Type III Interferons: Emerging Roles in Autoimmunity

Type III interferons (IFNs) or the lambda IFNs (IFNLs or IFN-λs) are antimicrobial cytokines that play key roles in immune host defense at endothelial and epithelial barriers. IFNLs signal via their heterodimeric receptor, comprised of two subunits, IFNLR1 and interleukin (IL)10Rβ, which defines the cellular specificity of the responses to the cytokines. Recent studies show that IFNL signaling regulates CD4+ T cell differentiation, favoring Th1 cells, which has led to the identification of IFNL as a putative therapeutic target for autoimmune diseases. Here, we summarize the IFNL signaling pathways during antimicrobial immunity, IFNL-mediated immunomodulation of both innate and adaptive immune cells, and induction of autoimmunity.

STUDY OF INDICATORS OF ANTIMICROBIAL RESISTANCE IN PATIENTS WITH ALLERGODERMATOSIS, СОMPLICATED BY STAPHYLOCOCCUS INFECTION, ACCORDING TO THE RESULTS OF TESTS WITH AUTOSTRAINS

The relevance of the study is due to the lack of data on the state of nonspecific cellular immunity in studies with sera and autostrains of S. aureus isolated from patients with allergic dermatoses, which would reflect the intensity of antimicrobial immunity in patients with allergic dermatoses, aggravated by staphylococcal infection, depending on the severity of dermatosis. The aim of the study was to determine and analyze the results of antimicrobial immunity indicators in patients with atopic dermatitis and true eczema, aggravated by staphylococcal infection, using sera and autostrains of S. aureus, depending on the severity of the disease. Material and methods. It was included 107 patients with different stage of the allergic dermatoses severity and control group of 15 healthy individuals to the research . The patients were divided into 3 groups in according to the severity of cutaneous process course. There were determined the basic indices of initial stages of phagocytosis and oxydepending bactericidal activity of the phagocytes. It was conducted the immunologic examinations using the autostrains patient from the locus morbi and standard strain S. aureus ATCC for the estimation of antimicrobial immunity. Results. Evaluation of phagocytosis indices in patients with allergodermatosеs showed a correlation between the severity of the disease course and the level of inhibition of the cellular level of nonspecific immunity. According to the results of studies using autostrains S. aureus, the most significant inhibition of phagocytosis (p ≤ 0,05), compared to the values of similar indicators in the control group of healthy individuals, it was found in the groups of patients with moderate and severe atopic dermatosis (AD) course, respectively: phagocytic activity (PhА) (78,1 ± 1,4) and (72,4 ± 1,4) and (71,7 ± 0,8) %; phagocytic number___ (PhN) (5,3 ± 0,2) and (4,3 ± 0,2) and (3,5 ± 0,1) absolute number (abs. num.); phagocytic index__ (PhI) (6,8 ± 0,2) and (6,2 ± 0,2) and (4,8 ± 0,1) abs. num.; phagocytic capacity (PhC) (30,3 ± 1,0) and (26,5 ± 1,8) and (22,6 ± 0,8) ×103 microbial cell /mm3; spontaneous test of the renovation of nitroblue tetrazolium (sNBT) (42,1 ± 1,3) and (48,1 ± 1,2) and (50,6 ± 0,3) %; induction test of the renovation of nitroblue tetrazolium (іNBT) (63,4 ± 1,6) and (53,4 ± 0,8) and (51,7 ± 0,7) %. In the patients with true eczema (TE), they revealed a similar regularity of phagocytosis inhibition, most pronounced in patients with a severe disease course (p ≤ 0,05), but with a slightly smaller degree of difference between the indicator values of phagocytosis compared with the group of healthy individuals, respectively: PhА (74,8 ± 1,3) and (78,1 ± 1,4) %; PhN (4,5 ± 0,1) and (5,3 ± 0,2) abs. num.; PhI (5,9 ± 0,2) and (6,8 ± 0,9) abs. num.; sНСТ (46,0 ± 0,6) and (42,1 ± 1,3) %; іНСТ (51,8 ± 0,8) and (63,4 ± 1,6) %. Conclusions. The results of identification of phagocytosis in patients with allergodermatosеs using the standard culture of S. aureus ATCC 25923 generally reflect the described regularities of inhibition in patients of the cellular level of nonspecific immunity, but are less presentable for their identification in comparison with the autostrains. Keywords: allergic dermatoses, severity of the course, S aureus autostrains, S. aureus ATCC 25923, antimicrobial resistance.

A Novel microRNA of Japanese Flounder Regulates Antimicrobial Immunity Involving a Bacteria-Binding CSF3

MicroRNAs (miRNAs) are small non-coding RNAs that regulate diverse biological processes including immunity. In a previous high-throughput RNA sequencing study, a novel miRNA, pol-miR-novel_642, was identified from Japanese flounder (Paralichthys olivaceus), a farmed fish species with important economic value. In this study, we investigated the regulatory mechanism and the function of pol-miR-novel_642 and its target gene. We found that pol-miR-novel_642 targeted, in a sequence-specific manner, a flounder gene encoding an uncharacterized protein that is a structural homologue of murine granulocyte colony stimulating factor 3 (CSF3). The expression of pol-miR-novel_642 and its target gene (named PoCSF3-1) was regulated, in different manners, by the bacterial pathogen Edwardsiella tarda and the viral pathogen megalocytivirus. Overexpression of pol-miR-novel_642 or interference with PoCSF3-1 expression in flounder cells strongly potentiated E. tarda infection. Consistently, in vivo knockdown of PoCSF3-1 enhanced bacterial dissemination in flounder tissues but blocked viral replication, whereas in vivo overexpression of PoCSF3-1 inhibited bacterial dissemination and facilitated viral infection. Overexpression/knockdown of PoCSF3-1 and pol-miR-novel_642 also affected the activation of autophagy. Recombinant PoCSF3-1 (rPoCSF3-1) interacted with and inhibited the growth of Gram-negative bacteria in a manner relying on a PoCSF3-1-characteristic structural motif that is absent in mouse CSF3. rPoCSF3-1 also regulated the proliferation, inflammatory response, and immune defense of flounder head kidney leukocytes in a structure-dependent fashion. Together, these results reveal the function of a novel miRNA-CSF3 regulatory system of flounder, and add new insights into the role and mechanism of fish miRNA and CSF3 in antimicrobial immunity.

Multiplexed proteomics of autophagy-deficient murine macrophages reveals enhanced antimicrobial immunity via the oxidative stress response

Defective autophagy is strongly associated with chronic inflammation. Loss-of-function of the core autophagy gene Atg16l1 increases risk for Crohn’s disease in part by enhancing innate immunity through myeloid cells such as macrophages. However, autophagy is also recognized as a mechanism for clearance of certain intracellular pathogens. These divergent observations prompted a re-evaluation of ATG16L1 in innate antimicrobial immunity. In this study, we found that loss of Atg16l1 in myeloid cells enhanced the killing of virulent Shigella flexneri (S.flexneri), a clinically relevant enteric bacterium that resides within the cytosol by escaping from membrane-bound compartments. Quantitative multiplexed proteomics of murine bone marrow-derived macrophages revealed that ATG16L1 deficiency significantly upregulated proteins involved in the glutathione-mediated antioxidant response to compensate for elevated oxidative stress, which simultaneously promoted S.flexneri killing. Consistent with this, myeloid-specific deletion of Atg16l1 in mice accelerated bacterial clearance in vitro and in vivo. Pharmacological induction of oxidative stress through suppression of cysteine import enhanced microbial clearance by macrophages. Conversely, antioxidant treatment of macrophages permitted S.flexneri proliferation. These findings demonstrate that control of oxidative stress by ATG16L1 and autophagy regulates antimicrobial immunity against intracellular pathogens.