Biology subjects

Domingues, R. G.

Publications and source records attributed to Domingues, R. G..

4 recordsLinked to original sources

bioRxiv2024

CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity

Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to help regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood. Following CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of innate immune cells. Deletion of C-C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation induced toxicities, suggesting an important role for an innate immune cell population in limiting RT-mediated bowel damage. Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C+ monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was found to be reduced in irradiated CCR2-/-, however the transfer of Ly6C+ monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities. One Sentence SummaryCCR2-mediated monocyte recruitment protects against RT-induced intestinal toxicity via IL-17, highlighting a therapeutic target.

immunology↗

bioRxiv2021

Rhythmicity of Intestinal IgA Responses Confers Oscillatory Commensal Microbiota Mutualism

Mutualistic interactions with the commensal microbiota are enforced through a range of immune responses that confer metabolic benefits for the host and ensure tissue health and homeostasis. Immunoglobulin (Ig)A responses directly determine the composition of commensal species that colonize the intestinal tract but require significant metabolic resources to fuel antibody production by tissue-resident plasma cells. Here we demonstrate IgA responses are subject to diurnal regulation by dietary-derived metabolic cues and a cell-intrinsic circadian clock. Rhythmicity in IgA secretion conferred oscillatory patterns on the commensal microbial community and its associated metabolic activity, resulting in changes to metabolite availability over the course of the circadian day. Our findings suggest circadian networks comprising intestinal IgA, the diet and the microbiota align to ensure metabolic health. One-Sentence SummaryWe demonstrate diurnal rhythms in intestinal IgA act to cross-regulate oscillations in the abundance of commensal microbes to foster mutualism.

immunology↗

bioRxiv2021

The skin environment controls local dendritic cell differentiation and function through innate IL-13

The signals driving the adaptation of type-2 dendritic cells (DC2s) to diverse peripheral environments are not well understood. We show that the development of CD11blow migratory DC2s, a DC2 population unique to the dermis, requires STAT6- and KLF4-dependent IL-13 signaling, whereas DC2s in lung and small intestine are STAT6-independent. Dermal IL-13 is mostly derived from innate lymphoid cells expressing a resting ICOS+ KLRG1-ST2-phenotype. Analysis of public datasets indicates that human skin DC2s also express an IL-4/IL-13 gene signature compared to blood or spleen, suggesting a similar developmental pathway in mice and humans. In the absence of IL-13 signaling, dermal DC2s are stable in number but remain CD11bhi and show defective activation in response to allergen with diminished ability to support IL-4+ GATA3+ Th development, whereas anti-fungal IL-17+ ROR{gamma}t+ responses are increased. Thus, steady-state IL-13 fosters a non-inflammatory and pro-allergic environment in healthy skin via conditioning of local DC2s.

immunology↗

bioRxiv2019

Light-entrained and brain-tuned circadian circuits regulate ILC3 and gut homeostasis

Group 3 innate lymphoid cells (ILC3) are major regulators of inflammation, infection, microbiota composition and metabolism1. ILC3 and neuronal cells were shown to interact at discrete mucosal locations to steer mucosal defence2,3. Nevertheless, whether neuroimmune circuits operate at an organismal level, integrating extrinsic environmental signals to orchestrate ILC3 responses remains elusive. Here we show that light-entrained and brain-tuned circadian circuits regulate enteric ILC3, intestinal homeostasis, gut defence and the host lipid metabolism. We found that enteric ILC3 display circadian expression of clock genes and ILC3-related transcription factors. ILC3-autonomous ablation of the circadian regulator Arntl led to disrupted gut ILC3 homeostasis, impaired epithelial reactivity, deregulated microbiome, increased susceptibility to bowel infection and disrupted lipid metabolism. Loss of ILC3-intrinsic Arntl shaped the gut postcode receptors of ILC3. Strikingly, light-dark cycles, feeding rhythms and microbial cues differentially regulated ILC3 clocks, with light signals as major entraining cues of ILC3. Accordingly, surgical- and genetically-induced deregulation of brain rhythmicity led to disrupted circadian ILC3 oscillations, deregulated microbiome and altered lipid metabolism. Our work reveals a circadian circuitry that translates environmental light cues into enteric ILC3, shaping intestinal health, metabolism and organismal homeostasis.

immunology↗