Department of Animal Physiology, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China.
Henan International Joint Laboratory of Animal Welfare and Health Breeding, College of Animal Science and Technology, Henan University of Science and Technology, Luoyang, China.
Front Immunol. 2023 May 3;14:1193798. doi: 10.3389/fimmu.2023.1193798. eCollection 2023.
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.
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.
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.
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.
肉鸡的免疫应激表现为持续性促炎反应的发展，这会导致生产性能下降。然而，导致免疫应激肉鸡生长抑制的潜在机制尚不清楚。
将 252 只 1 日龄的 Arbor Acres（AA）肉鸡随机分为三组，每组 6 个重复，每个重复 14 只肉鸡。三组包括生理盐水对照组、脂多糖（LPS）（免疫应激）组和 LPS 加塞来昔布组，对应于用选择性 COX-2 抑制剂治疗的免疫应激组。LPS 组和生理盐水组的鸡从 14 日龄起连续 3 天腹腔注射等量 LPS 或生理盐水。并且 LPS 和塞来昔布组的鸡在 14 日龄时给予 LPS 注射前 15 分钟单次腹腔注射塞来昔布。
LPS 作为革兰氏阴性菌外膜的固有成分，可诱导肉鸡产生免疫应激，从而抑制肉鸡的采食量和体重增加。环氧化酶-2（COX-2）是介导前列腺素合成的关键酶，在 LPS 作用下激活的肉鸡小胶质细胞中通过 MAPK-NF-κB 途径上调。随后，前列腺素 E2（PGE2）与 EP4 受体结合维持小胶质细胞的激活，并促进细胞因子白细胞介素-1β和白细胞介素-8 以及趋化因子 CX3CL1 和 CCL4 的分泌。此外，食欲抑制蛋白 proopiomelanocortin 蛋白的表达增加，下丘脑生长激素释放激素水平降低。这些作用导致应激肉鸡血清中胰岛素样生长因子表达减少。相比之下，抑制 COX-2 可使促炎细胞因子水平正常化，并促进下丘脑神经肽 Y 和生长激素释放激素的表达，从而改善应激肉鸡的生长性能。应激肉鸡下丘脑的转录组分析表明，抑制 COX-2 活性可显著下调 MAPK-NF-κB 信号通路中 TLR1B、IRF7、LY96、MAP3K8、CX3CL1 和 CCL4 基因的表达。
本研究提供了新的证据，表明免疫应激通过激活 COX-2-PGE2-EP4 信号轴介导肉鸡生长抑制。此外，在应激条件下抑制 COX-2 的活性可逆转生长抑制。这些观察结果为促进集约化饲养肉鸡的健康提供了新的方法。
