Lipopolysaccharide-induced immune stress negatively regulates broiler chicken growth via the COX-2-PGE2-EP4 signaling pathway

Kexin Liu; Wenrui Zhen; Dongying Bai; Haiqiu Tan; Xianglong He; Yuqian Li; Yanhao Liu; Yi Zhang; Koichi Ito; Bingkun Zhang; Yanbo Ma

doi:10.3389/fimmu.2023.1193798

Lipopolysaccharide-induced immune stress negatively regulates broiler chicken growth via the COX-2-PGE₂-EP4 signaling pathway

Front Immunol. 2023 May 3:14:1193798. doi: 10.3389/fimmu.2023.1193798. eCollection 2023.

Authors

Kexin Liu¹, Wenrui Zhen^{1

2}, Dongying Bai^{1

2}, Haiqiu Tan¹, Xianglong He¹, Yuqian Li¹, Yanhao Liu¹, Yi Zhang^{1

2}, Koichi Ito³, Bingkun Zhang⁴, Yanbo Ma^{1

5

2}

Affiliations

¹ Department of Animal Physiology, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China.
² Henan International Joint Laboratory of Animal Welfare and Health Breeding, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China.
³ Department of Food and Physiological Models, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Ibaraki, Japan.
⁴ State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing, China.
⁵ Longmen Laboratory, Science & Technology Innovation Center for Completed Set Equipment, Luoyang, China.

Abstract

Aims: Immune stress in broiler chickens is characterized by the development of persistent pro-inflammatory responses that contribute to degradation of production performance. However, the underlying mechanisms that cause growth inhibition of broilers with immune stress are not well defined.

Methods: A total of 252 1-day-old Arbor Acres(AA) broilers were randomly allocated to three groups with six replicates per group and 14 broilers per replicate. The three groups comprised a saline control group, an Lipopolysaccharide (LPS) (immune stress) group, and an LPS and celecoxib group corresponding to an immune stress group treated with a selective COX-2 inhibitor. Birds in LPS group and saline group were intraperitoneally injected with the same amount of LPS or saline from 14d of age for 3 consecutive days. And birds in the LPS and celecoxib group were given a single intraperitoneal injection of celecoxib 15 min prior to LPS injection at 14 d of age.

Results: The feed intake and body weight gain of broilers were suppressed in response to immune stress induced by LPS which is an intrinsic component of the outer membrane of Gram-negative bacteria. Cyclooxygenase-2 (COX-2), a key enzyme that mediates prostaglandin synthesis, was up-regulated through MAPK-NF-κB pathways in activated microglia cells in broilers exposed to LPS. Subsequently, the binding of prostaglandin E2 (PGE2) to the EP4 receptor maintained the activation of microglia and promoted the secretion of cytokines interleukin-1β and interleukin-8, and chemokines CX3CL1 and CCL4. In addition, the expression of appetite suppressor proopiomelanocortin protein was increased and the levels of growth hormone-releasing hormone were reduced in the hypothalamus. These effects resulted in decreased expression of insulin-like growth factor in the serum of stressed broilers. In contrast, inhibition of COX-2 normalized pro-inflammatory cytokine levels and promoted the expression of Neuropeptide Y and growth hormone-releasing hormone in the hypothalamus which improved the growth performance of stressed broilers. Transcriptomic analysis of the hypothalamus of stressed broilers showed that inhibition of COX-2 activity significantly down-regulated the expression of the TLR1B, IRF7, LY96, MAP3K8, CX3CL1, and CCL4 genes in the MAPK-NF-κB signaling pathway.

Conclusion: This study provides new evidence that immune stress mediates growth suppression in broilers by activating the COX-2-PGE2-EP4 signaling axis. Moreover, growth inhibition is reversed by inhibiting the activity of COX-2 under stressed conditions. These observations suggest new approaches for promoting the health of broiler chickens reared in intensive conditions.

Keywords: COX-2; broilers; growth; hypothalamus; immune stress.

Publication types

Randomized Controlled Trial, Veterinary
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Celecoxib / pharmacology
Chickens* / growth & development
Cyclooxygenase 2 / genetics
Cyclooxygenase 2 / metabolism
Cytokines / metabolism
Dinoprostone / metabolism
Inflammation*
Lipopolysaccharides / toxicity
NF-kappa B / metabolism
Signal Transduction*

Substances

Celecoxib
Cyclooxygenase 2
Cytokines
Dinoprostone
Lipopolysaccharides
NF-kappa B

Grants and funding

The research was funded in part by the National Key Research and Development Program of China (2022YFE0111100 and 2017YFE0129900), Program for International S&T Cooperation Projects of Henan (232102521012), the Key Scientific Research Foundation of the Higher Education Institutions of Henan Province (22A230001) and Science Foundation for Expat Scientist Studio for Animal Stress and Health Breeding of Henan Province (Grant Number GZS2021006).