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Obesity alters pathology and treatment response in inflammatory disease.

ABSTRACT: Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system^1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (T_H2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent T_H17 inflammation. We also observed divergent responses to biologic therapies targeting T_H2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in T_H2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo T_H response towards a T_H2-predominant state and prevent aberrant non-T_H2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of T_H17 pathology and unlocked therapeutic responsiveness to targeted anti-T_H2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

SUBMITTER: Bapat SP

PROVIDER: S-EPMC9165753 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Obesity alters pathology and treatment response in inflammatory disease.

Bapat Sagar P SP Whitty Caroline C Mowery Cody T CT Liang Yuqiong Y Yoo Arum A Jiang Zewen Z Peters Michael C MC Zhang Ling-Juan LJ Vogel Ian I Zhou Carmen C Nguyen Vinh Q VQ Li Zhongmei Z Chang Christina C Zhu Wandi S WS Hastie Annette T AT He Helen H Ren Xin X Qiu Wenli W Gayer Sarah G SG Liu Chang C Choi Eun Jung EJ Fassett Marlys M Cohen Jarish N JN Sturgill Jamie L JL Crotty Alexander Laura E LE Suh Jae Myoung JM Liddle Christopher C Atkins Annette R AR Yu Ruth T RT Downes Michael M Liu Sihao S Nikolajczyk Barbara S BS Lee In-Kyu IK Guttman-Yassky Emma E Ansel K Mark KM Woodruff Prescott G PG Fahy John V JV Sheppard Dean D Gallo Richard L RL Ye Chun Jimmie CJ Evans Ronald M RM Zheng Ye Y Marson Alexander A

Nature 20220330 7905

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system<sup>1-7</sup>, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we sho ...[more]

PMID: 35355021

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Obesity alters pathology and treatment response in inflammatory disease.

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Obesity alters pathology and treatment response in inflammatory disease.

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