Silveira, G. | Search bioRxiv

bioRxiv2025

A Specialized CD107a+ Macrophage Subset Drives Selective Mycobacterial Phagocytosis

Macrophages are essential for pathogen clearance, yet phagocytic specialization among subsets is poorly defined. Bone marrow-derived macrophages cultured with L929 supernatant or M-CSF separate into FSCloSSCloF4/80loCD11blo (FSCloSSClo) and FSChiSSChiF4/80hiCD11bhi (FSChiSSChi) subsets. Transcriptomic and functional analyses reveal that FSCloSSClo cells possess a hyperphagocytic program driven by enhanced actin cytoskeleton regulators (e.g., Arp2/3) and pro-inflammatory signaling (NF-{kappa}B). These cells excel at internalizing Mycobacterium tuberculosis virulent H37Rv and BCG through actin-mediated, cytochalasin D-sensitive mechanisms. High surface CD107a (LAMP1) expression marks this hyperphagocytic subset and correlates strongly with mycobacterial uptake. FSCloSSClo macrophages produce more TNF and IL-6 upon mycobacterial or TLR2/TLR5 stimulation yet retain IFN-{gamma}-mediated killing capacity. In vivo, CD107a alveolar macrophages in BCG-infected lungs preferentially capture bacilli and upregulate CD195, recapitulating the in vitro phenotype. These findings establish CD107a as a key surface marker of a hyperphagocytic macrophage subset and highlight its role in selective mycobacterial phagocytosis, providing new mechanistic understanding relevant to tuberculosis host defense and therapeutic development. HighlightsO_LIBone marrow-derived FSCloSSCloF4/80loCD11blo macrophage subset excels at M. tuberculosis and BCG uptake C_LIO_LIHyperphagocytic macrophages mount rapid pro-inflammatory TNF/IL-6 responses C_LIO_LICD107a (LAMP1) identifies a pre-existing hyperphagocytic macrophage subset in vitro and in vivo C_LIO_LIBCG infection triggers CD195 (CCR5) upregulation selectively on CD107a alveolar macrophages C_LI

immunology↗

bioRxiv2017

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double-blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-[A]sberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0{middle dot}019; Cohens d=0{middle dot}98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0{middle dot}04; at D7, p<0{middle dot}0001). Between-group effect sizes increased from D1 to D7 (D1: Cohens d=0{middle dot}84; D2: Cohens d=0{middle dot}84; D7: Cohens d=1{middle dot}49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4{middle dot}95; p = 0{middle dot}04; NNT = 2{middle dot}66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

clinical trials↗