Biology subjects

Santos, R. F.

Publications and source records attributed to Santos, R. F..

4 recordsLinked to original sources

bioRxiv2025

CD5L insufficiency exacerbates skeletal joint damage in rheumatoid arthritis

CD5L is an immunoregulatory protein induced during inflammation and makes a life-saving contribution in infection and sepsis. Here, we explored the overall impact of CD5L in rheumatoid arthritis (RA). Using experimental RA models, we demonstrated an early surge of CD5L expression in wild-type mice, as well as a higher incidence and increased severity of arthritis in CD5L-deficient mice. In the blood, CD5L-deficient mice exhibited enhanced inflammation, a higher proportion of CD11b mononuclear cells, and elevated levels of IL-1{beta}, IL-17, and IFN-{psi}, particularly at the pre-clinical stage of arthritis. In human RA, mononuclear cells conditioned with CD5L, as well as endogenous CD5L production, were associated with reduced CD11b expression, increased IL-10 and PD-L1 production, and an enrichment of non-classical CD16+ monocytes. Analysis of the CD5L-dependent transcriptome in CD14 cells from RA patients revealed the acquisition of an efferocytosis profile, with upregulation of C1Q subunits, GAS6, AXL, and ALOX15B. It also showed signs of insufficient cargo processing, which dampens the resolution of inflammation, permits the expansion of IFN-primed non-classical monocytes, and correlates strongly with joint damage accrual. Despite markedly low CD5L levels in the synovium, RA synovial tissue was enriched with non-classical monocytes carrying the GAS6-AXL signature, which fosters osteoclast progenitors. In conclusion, this study demonstrates that the anti-inflammatory and inflammation-resolving properties of CD5L in experimental and human RA are mediated through the induction of efferocytosis-related and IFN-primed monocyte programs. This harbors a potential risk of uncontrolled invasion of non-classical monocytes into the synovial tissue, leading to joint structural damage. The complex role of CD5L in inflammation and disease outcomes requires careful consideration of the disease phase and experimental context.

immunology↗

bioRxiv2023

Spatiotemporal dynamics of cytokines expression dictate fetal liver hematopoiesis.

During embryogenesis, yolk-sac and intra-embryonic-derived hematopoietic progenitors, comprising the precursors of adult hematopoietic stem cells, converge into the fetal liver. With a new staining strategy, we defined all non-hematopoietic components of the fetal liver and found that hepatoblasts are the major producers of hematopoietic growth factors. We identified mesothelial cells, a novel component of the stromal compartment, producing Kit ligand, a major hematopoietic cytokine. A high-definition imaging dataset analyzed using a deep-learning based pipeline allowed the unambiguous identification of hematopoietic and stromal populations, and enabled determining a neighboring network composition, at the single cell resolution. Throughout active hematopoiesis, progenitors preferentially associate with hepatoblasts, but not with stellate or endothelial cells. We found that, unlike yolk sac-derived progenitors, intra-embryonic progenitors respond to a chemokine gradient created by CXCL12-producing stellate cells. These results revealed that FL hematopoiesis is a spatiotemporal dynamic process, defined by an environment characterized by low cytokine concentrations.

developmental biology↗

bioRxiv2022

The dual character of the inhibitory functions of CD6

T-cell membrane scaffold proteins play important roles in T cell biology, functioning as multi-functional signaling hubs. CD6 assembles a large intracellular signalosome but, unlike typical membrane-attached scaffolds like LAT or PAG, it has a sizeable ectodomain that binds a well-characterized ligand, CD166. It is unclear whether CD6 has net inhibitory or costimulatory functions or how its ectodomain influences these activities. To explore these questions, we dissected the signaling functions of the extracellular and cytoplasmic regions of CD6. We found that CD6 was delivered to the immunological synapse and suppressed T cell responsiveness in vitro wholly dependently of its cytoplasmic domain, indicating that CD6 very potently imposes tonic inhibition, acting as a structural and signaling inhibitory hub. However, the cell-intrinsic suppression of autoimmunity by CD6 in vivo was also impacted by extracellular interactions, demonstrated by the increased susceptibility of mice to experimental autoimmune encephalomyelitis after removal of the ligand binding region of the ectodomain of CD6. Our work identifies CD6 as a new class of on/off switching scaffold-receptor that constrains immune responsiveness at two speeds. First, it sets signaling thresholds via tonic inhibition, functioning as a cytoplasmic membrane-bound scaffold and, second, by cycling between signaling-enabling and signalinginhibiting ectodomain isoforms it functions as an immune checkpoint.

immunology↗

bioRxiv2022

CD5L constraints acute and systemic inflammation and can be a novel potent therapeutic agent against sepsis

The global burden of sepsis, with an estimated 49 million cases and 11 million deaths in 2017, often passes unnoticed to the general public even though it is the direct cause of nearly 20% of all deaths worldwide. This unawareness is perhaps due to misconceptions, or miscoding in the reporting of the ultimate causes of death, as in many diseases it is not the actual infectious agent that causes the biggest harm. Rather, it is the uncontrolled inflammation leading to septic shock that is the most menacing manifestation associated with many infections, and becomes deadly serious once it has passed the stage where anti-microbial drugs no longer have any effect to inactivate or destroy the pathogen. Here we show that the combined anti-bacterial and anti-inflammatory properties of the scavenger receptor cysteine-rich (SRCR) protein CD5L contribute to a remarkable therapeutic effect of the protein to fight sepsis, such that when exogenously administered in C57BL/6 mice with induced lethal-grade sepsis, it can be a very effective curative agent to treat this condition. The resistance conferred by CD5L to polybacterial-induced sepsis using the cecal ligation and puncture (CLP) model is consistent with the reported observations that CD5L physically binds and inactivates diverse species and strains of bacteria. Accordingly, our CD5L-knockout mice are significantly more susceptible to experimentally-induced mid-grade CLP than wild-type animals. We show that CD5L is centered on promoting neutrophil recruitment and activation, overall contributing to reducing the bacteria burden of the animals. However, the dramatic susceptibility of CD5L-deficient animals is not necessarily correlated only with pathogen load, as these mice are also extremely susceptible to sterile sepsis induced by nonlethal doses of LPS. Notwithstanding the observed capacity of CD5L to directly bind to a broad range of pathogens, typical of many PRRs, our evidence suggests that the anti-inflammatory properties of the protein are at least as important as its pathogen-binding potential, and can, and should, be explored to treat the deadly inflammation storm that is sepsis.

immunology↗