Anabell Alvarado-Navarro

Neutrophil extracellular traps and its implications in inflammation: an overview

In addition to physical barriers, neutrophils are considered a part of the first line of immune defense. They can be found in the bloodstream, with a lifespan of 6–8 h, and in tissue, where they can last up to 7 days. The mechanisms that neutrophils utilize for host defense are phagocytosis, degranulation, cytokine production, and, the most recently described, neutrophil extracellular trap (NET) production. NETs are DNA structures released due to chromatin decondensation and spreading, and they thus occupy three to five times the volume of condensed chromatin. Several proteins adhere to NETs, including histones and over 30 components of primary and secondary granules, among them components with bactericidal activity such as elastase, myeloperoxidase, cathepsin G, lactoferrin, pentraxin 3, gelatinase, proteinase 3, LL37, peptidoglycan-binding proteins, and others with bactericidal activity able to destroy virulence factors. Three models for NETosis are known to date. (a) Suicidal NETosis, with a duration of 2–4 h, is the best described model. (b) In vital NETosis with nuclear DNA release, neutrophils release NETs without exhibiting loss of nuclear or plasma membrane within 5–60 min, and it is independent of reactive oxygen species (ROS) and the Raf/MERK/ERK pathway. (c) The final type is vital NETosis with release of mitochondrial DNA that is dependent on ROS and produced after stimuli with GM-CSF and lipopolysaccharide. Recent research has revealed neutrophils as more sophisticated immune cells that are able to precisely regulate their granular enzymes release by ion fluxes and can release immunomodulatory cytokines and chemokines that interact with various components of the immune system. Therefore, they can play a key role in autoimmunity and in autoinflammatory and metabolic diseases. In this review, we intend to show the two roles played by neutrophils: as a first line of defense against microorganisms and as a contributor to the pathogenesis of various illnesses, such as autoimmune, autoinflammatory, and metabolic diseases.

Correlation of IL-12, IL-22, and IL-23 in patients with psoriasis and metabolic syndrome. Preliminary report.

BACKGROUND Psoriasis is an autoimmune skin disease characterised by proliferation of keratinocytes, primarily due to cytokines Th1 and Th17. This profile is involved in pathogenesis of metabolic syndrome, a frequently found comorbidity in patients with psoriasis. OBJECTIVE In this study we determine the correlation of levels of pro-inflammatory cytokines TNF-α, IL-23, IL-12, and IL-22 in patients with psoriasis with and without metabolic syndrome and clinically healthy controls. METHODS We included 55 patients with plaque psoriasis: 30 with metabolic syndrome (PPMS), 25 without metabolic syndrome (PP), 15 healthy subjects (HS) and 15 with metabolic syndrome (MS). Quantification of serum levels of IL-12, TNF-α, IL-22, and IL-23 was done by ELISA. RESULTS We observed that serum levels of IL-12 were more elevated in PP group, while the lowest levels of TNF-α were seen in HS group. IL-22 was found to be higher in PP than in PPMS (p<0.05). PP patients with PASI scores rating as severe showed higher levels of IL-12. TNF-α level analysis showed significant differences in HS group compared with the others; levels of this cytokine were lower in patients with PP and moderate PASI scores than in MS group (p<0.05). We found no correlation between cytokine levels and psoriasis or between cytokines and PASI scores. In PP group, a positive correlation was observed between IL-23 and fasting glucose (r=0.432, p<0.05), as well as a negative correlation between IL-23, IL-22, and IL-12 versus waist circumference (r=-0.504, r=-0.556 and r=-0.511, respectively; p<0.05). CONCLUSIONS Psoriasis is not just a skin disorder, but rather a condition with systemic implications, with intervention of pro-inflammatory cytokines that contribute to metabolic syndrome and other comorbidities, which in turn increases the risk of developing cardiovascular disease.

Association between STR -794 CATT5-8 and SNP -173 G/C polymorphisms in the MIF gene and Lepromatous Leprosy in Mestizo patients of western Mexico

Lepromatous Leprosy (LL) is the most common presentation of leprosy in Mexico. LL patients are unable to activate an effective inflammatory response against Mycobacterium leprae probably due to the genetics of the host. Macrophage Migration Inhibitory Factor (MIF) is important to trigger inflammation processes. Two polymorphisms have been reported for human MIF: STR -794 CATT5-8 and SNP -173 G/C. 7-8 CATT repeats at -794 and the C allele at -173 increase the expression of MIF. We aim to determine the association between the polymorphisms in MIF gene and LL. We carried a case and controls study with 100 Mexican LL patients and 100 healthy subjects (HS). PCR was used for genotyping of STR -794 CATT5-8 polymorphism and PCR-RFLP for -173 G/C. We found that LL patients possess high -794 CATT repeats (47.1%) more often than HS (32.7%). In conclusion, a MIF polymorphism is associated with susceptibility to LL in Western Mexican population.

Differential expression of solute carrier family 11a member 1 and inducible nitric oxide synthase 2 in skin biopsies from leprosy patients

BACKGROUND Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae, an intracellular parasite that resides within macrophages and cannot be eliminated effectively. Solute carrier family 11a member 1 (Slc11a1) and inducible nitric oxide synthase (iNOS), both expressed in macrophages, play major roles in host defense against several intracellular pathogens. However, the roles of these molecules in natural infection with M. leprae remain unknown. OBJECTIVE We aimed to investigate the expression of Slc11a1 and iNOS in macrophages (CD68+ cells) infiltrating skin lesions in leprosy. METHODS Skin biopsies from 48 Mexican patients of leprosy [(33 lepromatous (LL), 15 tuberculoid (TT)] and from 10 healthy controls, were subjected to immunohistochemistry to determine expression of CD68, Slc11a1 and iNOS. RESULTS We found a high expression of Slc11a1 and iNOS in most lepromatous leprosy samples. In tuberculoid leprosy samples, Slc11a1 expression was moderate or low, and that of iNOS was almost always low. In addition, Slc11a1 and iNOS expression levels were positively associated with bacillary loads in lepromatous leprosy lesions (P=0.05). CONCLUSIONS These observations suggest that M. leprae infection promotes the expression of Slc11a1 and iNOS in macrophages and that lepromatous leprosy can occur despite this response.

Serum Levels of Migration Inhibitory Factor (MIF) and In Situ Expression of MIF and Its Receptor CD74 in Lepromatous Leprosy Patients: A Preliminary Report

Leprosy is a chronic disease caused by Mycobacterium leprae that affects the skin and peripheral nerves. It may present as one of two distinct poles: the self-limiting tuberculoid leprosy and the highly infectious lepromatous leprosy (LL) characterized by M. leprae-specific absence of cellular immune response. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) enhance the bactericide activities of macrophages after interaction with its receptor, CD74. Importantly, MIF also possesses chemoattractant properties, and it is a key factor in situ for the activation of macrophages and in blood to promote leukocytes migration. MIF-mediated activation of macrophages is a key process for the elimination of pathogens such as Mycobacterium tuberculosis; however, its participation for the clearance of M. leprae is unclear. The aim of this study was to evaluate the serum levels of MIF as well as MIF and CD74 expression in skin lesions of LL and compare it with healthy skin (HSk) taken from subjects attending to dermatological consult. Samples of serum and skin biopsies were taken from 39 LL patients and compared with 36 serum samples of healthy subjects (HS) and 10 biopsies of HSk. Serum samples were analyzed by ELISA and skin biopsies by immunohistochemistry (IHC). IHC smears were observed in 12 100× microscopic fields, in which percentage of stained cells and staining intensity were evaluated. Both variables were used to calculate a semi-quantitative expression score that ranged from 0 to 3+. We found no differences in MIF levels between LL patients and HS in sera. In addition, MIF was observed in over 75% of cells with high intensity in the skin of patients and HSk. Although we found no differences in MIF expression between the groups, a CD74 score statistically higher was found in LL skin than HSk (p < 0.001); this was the result of a higher percentage of cells positive for CD74 (p < 0.001). As a conclusion, we found that CD74-positive cells are intensely recruited to the skin with LL lesions. In this manner, MIF signaling may be enhanced in the skin of LL patients due to increased expression of its receptor, but further studies are required.