Unraveling Epithelial - Immune Crosstalk in Murine Skin Development and Disease

Datum

11.11.2024

Zeit

11:00 - 12:00

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 regula;ng developmental and inflammatory programs in the developing skin. Our study suggests that macrophages in the developing skin can respond to sterile inflammatory cues by augmen;ng the synthesis of ECM (extracellular matrix) remodeling enzymes called MMPs (matrix metalloproteinases). These MMPs exacerbate chronic inflamma;on by genera;ng DAMPs (damage-associated molecular paJerns). We further show that this func;onal state of the macrophages is partly directed by the metabolite lactate that is generated by the epithelial compartment of the skin in condi;ons of sterile inflamma;on. Remarkably, inhibi;on of the lactate-mediated metabolic crosstalk between the skin epithelia and macrophages leads to a substan;al reduc;on in the macrophage effector func;on and, in turn, inflamma;on. We further show that the principle of lactate metabolic crosstalk can be targeted to treat inflamma;on in the imiquimod-induced mice model of psoriasis. Finally, using a macrophage-depleted mouse model system we inves;gate the role of these cell types in regula;ng skin development. Our results suggest that macrophage-mediated remodeling of the skin ECM is essen;al for driving the development of skin appendages. These studies have elucidated the developmental and inflammatory roles of macrophages in the developing skin. Publica;ons and Patent: 1. Ayyangar U, Karkhanis A, Tay H, Afandi AFB, BhaJacharjee O, KS L, Lee SH, Chan J & Raghavan S (2024) Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflamma;on in the murine skin. EMBO J 2. BhaJacharjee O, Ayyangar U, Kurbet AS, Lakshmanan V, Palakode; D, Ginhoux F & Raghavan S (2021) Epithelial-Macrophage Crosstalk Ini;ates Sterile Inflamma;on in Embryonic Skin. Front Immunol 12. 3. BhaJacharjee 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 Preven;on and/or Treatment of Skin Disorders PCT Applica;on number: PCT/IB2022/061996 Date of Filing: 10.12.2022 Inventors: UJkarsh Ayyangar, Srikala Raghavan.

Letztmalig verändert: 10.11.2024, 07:48:34