Inflammatory Loop Research Articles

Correction to Inhibitory Effect of Methyl 2-(4'-Methoxy-4'-oxobutanamide) Benzoate from Jerusalem Artichoke ( Helianthus tuberosus) on the Inflammatory Paracrine Loop between Macrophages and Adipocytes.

The interaction between macrophages and adipocytes is known to aggravate inflammation of the adipose tissue, leading to decreased insulin sensitivity. Hence, attenuation of the inflammatory paracrine loop between macrophages and adipocytes is deemed essential to ameliorate insulin resistance and diabetes mellitus type 2. Methyl 2-(4'-methoxy-4'-oxobutanamide) benzoate (compound 1), a newly isolated compound from Jerusalem srtichoke (JA), has not been biologically characterized yet. Here, we investigated whether JA-derived compound 1 attenuates the inflammatory cycle between RAW 264.7 macrophages and 3T3-L1 adipocytes. Compound 1 suppressed the inflammatory response of RAW 264.7 cells to lipopolysaccharide through decreased secretion of IL-1β, IL-6, and TNF-α. Moreover, the mRNA expression of TNF-α, IL-6, IL-1β, MCP-1, and Rantes and MAPK pathway activation in 3T3-L1 adipocytes, incubated in macrophage-conditioned media, were inhibited. These findings suggest an anti-inflammatory effect of a newly extracted compound against adipose tissue inflammation and insulin resistance.

Apolipoprotein B binds to enolase-1 and aggravates inflammation in rheumatoid arthritis

ObjectiveImmune cells from patients with rheumatoid arthritis (RA) express more enolase-1 (ENO1) on their surface than those from healthy subjects, and they elicit an enhanced inflammatory response. This study is...

Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review

ABSTRACTIntroduction: Psoriasis (PsO) is an inflammatory disorder characterized by proliferation of keratinocytes, and it may be associated with a systemic inflammatory articular disorder, psoriatic arthritis (PsA). The presentations of PsO and PsA are heterogeneous, and our understanding of pathogenesis has led to a better understanding of the role of the interleukin (IL)-23/T-helper 17 (Th17) axis.Areas covered: Ustekinumab is a monoclonal antibody against IL-12 and IL-23. The pathogenesis of PsO and PsA is a multifactorial process involving genetic, environmental, and lifestyle factors. IL-23 signaling and activation of Th17 cells leads to a self-perpetuating inflammatory loop resulting in continuous keratinocyte proliferation and synovitis. Treatment options are varied, ranging from topical therapy to injection of targeted biologic disease-modifying antirheumatic drugs (bDMARDs). Evidence on the use of ustekinumab in the management of PsO is strong, but it is not as impressive in management of PsA.Expert opinion: IL-12/23 inhibition appears to be a good first-line option for plaque PsO, but efficacy in PsA does not compare favorably to IL-17 inhibition. In general, poorer responses to therapy with any bDMARD in PsA cohorts highlight psoriatic disease heterogeneity. Until new knowledge can remedy the failure of monotherapy, synergistic methods may have to be explored, including combination biologic therapy.

Inhibition of interleukin-12 and/or interleukin-23 for the treatment of psoriasis: What is the evidence for an effect on malignancy?

Immune cells and cytokines play an important role in the pathogenesis of psoriasis. Interleukin‐12 (IL‐12) and IL‐23 promote cellular responses mediated by T cells, which contribute to an inflammatory loop responsible for the induction and maintenance of psoriatic plaques. Antibodies that inhibit IL‐12/23 or IL‐23 are key treatment options for patients with psoriasis. IL‐12 and IL‐23 also play a key role in immune responses to infections and tumors. A growing body of information from clinical trials, cohort studies, postmarketing reports, genetic studies and animal models provides insights into the potential biological relationships between IL‐12/23 inhibition and malignancies. We summarize this information in tables and provide some context for the interpretation of these data with the goal of informing dermatologists who are using IL‐12/23 or IL‐23 inhibitors to treat patients with psoriasis.

IL-17C: A Unique Epithelial Cytokine with Potential for Targeting across the Spectrum of Atopic Dermatitis and Psoriasis

Both atopic dermatitis (AD) and psoriasis are characterized by complex inflammatory circuits that may be regulated through "feed-forward" mechanisms in the epidermis that amplify cellular immune responses through production of keratinocyte-derived cytokines and inflammatory mediators. IL-17C is a unique cytokine that is produced by keratinocytes and that is involved in such synergistic loops that may be responsible for amplifying the inflammation in both diseases. This may ultimately lead to induction of S100As and other molecules that accompany epidermal hyperplasia. Thus, antagonism of IL-17C may be beneficial in both psoriasis and AD patients. The IL-17C neutralizing antibody MOR 106 was able to inhibit both T helper type 2 cells and T helper type 17/T helper type 22-skewed inflammatory loops that drive different features of AD and psoriasis. The therapeutic potential of IL-17C antagonism in AD is supported by a recently reported small phase 1 clinical trial in patients with AD.

1228 Actinic lentigines from European and Japanese volunteers are characterized by a molecular and cellular inflammatory micro-environment

Actinic lentigines (AL), also called age spots, are benign skin hyperpigmented lesions associated with age and chronic sun exposure. Despite their high prevalence in elderly people, the biological events underlying the development of these lesions remain unclear. In order to better understand the pathophysiological characteristics of AL, we characterized the inflammation response in AL from European and Japanese volunteers, by analyzing the gene expression profile associated with inflammation and by immunostaining of inflammatory/immune cells in skin sections. Results showed that a large number of genes associated with inflammation/immune response were altered in AL versus adjacent non lesional skin (NL) representing ∼10% of total modulated genes. These genes were modulated in the same way in the two populations and indicate a proinflammatory process as attested by the activation of arachidonic acid pathway including PTGS2 (COX2). Furthermore, the overexpression of chemokines genes suggests that chemoattraction of inflammatory cells could take place in AL. To verify this, immunostaining of several cellular subsets was performed and revealed the increase of antigen-presenting cells (HLA-DR +), macrophages (CD68+) and CD4+ T-cells in the dermis of AL vs NL, which strengthens a chemoattraction role in the physiopathology of AL. Consequently, prostaglandins and chemokines release associated with the infiltration of inflammatory cells could contribute to the self-maintenance of an inflammatory microenvironment in AL which may alter skin homeostasis and pigmentation. Normalizing skin by targeting this inflammatory loop could help for efficient and long-term treatment of age spots.

Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop

Scientists from Germany investigated whether a cytokine called interleukin‐36 (IL‐36) might be important in hidradenitis suppurativa (HS), a chronic, painful, disfiguring and offensive‐smelling pustular skin disease that affects the armpits, groins, buttocks and breasts. A cytokine is a molecule produced by one cell that switches on other cells in some way ‐ for example, activating immune system cells to home in on sites of damage, including damage from infection. This is a complex chain reaction or loop. If cytokines are produced when they should not be produced, instead of the immune system repairing damage or combating infection as it should, inappropriate inflammation such as that seen in HS can result. This study of skin samples from 15 patients with moderately severe or severe HS found elevated levels of all three subtypes of IL‐36, mainly in the cells called keratinocytes: subtype IL‐36α particularly in affected skin, IL‐36β in skin around affected skin, and IL‐36γ in both. It also demonstrated an imbalance of cytokines IL‐37 and ‐38, which oppose the action of IL‐36. These findings suggest that the immune system plays an important role in the development of HS. They fit the theory that high IL‐36 levels kick off a chain reaction (which includes other interleukins and a particular type of white blood cell called a T‐helper cell) that results in inflammation and sufficient white blood cells to produce the pus that is a major feature of the condition.

The role of the microRNA-146a/complement factor H/interleukin-1β-mediated inflammatory loop circuit in the perpetuate inflammation of chronic temporal lobe epilepsy.

ABSTRACTIncreasing evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of temporal lobe epilepsy (TLE). However, it is unclear how the perpetuate inflammation develops. Some recent studies have suggested the possible involvement of microRNA-146a (miR-146a) in the modulation of inflammatory signaling occurring in TLE. To understand how miR-146a modulates inflammatory signaling in TLE, we investigated the role of interleukin-1β (IL-1β), miR-146a and human complement factor H (CFH) in the perpetuate inflammation in rat models of chronic TLE and U251 cells. We found that enhancive miR-146a could upregulate the expression of IL-1β and downregulate the expression of CFH, whereas reductive miR-146a could downregulate the expression of IL-1β and upregulate the expression of CFH, in hippocampi of chronic TLE rat models. Meanwhile, enhancive miR-146a could increase the abnormal wave forms in the chronic TLE rat models. Additionally, enhancive IL-1β could feedback downregulate the expression of CFH, upregulate the expression of miR-146a and increase the abnormal wave forms in chronic TLE rat models. After CFH gene knockdown in U251 cells, enhancive miR-146a did not upregulate the expression of IL-1β. In summary, this study shows that enhancive miR-146a can upregulate the inflammatory factor IL-1β in chronic TLE by downregulating CFH, and that upregulation of IL-1β plays an important feedback-regulating role in the expression of miR-146a and CFH, forming a miR-146a–CFH–IL-1β loop circuit that initiates a cascade of inflammation and then leads to the perpetuate inflammation in TLE. Therefore, modulation of the miR-146a–CFH–IL-1β loop circuit could be a novel therapeutic target for TLE.

Interleukin-36 in hidradenitis suppurativa: evidence for a distinctive proinflammatory role and a key factor in the development of an inflammatory loop.

Possible regulatory involvement of the interleukin (IL)-36 family in inflammatory diseases has been suggested. To analyse the expression of IL-36α, IL-36β, IL-36γ and the antagonistic cytokines IL-36 receptor agonist (IL-36Ra), IL-37 and IL-38 in the skin of patients with hidradenitis suppurativa (HS). Skin samples from lesional and corresponding perilesional HS skin, and from healthy controls were included in this study and analysed by quantitative real-time reverse-transcriptase polymerase chain reaction (PCR). To evaluate the PCR results of IL-36α, IL-36β and IL-36γ, a subset of skin samples was studied by immunohistochemistry. Expression levels of IL-36α, IL-36β, IL-36γ and IL-36Ra were all significantly higher in lesional HS skin than in healthy controls. IL-37 and IL-38 levels were significantly higher in perilesional HS skin than in healthy controls and were decreased in lesional HS skin. Limitations of the study are its descriptive nature and the small sample size. Our results showed a possible involvement of IL-36 cytokines in the inflammatory network of HS and a dysbalance between the agonistic and antagonistic cytokines in HS skin.

Glycobiology of Aging.

Glycosylation is one of the most frequent post-translational modification of proteins. Many membrane and secreted proteins are decorated by sugar chains mainly linked to asparagine (N-linked) or to serine or threonine (O-linked). The biosynthesis of the sugar chains is mainly controlled by the activity of their biosynthetic enzymes: the glycosyltransferases. Glycosylation plays multiple roles, including the fine regulation of the biological activity of glycoproteins. Inflammaging is a chronic low grade inflammatory status associated with aging, probably caused by the continuous exposure of the immune system to inflammatory stimuli of endogenous and exogenous origin. The aging-associated glycosylation changes often resemble those observed in inflammatory conditions. One of the most reproducible markers of calendar and biological aging is the presence of N-glycans lacking terminal galactose residues linked to Asn297 of IgG heavy chains (IgG-G0). Although the mechanism(s) generating IgG-G0 remain unclear, their presence in a variety of inflammatory conditions suggests a link with inflammaging. In addition, these aberrantly glycosylated IgG can exert a pro-inflammatory effect through different mechanisms, triggering a self-fueling inflammatory loop. A strong association with aging has been documented also for the plasmatic forms of glycosyltrasferases B4GALT1 and ST6GAL1, although their role in the extracellular glycosylation of antibodies does not appear likely. Siglecs, are a group of sialic acid binding mammalian lectins which mainly act as inhibitory receptors on the surface of immune cells. In general activity of Siglecs appears to be associated with long life, probably because of their ability to restrain aging-associated inflammation.

Negative legacy of obesity.

Obesity promotes excessive inflammation, which is associated with senescence-like changes in visceral adipose tissue (VAT) and the development of type 2 diabetes (T2DM) and cardiovascular diseases. We have reported that a unique population of CD44hi CD62Llo CD4+ T cells that constitutively express PD-1 and CD153 exhibit cellular senescence and cause VAT inflammation by producing large amounts of osteopontin. Weight loss improves glycemic control and reduces cardiovascular disease risk factors, but its long-term effects on cardiovascular events and longevity in obese individuals with T2DM are somewhat disappointing and not well understood. High-fat diet (HFD)-fed obese mice were subjected to weight reduction through a switch to a control diet. They lost body weight and visceral fat mass, reaching the same levels as lean mice fed a control diet. However, the VAT of weight reduction mice exhibited denser infiltration of macrophages, which formed more crown-like structures compared to the VAT of obese mice kept on the HFD. Mechanistically, CD153+ PD-1+ CD4+ T cells are long-lived and not easily eliminated, even after weight reduction. Their continued presence maintains a self-sustaining chronic inflammatory loop via production of large amounts of osteopontin. Thus, we concluded that T-cell senescence is essentially a negative legacy effect of obesity.

312 A Key signaling molecule for the establishment of inflammatory loop of IL-17 in the skin identified in keratinocytes

Epithelial cells are the first line of defense against external dangers, and are generally involved in immune regulation by the release of the contents from damaged cells and by de novo production of proinflammatory mediators. A specific cellular signaling in the epithelium essential for the specific type of inflammation, however, remains unknown. Genetic alterations of NF-κB and MAPK pathways in the epidermis are reported to be possible causes of psoriasis. We therefore considered that dysregulation of these pathways in epithelial cells might induce IL-17-mediated inflammation in psoriasis. TRAF6 is a E3 ubiquitin ligase that governs the downstream NF-κB and MAPK pathways. Thus, we sought to investigate whether TRAF6 signaling events in keratinocytes are critical in the establishment of IL-17-mediated inflammation in the skin. TRAF6-null keratinocytes showed defective activation of NF-κB and MAPK pathways in vitro. Their transcriptional response of proinflammatory genes, such as Il1b, Tnf, and Cxcl1, on stimulation with imiquimod was abrogated, whereas the imiquimod-induced cell death was comparable to that of intact keratinocytes. IL-17-induced transcription of the response genes, Il24, Ccl20, and Defb3, of TRAF6-null keratinocytes was also impaired, suggesting the TRAF6-dependent transcriptional products of keratinocytes may be essential for psoriatic inflammation. Indeed, Cre-mediated deletion of TRAF6 specifically in keratinocytes resulted in complete unresponsiveness to imiquimod-induced dermatitis in mice, and imiquimod treatment failed to activate dendritic cells, to produce IL-23, and to produce IL-17 from γδ T cells in these mice. Subcutaneous administration of IL-23 fully reconstituted the defective production of IL-17 in these animals, suggesting that IL-23 is the downstream effector of keratinocyte activation. Our findings in the skin provide direct evidence for the essential role of cellular signaling in the epithelium for the establishment of IL-17-mediated immune response.

Optimizing Anti-Inflammatory and Immunomodulatory Effects of Corticosteroid and Vitamin D Analogue Fixed-Dose Combination Therapy.

Fixed-dose combination topical therapy with corticosteroid and vitamin D analog provides effective treatment and possible long-term management of psoriasis. The anti-inflammatory and immunomodulatory effects of corticosteroids and vitamin D analogs in treating psoriasis are well investigated; their complementary effects lead to the disruption of the inflammatory feedback loop underlying psoriasis pathogenesis. Recent preclinical data showed that combination therapy is more effective than monotherapies of the active ingredients in preventing activation of resting pro-inflammatory cells, inducing immunomodulation, reducing inflammatory responses by regulating T cell production, and normalizing keratinocytes. The increased understanding of the mechanism of action of fixed-dose combination therapy from preclinical studies is supported by several clinical studies. As the efficacy of topical therapy is correlated with the skin penetration of the active ingredients, new drug delivery systems have been developed. The fixed-dose combination Cal/BD aerosol foam creates a modified supersaturated formulation when applied to the skin, which is maintained for at least 26 h in the laboratory setting. Clinical studies have demonstrated superior efficacy of fixed-dose combination calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g aerosol foam compared with monotherapies of the active ingredients. Furthermore, Cal/BD aerosol foam has shown significantly improved efficacy compared with more traditional formulations, such as Cal/BD ointment and gel, in other studies. Calcipotriol also mitigates risks associated with betamethasone dipropionate and vice versa, resulting in the favorable safety profile observed with fixed-dose combination treatment. Recent data also suggest that fixed-dose combination treatment could provide long-term management of psoriasis, although further clinical investigations are needed. Overall, these data support the value of fixed-dose combination therapy of corticosteroid and vitamin D analog and highlight the added potential of innovative drug delivery for the treatment of psoriasis.FundingLEO Pharma.

An autocrine inflammatory forward-feedback loop after chemotherapy withdrawal facilitates the repopulation of drug-resistant breast cancer cells

Stromal cells, infiltrating immune cells, paracrine factors and extracellular matrix have been extensively studied in cancers. However, autocrine factors produced by tumor cells and communications between autocrine factors and intracellular signaling pathways in the development of drug resistance, cancer stem-like cells (CSCs) and tumorigenesis have not been well investigated, and the precise mechanism and tangible approaches remain elusive. Here we reveal a new mechanism by which cytokines produced by breast cancer cells after chemotherapy withdrawal activate both Wnt/β-catenin and NF-κB pathways, which in turn further promote breast cancer cells to produce and secrete cytokines, forming an autocrine inflammatory forward-feedback loop to facilitate the enrichment of drug-resistant breast cancer cells and/or CSCs. Such an unexpected autocrine forward-feedback loop and CSC enrichment can be effectively blocked by inhibition of Wnt/β-catenin and NF-κB signaling. It can also be diminished by IL8-neutralizing antibody or blockade of IL8 receptors CXCR1/2 with reparixin. Administration of reparixin after chemotherapy withdrawal effectively attenuates tumor masses in a human xenograft model and abolishes paclitaxel-enriched CSCs in the secondary transplantation. These results are partially supported by the latest clinical data set. Breast cancer patients treated with chemotherapeutic drugs exhibited poor survival rate (66.7 vs 282.8 months, P=0.00071) and shorter disease-free survival time if their tumor samples expressed high level of IL8, CXCR1, CXCR2 genes and Wnt target genes. Taken together, this study provides new insights into the communication between autocrine niches and signaling pathways in the development of chemotherapy resistance and CSCs; it also offers a tangible approach in breast cancer treatment.

Natural Killer Cell Functions during the Innate Immune Response to Pathogenic Streptococci.

Dendritic cells (DCs) and NK cells play a crucial role in the first phase of host defense against infections. Group B Streptococcus (GBS) and Streptococcus suis are encapsulated streptococci causing severe systemic inflammation, leading to septicemia and meningitis. Yet, the involvement of NK cells in the innate immune response to encapsulated bacterial infection is poorly characterized. Here, it was observed that these two streptococcal species rapidly induce the release of IFN-γ and that NK cells are the major cell type responsible for this production during the acute phase of the infection. Albeit S. suis capacity to activate NK cells was lower than that of GBS, these cells partially contribute to S. suis systemic infection; mainly through amplification of the inflammatory loop. In contrast, such a role was not observed during GBS systemic infection. IFN-γ release by NK cells required the presence of DCs, which in turn had a synergistic effect on DC cytokine production. These responses were mainly mediated by direct DC-NK cell contact and partially dependent on soluble factors. Though IL-12 and LFA-1 were shown to be critical in S. suis-mediated activation of the DC-NK cell crosstalk, different or redundant molecular pathways modulate DC-NK interactions during GBS infection. The bacterial capsular polysaccharides also differently modulated NK cell activation. Together, these results demonstrated a role of NK cells in the innate immune response against encapsulated streptococcal infections; yet the molecular pathways governing NK activation seem to differ upon the pathogen and should not be generalized when studying bacterial infections.

Radiation-induced inflammatory cascade and its reverberating crosstalks as potential cause of post-radiotherapy second malignancies.

The disease-free survival following radiotherapy is often limited by the development of second/secondary cancers. This significant impediment to effective cancer treatment implicated even in the modern-day radiotherapy needs to be countered effectively. Critical analysis reveals that besides achieving effective tumor control, radiotherapy elicits certain cellular and systemic inflammatory events in tumor infiltrate, which remain relatively stable and tend to facilitate "in-field" or "out of field" oncogenesis in due course of time. Acute pro-inflammatory cytokines generated as a result of radiation-induced oxidative insult and DNA damage induce genetic instability that contributes to tumor heterogeneity and plasticity. The reverberating crosstalks between radiation-targeted tumor and its microenvironment in turn initiate inflammatory loops that feedback the immune system to manifest as systemic consequences. An "inflammatory switchover" within the tumor microenvironment is thus induced by cumulative radiation exposure, initiating pro-tumor events that can severely limit the outcome of radiotherapy. Various pro-survival tumorigenic pathways activated as a result regulate radiation-induced hypoxia, ECM remodeling, angiogenesis/vasculogenesis, and immune suppression/evasion within the tumor microenvironment. NF-κB, HIF and STAT are identified as central regulating mediators among others that orchestrate inflammatory switchover from apoptosis-mediated tumor surveillance to radiation-induced carcinogenesis. Radiation-induced interleukins stimulate recruited macrophages and endothelial cells to promote intravasation, which is further aided by release of chemokines favoring extravasation and secondary site lesions. We hence propose that delineating the inflammatory signaling network emanating from irradiation of complex tumor tissue is critical for devising suitable therapeutic strategies to prevent post-radiotherapy second cancers or metastasis. Graphical Abstract ᅟ.

703 Preclinical evidence for nitric oxide-releasing SB414 in a psoriasis animal model

Psoriasis is an immune-mediated inflammatory skin disease attributed to dysregulated interactions between keratinocytes and immune cells. IL-1β is a cytokine responsible for enhancing the infiltration of activated immune cells, triggering the release of additional pro-inflammatory cytokines, and is also a key signal responsible for the maturation of naïve T cells into Th17 cells. In several inflammatory skin disorders the aberrant activation of this helper T-cell subset results in the production and release of IL-17, which binds to its cognate receptor and prompts inflammasome activation and initiates a positive inflammatory feedback loop. Nitric oxide has the potential to disrupt IL-17 propagation locally in the skin via its ability to disrupt the assembly of the NLRP3 inflammasome. Topical application of imiquimod (IMQ) produces a cutaneous inflammatory phenotype on the back of Balb/c mice that is utilized as a model of psoriasis. In this study, IMQ was applied daily to the backs of mice. The mice were then treated with SB414, a topical nitric oxide-releasing cream, BID for 10 days. Compared to untreated controls, 6% SB414, demonstrated a statistically significant reduction in the psoriasis back pathology starting at day 3 and was maintained until the end of the experiment showing a 31%, 40%, and 28% decrease in composite psoriasis score, erythema and plaque score, respectively. In this model, pro-inflammatory cytokines associated with the IL-23/IL-17 axis are significantly upregulated (Day 4) in ear tissue after IMQ application. Compared to untreated controls, 6% SB414 treatment reduced tissue levels of pro-inflammatory cytokines: IL-1β, IL-6, IL-22, IL-17A, IL-17F and IL-33 by 84%, 55%, 64%, 87%, 71% and 71%, respectively. These data support the potential for a nitric-oxide releasing topical treatment to reduce the pro-inflammatory cytokines associated with perturbation of the IL-23/IL-17 axis and result in decreased psoriasis pathology.

Inhibitory Effect of Methyl 2-(4'-Methoxy-4'-oxobutanamide) Benzoate from Jerusalem Artichoke (Helianthus tuberosus) on the Inflammatory Paracrine Loop between Macrophages and Adipocytes.

The interaction between macrophages and adipocytes is known to aggravate inflammation of the adipose tissue, leading to decreased insulin sensitivity. Hence, attenuation of the inflammatory paracrine loop between macrophages and adipocytes is deemed essential to ameliorate insulin resistance and diabetes mellitus type 2. Methyl 2-(4'-methoxy-4'-oxobutanamide) benzoate (compound 1), a newly isolated compound from Jerusalem srtichoke (JA), has not been biologically characterized yet. Here, we investigated whether JA-derived compound 1 attenuates the inflammatory cycle between RAW 264.7 macrophages and 3T3-L1 adipocytes. Compound 1 suppressed the inflammatory response of RAW 264.7 cells to lipopolysaccharide through decreased secretion of IL-1β, IL-6, and TNF-α. Moreover, the mRNA expression of TNF-α, IL-6, IL-1β, MCP-1, and Rantes and MAPK pathway activation in 3T3-L1 adipocytes, incubated in macrophage-conditioned media, were inhibited. These findings suggest an anti-inflammatory effect of a newly extracted compound against adipose tissue inflammation and insulin resistance.

Pso p27, a SERPINB3/B4-derived protein, is most likely a common autoantigen in chronic inflammatory diseases

Autoimmune diseases are characterized by chronic inflammatory reactions localized to an organ or organ-system. They are caused by loss of immunologic tolerance toward self-antigens, causing formation of autoantibodies that mistakenly attack their own body. Psoriasis is a chronic inflammatory autoimmune skin disease in which the underlying molecular mechanisms remain elusive. In this review, we present evidence accumulated through more than three decades that the serpin-derived protein Pso p27 is an autoantigen in psoriasis and probably also in other chronic inflammatory diseases.Pso p27 is derived from the serpin molecules SERPINB3 and SERPINB4 through non-canonical cleavage by mast cell chymase. In psoriasis, it is exclusively found in skin lesions and not in uninvolved skin. The serpins are cleaved into three fragments that remain associated as a Pso p27 complex with novel immunogenic properties and increased tendency to form large aggregates compared to native SERPINB3/B4. The amount of Pso p27 is directly correlated to disease activity, and through formation of complement activating immune-complexes, Pso p27 contribute to the inflammation in the skin lesions. SERPINB3/B4 are expressed in skin fibroblasts and keratinocytes, but normally absent in mast cells. Overexpression of the serpins may be induced by inflammation and hypoxia, resulting in mast cell uptake via yet unknown mechanisms. Here the generation and subsequent release of Pso p27 aggregates may promote an inflammatory loop that contributes to the chronicity of psoriasis and other autoimmune diseases.

Alarmins firing arthritis: Helpful diagnostic tools and promising therapeutic targets

Alarmins are endogenous molecules with homeostatic roles that have reached the focus of research in inflammatory arthritis in the last two decades, mostly due to their ability to indicate tissue related damage after active or passive release from injured cells. From HMGB1, S100A8/A9 and S100A12 proteins, over heat-shock proteins (HSPs) and purine metabolites (e.g. uric acid, ATP) to altered matrix proteins and interleukin-33 (IL-33), a number of alarmins have been determined until now as having a role in rheumatoid arthritis, psoriatic and juvenile idiopathic arthritis, as well as spondyloarthritis and gout. Although formerly being linked to initiation and chronification of inflammatory arthritis, driving auto- and paracrine inflammatory loops, more recent research has also unraveled the alarmins’ role in the crosstalk between innate and adaptive immunity and in resolution of inflammation.Providing a state-of-the-art overview of known alarmins, this review lists the known modes of action and pathologic contribution of alarmins to inflammatory arthritis, as well as biomarker potential of alarmins in the clinical setting for tracking disease severity. Based upon research on animal experimental models (CIA, AIA) and clinical trials, a look is made into potentially viable strategies for modifying alarmin secretion and their target receptor (e.g. TLR, RAGE) interaction with the purpose of attenuating arthritic disease.