Peripheral Tissue Inflammation Research Articles

The Enigmatic Charcot-Leyden Crystal Protein (Galectin-10): Speculative Role(s) in the Eosinophil Biology and Function

Eosinophilic inflammation in peripheral tissues is typically marked by the deposition of a prominent eosinophil protein, Galectin-10, better known as Charcot-Leyden crystal protein (CLC). Unlike the eosinophil’s four distinct toxic cationic proteins and enzymes [major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO)], there is a paucity of information on the precise role of the crystal protein in the biology of the eosinophil. While its clinical significance at inflammatory foci remains highly speculative, its relative abundance (~10% of total eosinophil protein), as well as its dual nuclear and cytosolic localization is, however, suggestive of its biological and functional significance. In this article, we present a short review of the Charcot-Leyden crystal protein, specifically highlighting its most recently delineated modulatory role in regulatory T lymphocytes, and its speculative intracellular and extracellular role(s) in eosinophil function or associated inflammatory responses.

Steroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1.

Use of aromatase inhibitors (AIs), exemestane, letrozole and anastrozole, for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. The electrophilic nature of AIs suggests that they may target the transient receptor potential ankyrin 1 (TRPA1) channel, a major pathway in pain transmission and neurogenic inflammation. AIs evoke TRPA1-mediated calcium response and current in rodent nociceptors and human cells expressing the recombinant channel. In mice, AIs produce acute nociception, which is exaggerated by pre-exposure to proalgesic stimuli, and, by releasing sensory neuropeptides, neurogenic inflammation in peripheral tissues. AIs also evoke mechanical allodynia and decreased grip strength, which do not undergo desensitization on prolonged AI administration. These effects are markedly attenuated by TRPA1 pharmacological blockade or in TRPA1-deficient mice. TRPA1 is a major mediator of the proinflammatory/proalgesic actions of AIs, thus suggesting TRPA1 antagonists for the treatment of pain symptoms associated with AI use.

STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation.

T helper (TH)-cell subsets, such as TH1 and TH17, mediate inflammation in both peripheral tissues and central nervous system. Here we show that STAT5 is required for T helper-cell pathogenicity in autoimmune neuroinflammation but not in experimental colitis. Although STAT5 promotes regulatory T cell generation and immune suppression, loss of STAT5 in CD4+ T cells resulted in diminished development of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Our results showed that loss of encephalitogenic activity of STAT5-deficient autoreactive CD4+ T cells was independent of IFN-γ or interleukin 17 (IL-17) production, but was due to the impaired expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a crucial mediator of T-cell pathogenicity. We further showed that IL-7-activated STAT5 promotes the generation of GM-CSF-producing CD4+ T cells, which were preferentially able to induce more severe EAE than TH17 or TH1 cells. Consistent with GM-CSF-producing cells being a distinct subset of TH cells, the differentiation program of these cells was distinct from that of TH17 or TH1 cells. We further found that IL-3 was secreted in a similar pattern as GM-CSF in this subset of TH cells. In conclusion, the IL-7-STAT5 axis promotes the generation of GM-CSF/IL-3-producing TH cells. These cells display a distinct transcriptional profile and may represent a novel subset of T helper cells which we designate as TH-GM.

Pain in fibromyalgia and related conditions.

Pain is the hallmark symptom of fibromyalgia (FM) and other related syndromes, but quite different from that of other rheumatic diseases, which depends on the degree of damage or inflammation in peripheral tissues. Sufferers are often defined as patients with chronic pain without an underlying mechanistic cause, and these syndromes and their symptoms are most appropriately described as "central pain", "neuropathic pain", "nonnociceptive pain" or "central sensitivity syndromes". The pain is particular, regional or widespread, and mainly relates to the musculoskeletal system; hyperalgesia or allodynia are typical. Its origin is currently considered to be distorted pain or sensory processing, rather than a local or regional abnormality. FM is probably the most important and extensively described central pain syndrome, but the characteristics and features of FM-related pain are similar in other disorders of particular interest for rheumatologists, such as myofascial pain syndromes and temporo-mandibular joint disorders, and there is also an intriguing overlap between FM and benign joint hypermobility syndrome. This suggests that the distinctive aspects of pain in these idiopathic or functional conditions is caused by central nervous system hypersensitivity and abnormalities. Pharmacological and non-pharmacological therapies have been suggested for the treatment of these conditions, but a multidisciplinary approach is required in order to reduce the abnormal cycle of pain amplification and the related maladaptive and self-limiting behaviours.

Tachykinin: recent developments and novel roles in health and disease.

Over 80 years has passed since the discovery of substance P (SP), and a variety of peptides of the tachykinin (TK) family have been found and investigated. SP, neurokinin A (NKA), and neurokinin B (NKB) are representative peptides in mammalian species. SP and NKA are major excitatory neurotransmitters in the peripheral nervous system, while NKB is primarily involved in the central nervous system (CNS). Moreover, TK peptides play roles not only as neurotransmitters but also as local factors and are involved in almost all aspects of the regulation of physiological functions and pathophysiological processes. The role of SP as a mediator of pain processing and inflammation in peripheral tissues in coordination with transient receptor potential channels is well established, while novel aspects of TKs in relation to hematopoiesis, venous thromboembolism, tendinopathy, and taste perception have been clarified. In the CNS, the NKB signaling system in the hypothalamus has been shown to play a crucial role in the regulation of gonadotropin hormone secretion and the onset of puberty, and molecular biological studies have elucidated novel prophylaxic activities of TKs against neurogenic movement disorders based on their molecular structure. This review provides an overview of the novel aspects of TKs reported around the world in the last 5 years, with particular focus on nociception, inflammation, hemopoiesis, gonadotropin secretion, and CNS diseases.

Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.

Pharmacology of the capsaicin receptor, transient receptor potential vanilloid type-1 ion channel.

The capsaicin receptor, transient receptor potential vanilloid type 1 ion channel (TRPV1), has been identified as a polymodal transducer molecule on a sub-set of primary sensory neurons which responds to various stimuli including noxious heat (> -42 degrees C), protons and vanilloids such as capsaicin, the hot ingredient of chilli peppers. Subsequently, TRPV1 has been found indispensable for the development of burning pain and reflex hyperactivity associated with inflammation of peripheral tissues and viscera, respectively. Therefore, TRPV1 is regarded as a major target for the development of novel agents for the control of pain and visceral hyperreflexia in inflammatory conditions. Initial efforts to introduce agents acting on TRPV1 into clinics have been hampered by unexpected side-effects due to wider than expected expression in various tissues, as well as by the complex pharmacology, of TRPV1. However, it is believed that better understanding of the pharmacological properties of TRPV1 and specific targeting of tissues may eventually lead to the development of clinically useful agents. In order to assist better understanding of TRPV1 pharmacology, here we are giving a comprehensive account on the activation and inactivation mechanisms and the structure-function relationship of TRPV1.

Comparative Effect of Cannabis, Aspirin and Cataflam on Nociception in Cd1 Mice

The effects of cataflam, aspirin and the ethanolic extract of Cannabis sativa on nociception was studied in albino mice of both sexes. Forty (40) albino mice were divided into four (4) groups of ten (10) each. The control group was given normal saline (p.o). Test group one (1) was given (p.o) cataflam at a dose of 1.5mg/kg. Test group two (2) was given (p.o) aspirin at a dose of 13.5mg/kg. Test group three (3) was given the ethanolic extract of Cannabis sativa at a dose of 10mg/kg. All four (4) groups were given access to normal mice chow and water ad libitum. The hot plate test was used to assess the effects of the test substances on sensitivity to acute thermal pain while the formalin test was used to assess the sensitivity to persistent pain due to peripheral tissue injury and inflammation. The result shows that Cannabis, Cataflam and Aspirin all reduce sensitivity to pain. This is indicated by the reduction in frequency and duration of hind paw licking in both phases of the formalin test (p<0.05). Cataflam and Cannabis may not have any effect on sensitivity to acute thermal pain. There was no significant difference in the latency of jump in the groups treated with Cataflam and Cannabis during the hot plate test compared to control (p<0.05). But they all reduce sensitivity to persistent inflammatory pain.

Inflammasome-Mediated Secretion of IL-1β in Human Monocytes through TLR2 Activation; Modulation by Dietary Fatty Acids

Many studies have shown that TLR4- and TLR2-deficient mice are protected from high-fat diet-induced inflammation and insulin resistance, suggesting that saturated fatty acids derived from the high-fat diet activate TLR-mediated proinflammatory signaling pathways and induce insulin resistance. However, evidence that palmitic acid, the major dietary saturated fatty acid, can directly activate TLR has not been demonstrated. In this article, we present multiple lines of evidence showing that palmitic acid directly activates TLR2, a major TLR expressed on human monocytes, by inducing heterodimerization with TLR1 in an NADPH oxidase-dependent manner. Dimerization of TLR2 with TLR1 was inhibited by the n-3 fatty acid docosahexaenoic acid. Activation of TLR2 by palmitic acid leads to expression of pro-IL-1β that is cleaved by caspase-1, which is constitutively present in monocytes, to release mature IL-1β. Our results reveal mechanistic insight about how palmitic acid activates TLR2, upregulates NALP3 expression, and induces inflammasome-mediated IL-1β production in human monocytes, which can trigger enhanced inflammation in peripheral tissues, and suggest that these processes are dynamically modulated by the types of dietary fat we consume.

Non‐alcoholic steatohepatitis: Pathogenesis and novel therapeutic approaches

Non-alcoholic fatty liver disease (NAFLD) refers to a disease spectrum, ranging from mere hepatic steatosis to hepatic necroinflammation (NASH, non-alcoholic steatohepatitis). NASH often leads to fibrosis, which can progress to cirrhosis with a high risk of liver failure and hepatocellular carcinoma. The course of NAFLD is highly variable, and only a minority of patients (2-3%) progress to end-stage liver disease. However, due to a dramatic increase of the risk factors for NAFLD, that is obesity and insulin resistance/type 2 diabetes, that affect 15-30% and 7-15% of subjects, in most industrialized countries, respectively, NAFLD has become the most frequent liver disease and is even considered a pace setter of the metabolic syndrome. Sedentary lifestyle, modern Western nutrition, and genetic predispositions have been identified as major causes of NAFLD. These lead to liver injury via insulin resistance and an excess of free fatty acids in hepatocytes, resulting in oxidant stress and lipotoxicity that promote the activation of intracellular stress kinases and apoptosis or necroapoptosis (NASH). The damaged hepatocytes directly trigger inflammation and fibrogenesis, but can also lead to the emergence of fibrogenic progenitor cells. Moreover, NASH is linked to inflammation in peripheral adipose tissues that involves mainly macrophages and humoral factors, such as adipokines and cytokines. The most efficient treatment is by weight loss and exercise, but (adjunctive) pharmacological strategies are urgently needed. Here, we highlight the aspects of NAFLD epidemiology and pathophysiology that are beginning to lead to novel pharmacological approaches to address this growing health-care challenge.

Obesity induced by a high-fat diet is associated with increased immune cell entry into the central nervous system.

Obesity is associated with chronic low-grade inflammation in peripheral tissues caused, in part, by the recruitment of inflammatory monocytes into adipose tissue. Studies in rodent models have also shown increased inflammation in the central nervous system (CNS) during obesity. The goal of this study was to determine whether obesity is associated with recruitment of peripheral immune cells into the CNS. To do this we used a bone marrow chimerism model to track the entry of green-fluorescent protein (GFP) labeled peripheral immune cells into the CNS. Flow cytometry was used to quantify the number of GFP(+) immune cells recruited into the CNS of mice fed a high-fat diet compared to standard chow fed controls. High-fat feeding resulted in obesity associated with a 30% increase in the number of GFP(+) cells in the CNS compared to control mice. Greater than 80% of the GFP(+) cells recruited to the CNS were also CD45(+) CD11b(+) indicating that the GFP(+) cells displayed characteristics of microglia/macrophages. Immunohistochemistry further confirmed the increase in GFP(+) cells in the CNS of the high-fat fed group and also indicated that 93% of the recruited cells were found in the parenchyma and had a stellate morphology. These findings indicate that peripheral immune cells can be recruited to the CNS in obesity and may contribute to the inflammatory response.

Analgesic Effect of the Neuropeptide Cortistatin in Murine Models of Arthritic Inflammatory Pain

To investigate the role of the antiinflammatory neuropeptide cortistatin in chronic pain evoked by joint inflammation. Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo. Expression of cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi , impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors. These findings indicate that cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory states, including osteoarthritis and rheumatoid arthritis.

Abstract 4342: 2B3-201, glutathione pegylated liposomal methylprednisolone, prevents chemotherapy-induced neuropathic pain.

Abstract Chemotherapy-induced peripheral neuropathy is a dose-limiting debilitating symptom that can affect many patients treated with anticancer treatments. The resulting neuropathic pain is thought to be a peripheral symptom, however, central sensitization has recently been suggested as a possible causal mechanism for chronic pain conditions; nociceptive neurons in the dorsal horns of the spinal cord become sensitized by a neuroinflammatory response through chronic peripheral tissue damage or inflammation [Zhuo, 2012]. Centrally active anti-inflammatory therapies, such as methylprednisolone (MP), may therefore have beneficial therapeutic properties, but its effective use is limited by several (severe) acute and chronic side effects or highly invasive local delivery routes. Systemic administrations of encapsulated MP in glutathione PEGylated liposomes (2B3-201) have recently resulted in superior efficacy and reduced side effects compared to the free MP in rodent models with neuroinflammation [Gaillard, 2012]. Therefore, 2B3-201 was hypothesized to have therapeutic value in preventing chemo-induced neuropathic pain as well. 2B3-201 was initially investigated in a pharmacokinetic and biodistribution study and compared to free MP, showing an enhanced plasma circulation (half life of ∼7 hours vs. several minutes for free MP), and higher sustained levels of 2B3-201 in brain and spinal cord. Furthermore, 2B3-201 did not result in psychotic-like behavioral effects in rats, as were caused by free MP. Also, repeated weekly administrations of 2B3-201 were well tolerated in rats, while the same weekly doses of free MP were causing side effects. The efficacy of 2B3-201 was investigated at WuXi AppTec (Shanghai, China) in two chemo-induced neuropathic pain models with demonstrated spinal cord pathology as a consequence of repeated bortezomib or paclitaxel administrations. Rats received paclitaxel (1 mg/kg/day, 8x) or bortezomib (0.2 mg/kg/day, 8x), and the effect of 2B3-201 on mechanical allodynia was evaluated at three dose levels (10, 20, or 30 mg/kg). Rats were monitored daily and allodynic measurements were taken at baseline and from days 4 to 8 after treatment start. The body weight gain of the rats was slightly inhibited by paclitaxel and bortezomib, and co-therapy with 2B3-201 showed a dose-dependent larger inhibition of weight gain. Despite the increased signs of chemotherapeutic side effects on body weight, 2B3-201 dose-dependently relieved neuropathic pain in both models. At the highest dose, the significant effect of 2B3-201 on neuropathic pain was no longer observed, which was probably due to the more severe chemotherapeutic side effects. In conclusion, the positive treatment effect of 2B3-201 against chemotherapy-induced neuropathic pain, in combination with a good PK, biodistribution and safety profile, warrant the further development of 2B3-201 for this indication. Citation Format: Pieter J. Gaillard, Rick Dorland, Chantal C. Appeldoorn. 2B3-201, glutathione pegylated liposomal methylprednisolone, prevents chemotherapy-induced neuropathic pain. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2013-4342

Modulation of adipokines by n-3 polyunsaturated fatty acids and ensuing changes in skeletal muscle metabolic response and inflammation

Adipose tissue represents an important endocrine organ that secretes a multitude of adipokines known to mediate inflammation, lipid metabolism, and insulin sensitivity in peripheral tissues, such as skeletal muscle. Specifically, adiponectin stimulates skeletal muscle fatty acid oxidation and is associated with improvements in insulin response. Long-chain n-3 polyunsaturated fatty acids (PUFA) are well known for their anti-inflammatory and insulin-sensitizing properties, and their dietary consumption is associated with a more favourable circulating adipokine profile, including increased adiponectin. However, whether n-3 PUFA can directly stimulate adiponectin secretion from human adipocytes, as well as the underlying mechanisms involved, is unknown. In contrast to n-3 PUFA, diets high in saturated fatty acids (SFA) are thought to decrease adiponectin and increase pro-inflammatory adipokines, as well as blunt skeletal muscle response to both adiponectin and insulin, possibly via activation of inflammatory pathways. The role of n-3 PUFA in mediating the communication between adipose tissue and skeletal muscle, as well as preventing SFA-induced impairments in skeletal muscle function, has yet to be examined. In this thesis, it was found that long-chain n-3 PUFA increase adiponectin secretion from human adipocytes via a peroxisome proliferator-activated receptor γ-dependent mechanism. The effects of n-3 PUFA on adiponectin secretion were additive when combined with the thiazolidinedione, rosiglitazone. Second, incorporation of n-3 PUFA into a high SFA diet prevented impairments in adiponectin response and both prevented and restored impairments in insulin response in rodent skeletal muscle. Interestingly, these findings were paralleled by prevention of SFA-induced increases in toll-like receptor 4 expression by n-3 PUFA, suggesting inflammatory changes may be involved. Finally, dietary n-3 PUFA and SFA modulated the secretion of adipose tissue-derived factors from visceral rodent adipose tissue and subsequent exposure of isolated skeletal muscle to such factors induced acute changes in inflammatory gene expression without affecting insulin sensitivity. Together, the findings in this thesis suggest that n-3 PUFA modulate adipokine secretion from adipose tissue and that adipose-derived factors mediate skeletal muscle inflammation and response to adiponectin and insulin. Ultimately, this work highlights the importance of considering n-3 PUFA as a therapeutic strategy in the prevention and treatment of obesity and related pathologies.

Regional astrogliosis in the mouse hypothalamus in response to obesity.

Obesity is associated with chronic low-grade inflammation in peripheral tissues, which contributes to the development of comorbidities such as insulin resistance and cardiovascular disease. While less extensively characterized, obesity also promotes inflammation in the central nervous system (CNS) and the consequences of this inflammation for CNS function are only beginning to be examined. In response to CNS insults such as inflammation, astrocytes undergo a process of hypertrophy and hyperplasia known as reactive astrogliosis. We used immunohistochemistry to examine the differential distribution of the astrocyte marker glial-fibrillary acidic protein (GFAP) in the brains of diet-induced or genetically obese mice compared with their respective lean controls to determine whether different nuclei of the hypothalamus showed comparable astrogliosis in response to obesity. The areas that showed the highest differential GFAP immunoreactivity between lean and obese animals include the medial preoptic, paraventricular, and dorsomedial nuclei. Comparatively, little astrogliosis was seen in the ventromedial nucleus, lateral hypothalamus, or anterior hypothalamic area. In obese animals high levels of GFAP immunoreactivity were often associated with the microvasculature. There were no differences in the differential distribution of GFAP staining between obese animals and their lean controls in the diet-induced compared with the genetic model of obesity. The exact cause(s) of the astrogliosis in obesity is not known. The finding that obesity causes a distinct pattern of elevated GFAP immunoreactivity associated with microvessels suggests that the astrogliosis may be occurring as a response to changes at the blood-brain barrier and/or in the peripheral circulation.

Regulation of the β-endorphin precursor proopiomelanocortin in lymphocytes in a rat model of inflammatory pain

Our previous studies have shown that monocytes/macrophages, granulocytes, and lymphocytes release opioid peptides in the presence of different releasing factors at the site of peripheral tissue injury or inflammation and thereby contribute to opioid-mediated reduction of pain. We are interested in the regulation of β-endorphin and its precursor proopiomelanocortin (POMC) at the transcriptional and posttranslational level in lymphocytes, as such cells play a role in chronic inflammation. We hypothesized that (i) POMC gene expression in the lymph node draining inflamed tissue is up-regulated in inflammation, and (ii) that the precursor is cleaved by the prohormone convertases (PC)1 and PC2 similar to neuroendocrine cells in the pituitary gland. We found elevated POMC gene expression and β-endorphin levels in cells of lymph nodes draining inflamed tissue, as assessed by qPCR and radioimmunoassay. Our PCR and immunocytochemistry data show that PC1 mRNA and protein expression, respectively, are induced after induction of inflammation. PC2 required no stimulation and was detectable using PCR and immunocytochemistry, both, in cells from nai¨ve and activated lymph nodes. Our findings indicate that β-endorphin synthesis in lymphocytes may depend on the presence of PC1/3, while PC2 alone does not seem to be sufficient. Functional experiments are necessary to verify the specific roles of these enzymes for POMC processing in cells of the immune system.

Epigenetic Modifications of IL-12 Gene Expression in Bone Marrow Hematopoietic Stem Cells Promote An M1, Pro-inflammatory Phenotype in Diabetic Peripheral Macrophages

Diabetic peripheral wounds are characterized by a chronic inflammatory state that is maintained by an exaggerated M1 (pro-inflammatory) macrophage response. M1 macrophages produce pro-inflammatory cytokines, such as IL-12, that promote chronic inflammation in peripheral tissues. Accumulating evidence suggests that epigenetics plays a key role in influencing immune cell phenotype. It is our hypothesis that epigenetic changes occur in the bone marrow progenitor cells of diabetics that result in a “programmed and persistent” peripheral macrophage phenotype that results in chronic inflammation in peripheral tissue.

Activation of peripheral P2X receptors is sufficient to induce central sensitization in rat medullary dorsal horn nociceptive neurons

Central sensitization and purinergic receptor mechanisms have been implicated as important processes in acute and chronic pain conditions following injury or inflammation of peripheral tissues. This study has documented that application of the P2X1,2/3,3 receptor agonist αβ-meATP (100mM) to the rat tooth pulp induces central sensitization in medullary dorsal horn nociceptive neurons that is reflected in significant increases in mechanoreceptive field size and responses to noxious stimuli and decreased mechanical activation threshold. Furthermore, these responses can be blocked by pulp application of the P2X1,2/3,3 antagonist TNP-ATP and also attenuated by medullary application of TNP-ATP. These results suggest that activation of P2X1,2/3,3 receptors in orofacial tissues plays a critical role in producing central sensitization in medullary dorsal horn nociceptive neurons.

Lack of T cells in Act1-deficient mice results in elevated IgM-specific autoantibodies but reduced lupus-like disease

Act1 is a negative regulator of B-cell activation factor of the TNF family (BAFF) and CD40L-induced signaling. BALB/C mice lacking Act1 develop systemic autoimmunity resembling systemic lupus erythematosus (SLE) and Sjögren's syndrome (SjS). SLE and SjS are characterized by anti-nuclear IgG autoantibody (ANA-IgG) production and inflammation of peripheral tissues. As autoantibody production can occur in a T-cell dependent or T-cell independent manner, we investigated the role of T-cell help during Act1-mediated autoimmunity. Act1-deficiency was bred onto C57Bl/6 (B6.Act1(-/-) ) mice and B6.TCRβ(-/-) TCRδ(-/-) Act1(-/-) (TKO) mice were generated. While TCRβ/δ-sufficient B6.Act1(-/-) mice developed splenomegaly and lymphadenopathy, hypergammaglobulinemia, elevated levels of ANA-IgG, and kidney pathology, TKO mice failed to develop any such signs of disease. Neither B6.Act1(-/-) nor TKO mice developed SjS-like disease, suggesting that epigenetic interactions on the BALB/C background are responsible for this phenotype in BALB/C.Act1(-/-) mice. Interestingly, BAFF-driven transitional B-cell abnormalities, previously reported in BALB/C.Act1(-/-) mice, were intact in B6.Act1(-/-) mice and largely independent of T cells. In conclusion, T cells are necessary for the development of SLE-like disease in B6.Act1(-/-) mice, but not BAFF-driven transitional B-cell differentiation.

The Saturated Fatty Acid Palmitate Induces Human Monocytic Cell Toxicity Toward Neuronal Cells: Exploring a Possible Link Between Obesity-Related Metabolic Impairments and Neuroinflammation

Obesity is linked to increased risk of Alzheimer's disease and cognitive impairment. Microglia-mediated neuroinflammation is implicated in neuronal loss. Elevated levels of fatty acids seen in obesity induce inflammation in peripheral tissues. Whether fatty acids promote neuroinflammation is unknown. Using an established neuroinflammation model involving human microglia-like THP-1 cells and SH-SY5Y neuroblastoma cells, we show that the saturated fatty acid palmitate, but not the unsaturated fatty acids oleate or linoleate, induces THP-1 cell pro-inflammatory cytokine secretion and neurotoxicity. Inhibition of c-Jun NH2-terminal kinase (JNK) reduces this neurotoxicity. Therefore, elevated saturated fatty acids may induce neuroinflammation through pathways involving JNK activation.