MiR-23a Regulates Skin Langerhans Cell Phagocytosis and Inflammation-Induced Langerhans Cell Repopulation

Langerhans cells (LCs) are skin-resident macrophage that act similarly to dendritic cells for controlling adaptive immunity and immune tolerance in the skin, and they are key players in the development of numerous skin diseases. While TGF-β and related downstream signaling pathways are known to control numerous aspects of LC biology, little is known about the epigenetic signals that coordinate cell signaling during LC ontogeny, maintenance, and function. Our previous studies in a total miRNA deletion mouse model showed that miRNAs are critically involved in embryonic LC development and postnatal LC homeostasis; however, the specific miRNA(s) that regulate LCs remain unknown. miR-23a is the first member of the miR-23a-27a-24-2 cluster, a direct downstream target of PU.1 and TGF-b, which regulate the determination of myeloid versus lymphoid fates. Therefore, we used a myeloid-specific miR-23a deletion mouse model to explore whether and how miR-23a affects LC ontogeny and function in the skin. We observed the indispensable role of miR-23a in LC antigen uptake and inflammation-induced LC epidermal repopulation; however, embryonic LC development and postnatal homeostasis were not affected by cells lacking miR23a. Our results suggest that miR-23a controls LC phagocytosis by targeting molecules that regulate efferocytosis and endocytosis, whereas miR-23a promotes homeostasis in bone marrow-derived LCs that repopulate the skin after inflammatory insult by targeting Fas and Bcl-2 family proapoptotic molecules. Collectively, the context-dependent regulatory role of miR-23a in LCs represents an extra-epigenetic layer that incorporates TGF-b- and PU.1-mediated regulation during steady-state and inflammation-induced repopulation

Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation is required for SARS-CoV-2 infection in circulating monocytes

Infection of human peripheral blood cells by SARS-CoV-2 has been debated because immune cells lack mRNA expression of both angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease type 2 (TMPRSS2). Herein we demonstrate that resting primary monocytes harbor abundant cytoplasmic ACE2 and TMPRSS2 protein and that circulating exosomes contain significant ACE2 protein. Upon ex vivo TLR4/7/8 stimulation, cytoplasmic ACE2 was quickly translocated to the monocyte cell surface independently of ACE2 transcription, while TMPRSS2 surface translocation occurred in conjunction with elevated mRNA expression. The rapid translocation of ACE2 to the monocyte cell surface was blocked by the endosomal trafficking inhibitor endosidin 2, suggesting that endosomal ACE2 could be derived from circulating ACE2-containing exosomes. TLR-stimulated monocytes concurrently expressing ACE2 and TMPRSS2 on the cell surface were efficiently infected by SARS-CoV-2, which was significantly mitigated by remdesivir, TMPRSS2 inhibitor camostat, and anti-ACE2 antibody. Mass cytometry showed that ACE2 surface translocation in peripheral myeloid cells from patients with severe COVID-19 correlated with its hyperactivation and PD-L1 expression. Collectively, TLR4/7/8-induced ACE2 translocation with TMPRSS2 expression makes circulating monocytes permissive to SARS-CoV-2 infection

Histone deacetylase 3 controls lung alveolar macrophage development and homeostasis

Alveolar macrophages are known to derive from embryonic precursors although the regulation of this process is poorly understood. Here the authors propose a key role for histone deacetylase 3 as an epigenetic regulator of lung alveolar macrophage development

222 Whole-blood immune profile in hidradenitis suppurativa

Hidradenitis suppurativa (HS), a chronic inflammatory skin condition with a multifactorial etiology, has a complex cutaneous immune reaction localized around the hair follicles in intertriginous skin. HS pathogenesis remains enigmatic, although some hypotheses have been proposed. Increasing evidence of the association between HS and other inflammatory conditions (e.g. inflammatory bowel disease) and cardiovascular disease suggests that patients with HS have underlying systemic inflammation. To date, few studies have sought to understand the systemic changes that occur in the immune system of HS patients. One recent study performed bulk RNA-sequencing on peripheral blood mononuclear and showed minor differences in transcriptomes of peripheral blood mononuclear cells, but bulk RNA-sequencing does not have the capacity to identify specific changes in cellular subsets. To determine whether specific systemic changes occur in HS patients we performed CyTOF using a standardized panel that identifies 37 immune cell subpopulations in whole blood. We analyzed whole blood samples from 8 HS and 7 healthy controls. Compared to healthy controls, HS patients had an increased frequency of plasmablasts and a decreased frequency of CD66b- neutrophils. Furthermore, marked differences in monocyte subclasses showed a shift from classical monocytes (CD14+ CD16-) towards intermediate (CD14+ CD16+) and non-classical subsets (CD14dim CD16+) in HS. We also identified a large population of CDR45RO+ CCR6+ CD38+ intermediate monocytes in HS, which was largely absent in healthy controls. Taken together our results support previous studies highlighting the role of neutrophils and B cells in HS pathogenesis, and identify newly discovered monocyte dynamics in peripheral blood of HS patients further supporting widespread inflammation as a feature of HS