ADAMDEC1 promotes skin inflammation in rosacea via modulating the polarization of M1 macrophages

Rosacea is a chronic inflammatory cutaneous disease which mainly affects central face, leading to cosmetic disfigurement and compromised social psychology in billions of rosacea patients. Though the exact etiology of rosacea remains elusive, accumulating evidence has highlighted the dysfunction of innate immunity and inflammation in rosacea pathogenesis. Disintegrin Metalloprotease ADAM-like Decysin-1 (ADAMDEC1) is an orphan ADAM-like metalloprotease which is believed to be closely related to inflammation. Here for the first time, we reported that Adamdec1 expression was significantly increased in the skin lesions of rosacea patients and LL37–induced rosacea-like mouse models. Immunofluorescence analysis revealed co-localization of ADAMDEC1 and macrophages in patient and mouse biopsies. In cellular experiment, the expression of ADAMDEC1 was prominently elevated in M1 but not M2 macrophages. Knocking down of ADAMDEC1 significantly blunted M1 polarization in macrophages induced from human monocytes and THP-1 cell lines. Furthermore, silencing of Adamdec1 in LL-37-induced mouse model also suppressed the expression of M1 signature genes such as IL-6, iNOS and TNF-α, resulting in attenuated rosacea-like phenotype and inflammation. Taken together, our results demonstrate that ADAMDEC1 plays a pro-inflammatory role in rosacea via modulating the M1 polarization of macrophages.     

Assessing high conservation value areas for rare,endemic and threatened (RET) species: A study in high altitude Changthang landscape of India

The Forest Stewardship Council developed the concept of High Conservation Values (HCVs) as a criteria in the forest certification process in order to promote sustainable forest management. It has six major components or values and component one and two of HCVs deal with the habitat for viable populations of “rare, endemic and threatened (RET) species” using the IUCN Red List category and other national / regional / local lists. But a consistent robust methodology for identification of these areas, does not exist. The present study tried to develop for the first time, a straight forward inclusive methodology for identification of HCVAs for the RET species on a spatio-temporal scale. A total of 50 RET and other significant species (32 flora, 10 fauna and 8 avifauna) were identified after a thorough literature review, field surveys and consultations with experts. Occurrence data of the selected species was collected from different secondary sources, field surveys, institutes and scientists who have worked on them. A 10 km grid-based approach and stratified random sampling was used for the primary GPS field surveys conducted during 2018–2019. MaxEnt species distribution model (SDM) software was used based on the occurrence data and environmental variables for identification of potential suitable habitats for the selected species. Linear support vector machine (LSVM) model was used for assessing the performance of the SDMs. The performance of each SDM has been validated through Cohen's Kappa (KAPPA), true skill statistic (TSS) and receiver operating characteristics (ROC) models. The proposed methodology addresses the urgent need for a holistic and robust set of techniques to apply the HCV toolkit. This is key to identify and map HCVAs for RET species at the landscape level and can be easily adapted to and adopted at the national, regional, state or local level in India. The methods offer an efficient, reliable approach for the application of the HCV concept, elsewhere in the world.     

Imbalanced production of IL-18 and its antagonist in human diseases,and its implications for HIV-1 infection

IL-18 is a pleiotropic and multifunctional cytokine that belongs to the IL-1 family. It is produced as a biologically inactive precursor, which is cleaved into its active mature form mainly by caspase-1. The caspase becomes active from its inactive precursor (procaspase-1) upon assembly of an inflammasome. Because of IL-18’s potential pro-inflammatory and tissue destructive effects, its biological activities are tightly controlled in the body by its naturally occurring antagonist called IL-18BP. The antagonist is produced in the body both constitutively and in response to an increased production of IL-18 as a negative feedback mechanism. Under physiological conditions, most of IL-18 in the circulation is bound with IL-18BP and is inactive. However, an imbalance in the production of IL-18 and its antagonist (an increase in the production of IL-18 with a decrease, no increase or an insufficient increase in the production of IL-18BP) has been described in many chronic inflammatory diseases in humans. The imbalance results in an increase in the concentrations of free IL-18 (unbound with its antagonist) resulting in increased biological activities of the cytokine that contribute towards pathogenesis of the disease. In this article, we provide an overview of the current biology of IL-18 and its antagonist, discuss how the imbalance occurs in HIV infections and how it contributes towards development of AIDS and other non-AIDS-associated clinical conditions occurring in HIV-infected individuals undergoing combination anti-retroviral therapy (cART). Finally, we discuss challenges facing immunotherapeutic strategies aimed at restoring balance between IL-18 and its antagonist in these patients.     

LL-37, the only human member of the cathelicidin family of antimicrobial peptides

Antimicrobial peptides and their precursor molecules form a central part of human and mammalian innate immunity. The underlying genes have been thoroughly investigated and compared for a considerable number of species, allowing for phylogenetic characterization. On the phenotypical side, an ever-increasing number of very varied and distinctive influences of antimicrobial peptides on the innate immune system are reported. The basic biophysical understanding of mammalian antimicrobial peptides, however, is still very limited. This is especially unsatisfactory since knowledge of structural properties will greatly help in the understanding of their immunomodulatory functions. The focus of this review article will be on LL-37, the only cathelicidin-derived antimicrobial peptide found in humans. LL-37 is a 37-residue, amphipathic, helical peptide found throughout the body and has been shown to exhibit a broad spectrum of antimicrobial activity. It is expressed in epithelial cells of the testis, skin, the gastrointestinal tract, and the respiratory tract, and in leukocytes such as monocytes, neutrophils, T cells, NK cells, and B cells. It has been found to have additional defensive roles such as regulating the inflammatory response and chemo-attracting cells of the adaptive immune system to wound or infection sites, binding and neutralizing LPS, and promoting re-epthelialization and wound closure. The article aims to report the known biophysical facts, with an emphasis on structural evidence, and to set them into relation with insights gained on phylogenetically related antimicrobial peptides in other species. The multitude of immuno-functional roles is only outlined. We believe that this review will aid the future work on the biophysical, biochemical and immunological investigations of this highly intriguing molecule.     

Calcium flux control by Pacs1‐Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases

Endoplasmic reticulum (ER) calcium (Ca²⁺) stores are critical to proteostasis, intracellular signaling, and cellular bioenergetics. Through forward genetic screening in mice, we identified two members of a new complex, Pacs1 and Wdr37, which are required for normal ER Ca²⁺ handling in lymphocytes. Deletion of Pacs1 or Wdr37 caused peripheral lymphopenia that was linked to blunted Ca²⁺ release from the ER after antigen receptor stimulation. Pacs1‐deficient cells showed diminished inositol triphosphate receptor expression together with increased ER and oxidative stress. Mature Pacs1 ^−/− B cells proliferated and died in vivo under lymphocyte replete conditions, indicating spontaneous loss of cellular quiescence. Disruption of Pacs1‐Wdr37 did not diminish adaptive immune responses, but potently suppressed lymphoproliferative disease models by forcing loss of quiescence. Thus, Pacs1‐Wdr37 plays a critical role in stabilizing lymphocyte populations through ER Ca²⁺ handling and presents a new target for lymphoproliferative disease therapy.