Unraveling Epithelial - Immune Crosstalk in Murine Skin Development and Disease

Datum

23.10.2024

Zeit

10:00 - 11:00

Sprecher

Uttkarsh Ayyangar

Zugehörigkeit

Institute of Stem Cell Science and Regenerative Medicine (InStem), Bengaluru, India

Sprache

en

Hauptthema

Biologie

Host

Meritxell Huch

Beschreibung

Macrophages are the earliest set of immune cells that populate the murine skin. However, much less is understood about their role in regulating developmental and inflammatory programs in the developing skin. Our study suggests that macrophages in the developing skin can respond to sterile inflammatory cues by augmenting the synthesis of ECM (extracellular matrix) remodeling enzymes called MMPs (matrix metalloproteinases). These MMPs exacerbate chronic inflammation by generating DAMPs (damage-associated molecular patterns). We further show that this functional state of the macrophages is partly directed by the metabolite lactate that is generated by the epithelial compartment of the skin in conditions of sterile inflammation. Remarkably, inhibition of the lactate-mediated metabolic crosstalk between the skin epithelia and macrophages leads to a substantial reduction in the macrophage effector function and, in turn, inflammation. We further show that the principle of lactate metabolic crosstalk can be targeted to treat inflammation in the imiquimod-induced mice model of psoriasis. Finally, using a macrophage-depleted mouse model system we investigate the role of these cell types in regulating skin development. Our results suggest that macrophage-mediated remodeling of the skin ECM is essential for driving the development of skin appendages. These studies have elucidated the developmental and inflammatory roles of macrophages in the developing skin. Publications and Patent: 1. Ayyangar U, Karkhanis A, Tay H, Afandi AFB, Bhattacharjee O, KS L, Lee SH, Chan J & Raghavan S (2024) Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin. EMBO J 2. Bhattacharjee O, Ayyangar U, Kurbet AS, Lakshmanan V, Palakodeti D, Ginhoux F & Raghavan S (2021) Epithelial-Macrophage Crosstalk Initiates Sterile Inflammation in Embryonic Skin. Front Immunol 12. 3. Bhattacharjee O, Ayyangar U, Kurbet AS, Ashok D & Raghavan S (2019) Unraveling the ECM-immune cell crosstalk in skin diseases. Front Cell Dev Biol 7 doi:10.3389/fcell.2019.00068. 4. [Patent] Citric Acid Cycle and Lactate Transport Inhibitors for Prevention and/or Treatment of Skin Disorders PCT Application number: PCT/IB2022/061996 Date of Filing: 10.12.2022 Inventors: Uttkarsh Ayyangar, Srikala Raghavan.

Letztmalig verändert: 23.10.2024, 07:37:17