Biology subjects

Orlov, M.

Publications and source records attributed to Orlov, M..

3 recordsLinked to original sources

bioRxiv2026

Amoxicillin induces gut dysbiosis leading to long term suppression of type-17 immune tone in the lungs

T-helper (Th)-17 lymphocytes are central mediators of adaptive type 17 immunity. Decreased type-17 signaling increases severity of infections in humans and mice. However, detrimental effects of excessive type 17 responses in autoimmune and other inflammatory diseases highlight a need for type-17 immune calibration to support beneficial host defense requirements. Mechanisms of type 17 calibration are poorly understood. A gut-lung axis has been proposed to coordinate homeostatic protection and acute host defense. Factors that acutely alter the gut microbiome are heterogeneous and include acute intestinal infections, non-infectious colitis, and medical treatments such as antibiotics. How changes in the gut microbiome affect lung immune tone during homeostasis and acute pulmonary infections are also poorly understood. Prior studies have shown that antibiotics reduce expression of IL-17-mediated host defense in the gut. Since gut microbial homeostasis influences Th17 cell numbers in both the intestine and remote tissues, we postulated that antibiotic treatment would result in gut dysbiosis and weakened type-17 host defense in the lungs. We found that amoxicillin induces significant dysbiosis that is long-lasting and that there is a long-term decrease in type-17 tone in the lungs. We also found that in mice lacking the gut mucin, Muc2, Th17 cells increased in the lungs following inflammatory challenge. These findings suggest that antibiotic-induced dysbiosis can decrease lung immune defenses for long periods of time after cessation of antibiotic treatment.

immunology↗

bioRxiv2025

Siglec-F Protects Against Elastase-induced Lung Inflammation and Emphysema in Mice

Respiratory surfaces are exposed daily to billions of inhaled particles that could cause injury to alveolar tissues where gas exchange occurs. Accordingly, robust defense is essential but must involve minimal physiologic disruption. Airspace macrophages (AMs) protect lung surfaces while also maintaining tissue integrity through non-inflammatory homeostatic responses in health. However, in chronic obstructive pulmonary disease (COPD), AMs contribute to emphysematous alveolar destruction through mechanisms that are poorly understood. We hypothesized that damaging effects of AMs in emphysema result from loss of mechanisms that normally restrain homeostatic AMs. We found that Siglec-F, a common marker of AMs, exerts suppressive effects on tissue resident AMs (RAMs), thereby supporting alveolar integrity in mouse lungs during health and in a model of elastase-induced alveolar destruction. Siglec-F-deficient mice exhibited decreased alveolar numbers at baseline, and they had worsened alveolar damage after elastase challenge that was unexpectedly RAM-mediated. Transcriptomic profiling revealed dysregulation of key pathways involved in tissue remodeling and repair, including extracellular matrix degradation, TGF-{beta} signaling, and phagocytosis. These findings uncover previously unrecognized roles for RAMs and Siglec-F in preserving alveolar integrity. Our findings implicate RAMs and Siglecs as potential therapeutic targets for preserving alveolar integrity in health and for limiting alveolar damage in COPD.

immunology↗

bioRxiv2024

Siglec-F Deficiency Prevents Fibrosis After Bleomycin-Induced Acute Lung Injury

Injury to the lungs causes acute inflammation that can lead to pathological lung fibrosis. Airspace macrophages (AMs) are critical for repair of injured tissue, but they can contribute fibrosis through mechanisms that are incompletely understood. Siglecs are expressed by immune cells. In mice, Siglec-F is chiefly expressed AMs where it is considered inflammosuppressive. We hypothesized that its deletion would worsen lung injury and fibrosis in response to intratracheal bleomycin challenge. We evaluated Siglec-F expression and function in mice challenged with bleomycin on days 7, 14, and 21 post-challenge (2.5 U/kg). AMs were the predominant inflammatory cells at all timepoints, and they included resident (RAM) and recruited (RecAM) subsets. Siglec-F deficiency prevented fibrosis than in Siglecf-/- mouse lungs, as evident from biochemical and histologic readouts. We performed RNAseq on pooled RAMs and RecAMs from wild type and Siglec-F deficient mice. Lung fibrosis 21 d after bleomycin challenge was associated with differentially expressed genes (DEGs) related to cholesterol synthesis and metabolism. In AMs from healthy lung lavage fluid and idiopathic pulmonary fibrosis patient tissues, the human paralogs Siglec-7 and Siglec-9 were expressed. Findings here identify novel mechanisms that control protective and detrimental functions of AMs after lung injury.

physiology↗