular acidosis is a novel danger signal alerting innate immunity via the NLRP3 inflammasome.

BACKGROUND: Local acidosis has been demonstrated in ischemic tissues and at inflammatory sites. RESULTS: Acidic extracellular pH triggers NLRP3 inflammasome activation and interleukin-1ß secretion in human macrophages. CONCLUSION: Acidic pH represents a novel danger signal alerting the innate immunity. SIGNIFICANCE: Local acidosis may promote inflammation at ischemic and inflammatory sites. Local extracellular acidification has been demonstrated at sites of ischemia and inflammation. IL-1ß is one of the key proinflammatory cytokines, and thus, its synthesis and secretion are tightly regulated. The NLRP3 (nucleotide-binding domain leucine-rich repeat containing family, pyrin domain containing 3) inflammasome complex, assembled in response to microbial components or endogenous danger signals, triggers caspase-1-mediated maturation and secretion of IL-1ß. In this study, we explored whether acidic environment is sensed by immune cells as an inflammasome-activating danger signal. Human macrophages were exposed to custom cell culture media at pH 7.5-6.0. Acidic medium triggered pH-dependent secretion of IL-1ß and activation of caspase-1 via a mechanism involving potassium efflux from the cells. Acidic extracellular pH caused rapid intracellular acidification, and the IL-1ß-inducing effect of acidic medium could be mimicked by acidifying the cytosol with bafilomycin A1, a proton pump inhibitor. Knocking down the mRNA expression of NLRP3 receptor abolished IL-1ß secretion at acidic pH. Remarkably, alkaline extracellular pH strongly inhibited the IL-1ß response to several known NLRP3 activators, demonstrating bipartite regulatory potential of pH on the activity of this inflammasome. The data suggest that acidic environment represents a novel endogenous danger signal alerting the innate immunity. Low pH may thus contribute to inflammation in acidosis-associated pathologies such as atherosclerosis and post-ischemic inflammatory responses.

[Remaxol in pharmacological correction of long-term disorders caused by acute ethylene glycol poisoning].

The effect of remaxol therapy as a part of the complex acute treatment of ethylene glycol poisoning has been experimentally studied on rats. Special attention was paid to the development of acidosis and hypoxia and a decrease in the functional activity of the urinary and immune systems. It was shown that remaxol is capable of restoring the functional activity of organs and systems susceptible to the toxic effect of ethylene glycol. It is suggested that the therapeutic efficiency of remaxol is based on the normalization of metabolic processes in the cell.

Extracellular acidosis promotes neutrophil transdifferentiation to MHC class II-expressing cells.

Inflammation in peripheral tissues is usually associated with local acidosis. In the present study, we demonstrate that extracellular acidification enhances GM-CSF- and IFN-γ-induced expression of HLA-DR, CD80 and CD86 in human neutrophils (neutrophil transdifferentiation), and potentiates antigen-capturing capacities (both endocytosis and phagocytosis) of the transdifferentiated cells. Furthermore, in acidic conditions the transdifferentiated neutrophils have stronger antigen-presenting capacity, inducing more intense proliferation of autologous T lymphocytes in the presence of staphylococcal enterotoxin A. Thus, extracellular acidosis can represent a factor that promotes neutrophil transdifferentiation and potentiates the functional abilities of the transdifferentiated cells in inflammatory foci in vivo.